Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action,Effects of Natural and Monoclonal Anti-Aβ Antibodies,and Downstream Effects

Abstract

Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab’s phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies.

Keywords

Alzheimer’s disease amyloid-β amyloid hypothesis antibodies clearance clinical trials downstream effects intravenous immunoglobulin

The number of Americans 65 years of age and older with Alzheimer’s disease (AD) was estimated by the Alzheimer’s Association in its “2022 Alzheimer’s Disease Facts and Figures” report to be 6.5 million and is expected to increase to nearly 13 million by 2050 [1]. That report indicated that caregivers for people with dementia are twice as likely to report emotional, financial, and physical problems as caregivers of non-demented individuals. These statistics underscore the importance of developing treatments to slow the clinical progression of AD in order to improve the quality of life for AD patients and their caregivers.

AD’s hallmark neuropathological findings are amyloid-β (Aβ)-containing plaques and tau protein-containing neurofibrillary tangles. The plaques may be neuritic plaques (also referred to as senile plaques [SP]), which contain dense cores of fibrillar Aβ as well as dystrophic, tau paired helical filament-containing neurites [2], or they may be diffuse plaques, containing filamentous Aβ and lacking dense cores. Although diffuse plaques generally do not contain neurites, they may do so in late-stage AD [3]. The amyloid hypothesis, published by Hardy and colleagues in the early 1990 s [4, 5], postulated that increased deposition of fibrillar Aβ initiated AD-type pathology. The hypothesis was challenged by findings of increased SP densities in some subjects with little or no cognitive impairment [6], weak correlations between SP densities, insoluble Aβ levels, and PET-detectable Aβ with measures of cognitive impairment [7 –10], and failures of Aβ-targeting approaches in large-scale AD clinical trials [11 –13]. The hypothesis was subsequently revised to suggest that Aβ oligomers may initiate AD pathology [14, 15]. Since publication of the hypothesis, efforts to slow AD’s progression have focused primarily on lowering of brain Aβ. Aβ can be cleared from the brain by enzymatic degradation and by efflux from the brain. It is degraded via the endosomal-lysosomal system [16], the ubiquitin-proteasome system [17], and autophagy [18]; Aβ efflux from the brain is via the blood-brain barrier (BBB) [19], the blood cerebrospinal fluid (CSF) barrier [20], glymphatic (paravascular) drainage [21], and perivascular drainage [22]. Antibody binding to Aβ promotes clearance of cerebral Aβ by several mechanisms, as discussed below.

Approaches which have attempted to slow AD’s progression by lowering brain Aβ have included Aβ vaccination [23], Aβ aggregation inhibitors [24], β-secretase inhibitors [25], γ-secretase modulators [26], γ-secretase inhibitors [27], intravenous immunoglobulin (IVIG) products [28, 29], and monoclonal anti-Aβ antibodies [30 –32]. Most of these approaches have failed to meet primary end points in large-scale clinical trials, with the notable recent exceptions of some monoclonal antibodies. Statistically significant treatment effects for some measures of cognition were reported in 2014 in a phase III trial for a monoclonal antibody, Solanezumab, but the antibody did not meet its primary end point in either of its phase III trials [31]. Conflicting results in two phase III trials were reported in 2019 for the monoclonal antibody Aducanumab [33, 34]. Despite a recommendation from the Unites States Food and Drug Administration (FDA) advisory board not to approve it, Aducanumab received FDA approval for treatment of AD in June 2021 based on its ability to reduce PET-detectable Aβ. Another monoclonal antibody, Lecanemab, was approved for treatment of AD by the FDA in January 2023 based on results in its phase IIb trial [35]. Although Lecanemab failed to meet its primary end point in that trial, bi-weekly administration of the highest dose of the antibody produced a significant reduction in PET-detectable Aβ. In a later phase III trial, Lecanemab did meet its primary end point [36]. The monoclonal antibody Donanemab was shown, in topline results announced in May 2023, to have met its primary end point and all secondary end points in a phase III trial [37]. Donanemab’s manufacturer Lilly has indicated that it intends to pursue regulatory approval for the antibody in the near future.

Grifols Biologicals’ AMBAR (Alzheimer Management by Albumin Replacement) clinical trial [38, 39], in which AD patients underwent plasmapheresis with albumin replacement, intended to reduce cerebral Aβ levels by a “peripheral sink” mechanism (discussed below). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. Results were published by Boada et al. [38]. Slowing of disease progression in comparison with sham-treated subjects was achieved based on some measures of cognition (Alzheimer’s Disease Assessment Scale–Cognitive subscale [ADAS-Cog] and Alzheimer’s Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]; p-values were 0.05 and 0.002, respectively, for patients with moderate AD (Mini-Mental State Examination [MMSE] scores of 18-21), while the differences in ADAS-Cog and ADCS-ADL scores between treated and sham-treated subjects with mild AD (MMSE scores 22-26) were not statistically significant, possibly due in part to an unexpected slowing of disease progression in the sham-treated mild AD patients. Whether the slowing of disease progression in patients with moderate AD was due to lowering of brain Aβ was unclear. The inclusion criteria for AMBAR included clinical diagnosis of AD and MMSE scores between 18 and 26 [40], but eligible subjects were not screened for PET-detectable Aβ so the possibility that some of the study subjects may not have had AD cannot be ruled out.

Prior to the recent successes with some monoclonal anti-Aβ antibodies, several reasons were suggested for the failure of this and other approaches to significantly slow AD clinical progression in large-scale trials. The reasons included inappropriate selection of study subjects in some trials (i.e., inclusion of individuals with the clinical diagnosis of AD but without biomarker evidence of increased cerebral Aβ, or individuals with too advanced disease) [12], targeting of the wrong pathological substrates [12, 41], antibody-resistant Aβ conformations [42], initiation of treatment too late in the disease process, inappropriate drug dosages, and the possibility that combination treatments rather than monotherapy may be required [41]. The possibility was also suggested that Aβ may not be an appropriate therapeutic target (or not the best target) for slowing AD progression [11 , 43–46].

The ability of anti-Aβ monoclonal antibodies to slow AD progression may depend not only on the extent to which the antibodies lower soluble and/or insoluble Aβ levels in the brain, but also on their effects on neuropathological mechanisms suggested by the amyloid hypothesis to occur downstream of Aβ aggregation. This review discusses the mechanisms by which antibodies are known to promote clearance of brain Aβ, the effects of Aβ binding by vaccine-induced antibodies, naturally-occurring antibodies (“natural antibodies”), and monoclonal antibodies, the downstream effects reported for treatment with these antibodies in clinical trials, and approaches which might increase the ability of anti-Aβ monoclonal antibodies to reduce cerebral Aβ.

MECHANISMS OF ANTIBODY-MEDIATED CLEARANCE OF CEREBRAL Aβ

Microglia are the resident macrophages of the brain’s immune system [47, 48]. When antibodies bind via their Fab (“fragment antigen-binding) regions to fibrillar Aβ, the Fc (“fragment crystallizable”) portions of the antibodies are available for binding to microglia by microglial Fc receptors (FcR). Binding of the Fc portion of an antibody to microglial FcR activates the microglia and increases their phagocytic ability [49, 50]. However, treatment with anti-Aβ antibodies may also induce a shift in microglial activation phenotype from anti-inflammatory (M2) to pro-inflammatory (M1), decreasing the ability of the microglia to clear Aβ [51]. The microglial M1 phenotype is characterized by production of pro-inflammatory molecules including cytokines such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, as well as chemokines, prostaglandins, and reactive oxygen species [47], whereas M2-activated microglia produce anti-inflammatory cytokines including IL-4, IL-10, IL-13, and transforming growth factor-β [52, 53]. (A switch in microglial activation phenotype from M2 to M1 has also been suggested to occur during AD progression [54 –57]). Microglial uptake of Aβ is facilitated by other “pattern recognition receptors” in addition to FcRs (reviewed by Ries and Sastre [58]) including low density lipoprotein receptor related protein 1 (LRP1) [59], complement receptors [60, 61], formyl peptide receptors [62], scavenger receptors [63], and toll-like receptors [64]. Whether microglial uptake of soluble Aβ is via phagocytosis or fluid-phase macropinocytosis is unclear [65]. Interestingly, microglial uptake of fibrillar Aβ may decrease in the presence of oligomeric Aβ [66].

In addition to microglia, other cells in the CNS also express FcRs (reviewed by Okun et al. [67]) including neurons [68], astrocytes [69, 70], oligodendrocytes [71], and dendritic cells [72], but it is unclear if these cells can phagocytose antibody-bound Aβ. Uptake of complexes containing antibody bound to the extracellular Aβ domain of amyloid-β protein precursor (AβPP) was reported for neuroblastoma cells and primary neurons; after internalization, AβPP was transported to early endosomes, then cleaved by beta-site amyloid precursor protein cleaving enzyme (BACE) [73]. Antibody-mediated uptake of Aβ by neurons was reported in another study [74] but the source of the antibodies in that study was sera from AD patients, and the antibodies which bound to Aβ were hypothesized to be “brain-reactive” rather than Aβ-specific. The possibility that neurons may phagocytose antibody-Aβ complexes is supported by reports of neuronal endocytosis of antibodies bound to other antigens such as tau [75, 76] and gangliosides [77]. Astrocytes phagocytose Aβ [78 –80] but no reports were found of antibody-mediated promoting of this process for these cells; in fact, one study found the opposite result: incubating Aβ with anti-Aβ antibodies prevented its degradation by astrocytes [81]. Phagocytosis by astrocytes is an emerging area of investigation which was recently reviewed by Konishi et al. [82]. That review discussed crosstalk between astrocytes and microglia. Astrocytes can promote microglial phagocytosis, whereas pro-inflammatory microglia or microglia activated by triggering receptor expressed on myeloid cells 2 (TREM2) may inhibit astrocytic phagocytosis. Oligodendrocytes have also been reported to phagocytose Aβ [83], although Aβ may be cytotoxic to these cells [84].

In addition to phagocytosis, antibody binding to Aβ can promote microglial uptake of Aβ indirectly, by activating the classical complement pathway [85, 86]. Three complement activation mechanisms are known, namely the classical, alternative, and lectin-binding pathways. Crosslinking of C1q, the first protein in the classical complement pathway, between adjacent Fc portions of immunoglobulin G (IgG) molecules bound to a cell surface antigen activates the classical complement cascade. This pathway can also be activated by C1q binding to the Fc portion of a single immunoglobulin M (IgM) molecule [87]. The classical and alternative complement pathways can also be activated by fibrillar Aβ, promoting its uptake by microglia [85 , 89]. When anti-Aβ antibody levels are suboptimal for promoting microglial phagocytosis of antibody-Aβ complexes, microglial uptake of these complexes can be facilitated by binding of C1q to the antibodies [60]. Complement activation has been characterized as a “double-edged sword” because early complement activation proteins promote clearance of Aβ, whereas complete complement activation generates the neurotoxic membrane attack complex C5b-9 [90, 91].

Anti-Aβ antibodies have been shown to reduce brain Aβ by other mechanisms in addition to promoting microglial phagocytosis (reviewed by Deane et al. [19] and Morgan [92]). Surprisingly, studies in transgenic mouse models of AD found that uptake of anti-Aβ antibodies via microglial FcR did not account for the majority of antibody-mediated clearance of SPs [93] and microglia were not required for immunotherapeutic clearance of SP to occur [94, 95]. Non-microglial mechanisms of antibody-mediated Aβ clearance include dissolving of Aβ aggregates [94 , 97] (anti-Aβ antibodies were also reported to inhibit Aβ aggregation [98]) and promoting efflux of antibody-Aβ aggregates from the brain via the BBB, after binding of these complexes to BBB receptors including LRP1 and the neonatal FcR [99, 100]. The expression of LRP1 on brain endothelial cells has been suggested to decrease during normal aging [101, 102] and in AD [103, 104], which could reduce the ability of antibodies to clear Aβ from the brain via this mechanism. However, other studies found increased LRP1 expression in AD [105, 106].

A final mechanism by which antibodies may promote clearance of cerebral Aβ is via “peripheral sink” activity [107, 108], mentioned above in conjunction with the AMBAR trial. The peripheral sink hypothesis postulates that peripheral blood anti-Aβ antibodies do not need to enter the brain to promote clearance of brain Aβ (and if the antibodies do enter the brain, this may reduce their peripheral sink activity [19]). Rather, antibody binding to Aβ in peripheral blood may change the equilibrium between circulating and brain Aβ levels, resulting in increased efflux of soluble Aβ from the brain via LRP1 expressed on the BBB [101, 109]. Binding of antibodies to Aβ in peripheral blood may also lower brain Aβ levels by reducing the influx of Aβ into the brain via its binding to the receptor for advanced glycation end products [19]. Peripheral sink-mediated efflux of Aβ from the brain may also be induced in the absence of anti-Aβ antibodies, by binding of Aβ to peripheral blood proteins such as albumin [110, 111] and soluble LRP1 (sLRP1), which is generated by proteolytic cleavage of cell-surface LRP1 [112]. It should be noted that some investigators have challenged the validity of the peripheral sink hypothesis [113, 114].

NATURALLY OCCURRING ANTI-Aβ ANTIBODIES (Nabs-Aβ)

Antibodies which bind to Aβ are found in peripheral blood and CSF in non-cognitively impaired subjects as well as individuals with AD. These antibodies have been referred to as natural antibodies to Aβ (Nabs-Aβ) [115 –117]. Natural antibodies typically have broad reactivity (“polyreactivity”) against self antigens [118, 119] and low antigen-binding affinity and may be generated in the absence of antigenic stimulation (i.e., they may not be truly antigen-specific) [120]. Conflicting findings have been published as to whether the levels of peripheral blood antibodies to Aβ differ between AD patients and non-cognitively impaired subjects; the levels of these antibodies in AD have been reported to be decreased [121 –128] or increased [129, 130]. A recent study found that plasma antibodies to Aβ’s N-terminus increased during AD progression while antibodies to its mid-domain decreased [117]. Because of IgG’s large size (molecular weight ca. 150 kDa), under normal conditions peripheral blood IgG is almost completely excluded from the brain; in normal mice, only 0.1% of systemically-administered IgG crosses the BBB [131, 132]. However, in AD, BBB damage is an early event [133 –135] and likely increasing the penetration of peripheral blood IgG into the brain [136 –138]. Whether the levels of peripheral blood anti-Aβ antibodies entering the brain are sufficient to promote Aβ clearance is unknown. This was suggested by a study which detected IgG binding to SPs in AD brain specimens (although the antigenic specificity of the IgG was not determined), with decreased SP numbers in specimens in which IgG immunoreactivity on SPs was prominent [139]. Other investigators have also reported the presence of IgG (or its light chains) of unknown antigenic specificity on SPs [140 –143]. The possibility that peripheral blood antibodies to Aβ may enter the brain and slow AD’s neuropathological progression was also suggested by the finding of an inverse association between the level of CSF anti-Aβ antibodies and atrophy of medial temporal structures including hippocampus, entorhinal cortex, and amygdala in patients with AD but not in patients with amnestic mild cognitive impairment (MCI) or non-AD dementia [144]. Whether anti-Aβ antibody levels in CSF differ between AD and non-demented subjects has not been extensively investigated, although one study found lower levels of these antibodies in AD CSF [121]. Anti-Aβ antibodies have also been reported in CSF from patients with cerebral amyloid angiopathy (CAA), which is often present in AD [145, 146]. BBB damage occurs in CAA [147, 148] and may increase passage of peripheral blood anti-Aβ antibodies into the brain.

IVIG products, which are prepared from plasma immunoglobulins from large numbers (usually > 10,000) of healthy donors, contain Nabs-Aβ [149 –151]. Aβ-related effects which have been reported for IVIG or its purified anti-Aβ antibodies include dissolving of Aβ fibrils and promoting of Aβ phagocytosis [152], inhibiting of Aβ oligomer formation [151], and protecting of SH-SY5Y neuroblastoma cells from the cytotoxic effects of Aβ oligomers [153]. In addition to Nabs-Aβ, IVIG products also contain specific antibodies to non-phosphorylated tau (recombinant human tau peptide, Tau-441, 2N4 R) and phosphorylated tau (p-tau-199 and p-tau-202) [154, 155], and they exert anti-inflammatory and antioxidant effects [156 –160]. Administration of IVIG to transgenic mouse models of AD produced conflicting results for its ability to prevent Aβ pathology and clear Aβ from the brain [153 , 162]. A recent study found that treatment of TgCRND8 mice with IVIG reduced hippocampal plaques, an effect that was increased by the use of focused ultrasound to increase cerebral uptake of the IVIG [163]. Based on the presence of anti-Aβ antibodies in IVIG, and the possibility that peripheral blood anti-Aβ antibodies may be reduced in AD patients (therefore, administering these antibodies might have beneficial effects in AD) [161], the effects on AD progression of two IVIG products, Octapharma’s Octagam and Baxter Healthcare’s Gammagard, were investigated in phase II and phase III trials respectively. Neither product slowed cognitive decline in AD patients compared to placebo-treated AD patients [28, 29].

INITIAL ATTEMPT WITH Aβ IMMUNOTHERAPY: THE AN1792 VACCINATION TRIAL

The development of transgenic mice expressing the human APP, presenilin 1, and presenilin 2 gene mutations associated with early onset AD [164 –169] led to studies of the effects of active immunization (Aβ vaccination) and passive immunization (systemic administration of monoclonal anti-Aβ antibodies) in these mice. Vaccination of young PDAPP mice with Aβ_1-42 prevented development of SPs, neuritic dystrophy, and astrocytosis, while vaccination of older PDAPP mice decreased this pathology [170, 171]. These results were confirmed by other investigators [95 , 172–174] leading to the AN1792 clinical trial in which AD patients (n = 300) were vaccinated with Aβ plus the adjuvant QS-21 in the emulsifying agent polysorbate 80; a control group of AD patients (n = 72) were administered saline. The trial was stopped after meningoencephalitis developed in 18 (6%) of the vaccinated subjects [23 , 175–178]. Meningoencephalitis was later suggested to have been caused by induction of a proinflammatory T lymphocyte response by the QS-21 adjuvant [179, 180] and/or the presence of the dominant T cell epitope Aβ_10-24 in the vaccine preparation [181]. An antibody response to the vaccine, prospectively defined by the study investigators as a serum anti-Aβ IgG titer ≥ 1 : 2,200, was achieved in only 20% of the vaccinated subjects [23]. The inability of many of the subjects to qualify as “antibody responders” was suggested to have been due to immunological tolerance or an age-associated decline in their immune responsiveness [182]. The antibodies induced by the vaccine were primarily against Aβ’s N-terminal amino acids [183, 184], a finding replicated in PSAPP mice [174]. Although postmortem examinations on some of the vaccinated subjects revealed marked reductions in SP numbers [177 , 184–186], no significant differences were found between “antibody responder” subjects and placebo-treated subjects for measures of clinical disease progression [23], and when all study subjects were considered, immunization did not improve survival time or time to severe dementia [187]. The development of meningoencephalitis in some of the subjects led to studies in transgenic mouse AD models of the effects of immunization with different Aβ peptides [174 , 188–193], as well as the effects in these AD models of monoclonal antibodies targeting different Aβ epitopes [12 , 194–199]. Both approaches reduced SP numbers and slowed development and progression of cognitive and memory deficits in the mouse models. These findings led to clinical trials investigating the effects of humanized or fully human monoclonal anti-Aβ antibodies, and also IVIG, in AD patients.

MONOCLONAL ANTI-Aβ ANTIBODIES IN CLINICAL TRIALS

Monoclonal anti-Aβ antibodies whose efficacy in AD patients has been evaluated in phase II or phase III clinical trials are shown in Table 1.

Table 1

Anti-Aβ monoclonal antibodies whose efficacy in AD patients has been evaluated in phase II and/or phase III clinical trials. The antibodies target different Aβ epitopes and bound different conformations of Aβ

Antibody	IgG Subclass	Aβ Sequence Targeted	Aβ Conformation Specificity	Highest Trial Phase Completed
Bapineuzumab	IgG1 (humanized mouse mAb 3D6)	Aβ_1-5	Monomers, oligomers, fibrils	III
Solanezumab	IgG1 (humanized mouse mAb m266)	Aβ_16-26	Monomers	III
Ponezumab	IgG2 (humanized; similar to mouse mAB 2H6)	Aβ_33-40	Monomers	II
Crenezumab	IgG4 (humanized)	Aβ_13-24	Monomers, oligomers, fibrils	III
Gantenerumab	Human IgG1	Aβ_2–11 and Aβ_18–27	Oligomers, fibrils	III^a
Aducanumab	Human IgG1	Aβ_3-7	Oligomers, fibrils	III^b
Lecanemab	IgG1 (humanized mouse mAb158)	Aβ_1-16	Oligomers, protofibrils^d, fibrils	III^c
Donanemab	humanized IgG1 (developed from mouse IgG2a mE8)	Aβ_p3-42	Fibrils	III^e

^aGantenerumab phase III and phase III trials were terminated based on futility analysis; both were continued as open-label extensions. A phase III secondary prevention trial, SKYLINE, is in progress. ^bAducanumab’s phase IIIb open-label study EMBARK, for previous Aducanumab trial participants, is in progress; phase IV confirmatory trial ENVISION is planned. ^eLecanemab’s phase III trial AHEAD 3-45 is in progress. ^dLecanemab’s binding to Aβ oligomers and protofibrils is approximately 10–15 fold greater than its binding to Aβ fibrils [35]. ^eDonanemab’s phase III trial TRAILBLAZER-ALZ 2 has been completed. Phase III trials TRAILBLAZER-ALZ 3, TRAILBLAZER-ALZ 4, and TRAILBLAZER-ALZ 5 are in progress. Table includes information (used with permission) from Dong et al., Int J Mol Sci, Multidisciplinary Digital Publishing Institute [200] and Tian Hui Kwan et al., Dement Geriatr Cogn Disord, S Karger AG, Basel [201].

The monoclonal antibodies bind to different regions of Aβ, including its N-terminal amino acids (which influence Aβ’s ability to aggregate [202] and are accessible for antibody binding to fibrillar Aβ [203 –205]), its central domain, its C-terminal residues (whose binding by antibodies in peripheral blood should result in sequestering of Aβ in peripheral blood [206, 207]), and conformation-specific epitopes such as pyroglutamate-bound Aβ, which is present on SPs [208]). (The monoclonal antibody Donanemab binds to an N-terminal epitope on Aβ_p3-42, a species of Aβ in which the first two N-terminal amino acids have been removed by proteases and a pyrol ring has been formed at the N-terminus; the latter modification is termed pyroglutamate. Aβ_p3-42 is likely SP-specific [209]). Although anti-Aβ antibodies bind to linear epitopes, they are also able to recognize conformational epitopes [210, 211], and this may account for the specificities of the monoclonal antibodies to different Aβ conformations. Aducanumab was developed from blood lymphocytes collected from elderly subjects without cognitive impairment or with unusually slow cognitive decline [212, 213], so it may be considered to be a naturally-occurring antibody. In contrast to the neuroprotective effects of systemically administered anti-Aβ monoclonal antibodies in mouse AD models [212 , 214–217], some studies have suggested that antibody binding to some Aβ epitopes (particularly its N-terminal amino acids) may result in (or may be associated with) a shift in AβPP proteolysis from α-secretase to β-secretase cleavage [218], increased Aβ production [117, 219], and increased Aβ-mediated neurotoxicity [205]. Whether any of these effects occurred in the monoclonal antibody clinical trials is unknown.

The abilities of the monoclonal anti-Aβ antibodies investigated in large-scale AD trials to reduce insoluble (PET-detectable) brain Aβ levels have varied. It should be noted that although “PET-detectable Aβ” is primarily associated with neuritic plaques, the radioligands used for PET detection of Aβ can also bind to diffuse plaques and to Aβ deposited as CAA [220], and PET cannot differentiate between parenchymal and vascular amyloid [221]. Ikonomovic et al. [220], discussing PET detection of Aβ, stated that “Although it has become commonly assumed that diffuse plaques do not contain fibrillar amyloid, electron microscopic observations have indicated that diffuse plaques contain sparse, loosely-textured amyloid fibrils ... fibrillar amyloid is often present, although at lower densities than within neuritic or core-only plaques”. Thus, while data indicating the extent to which anti-Aβ monoclonal antibodies have reduced PET-detectable Aβ in clinical trials likely reflect mainly the effects of these antibodies on neuritic plaques, the data are not specific for neuritic plaques because some clearance of diffuse plaques and/or of CAA-associated Aβ may also have occurred. Reductions in PET-detectable Aβ for the monoclonal antibodies which targeted Aβ’s N-terminal amino acids (summarized by Liu et al. [117]) were: Bapineuzumab, 20%; Gantenerumab, nearly 100%; Donanemab, 70%; Aducanumab, 70%; and Lecanemab, 70%. (Note, however, that in Lecanemab’s phase IIb study, the highest dose of the antibody, administered bi-weekly, lowered PET-detectable Aβ by up to 93% [35, 222]), and in Donanemab’s TRAILBLAZER-ALZ3 phase III trial [37], treatment was stopped when PET-detectable Aβ decreased to levels considered to be “negative for pathology” according to criteria defined by a previous study [223]). Although some of the monoclonal antibodies bind to soluble Aβ conformations (monomers, oligomers, and protofibrils), the extent to which brain levels of these Aβ conformations may have been reduced in the clinical trials is unknown because soluble Aβ is not detectable with currently available PET radioligands [224]. Interestingly, Crenezumab, which targets Aβ_13-24, binds to both monomeric and aggregated forms of Aβ, with highest affinity to Aβ oligomers [225], but no significant difference between Crenezumab-treated and placebo-treated subjects was found in pooled data from two phase III trials for the change from baseline in CSF Aβ oligomer concentration. This finding suggested that clearance of cerebral Aβ oligomers by the antibody may have been poor.

COMPARISON OF THE EFFECTS OF SOLANEZUMAB, ADUCANUMAB, LECANEMAB, AND DONANEMAB ON CLINICAL PROGRESSION OF AD, PET-DETECTABLE Aβ, AND AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA)

Solanezumab did not meet its primary end point, the change in score from baseline to week 80 on the ADAS-Cog11, in two phase III trials, EXPEDITION 1 AND EXPEDITION 2. But in EXPEDITION 2, a significant treatment effect was found in patients with mild AD (defined as MMSE score 20-26 at baseline) for the change in score in the ADCS-ADL scale, while in patients with moderate AD (defined as baseline MMSE score 16-19), a significant treatment effect was found for the change in the MMSE score (both p = 0.04) [31]. 17% of patients in EXPEDITION 1 and 9% of patients in EXPEDITION 2 underwent baseline and follow-up PET imaging of Aβ. The “composite standardized uptake value ratio” for PET-detectable Aβ in multiple AD pathology-containing brain regions (normalized to values for cerebellum) showed no significant changes in Solanezumab-treated or placebo-treated subjects in either study [31]. Among the subjects who underwent Aβ PET imaging, the rates of ARIA were similar between Solanezumab- and placebo-treated patients, for both ARIA with edema/effusion (ARIA-E) and ARIA with hemorrhage/hemosiderin deposition (ARIA-H). A subsequent phase III trial with Solanezumab which was limited to patients with mild AD with evidence of cerebral Aβ deposition (based on PET scan or CSF Aβ_1-42 measurement) did not meet its primary end point, which was the change from baseline to week 80 in ADAS-Cog14 [226, 227].

The effects of Aducanumab on patients with early AD were examined in two phase III trials, EMERGE and ENGAGE. “Early AD” was defined as MCI due to AD, or mild dementia due to AD; the presence of amyloid pathology was confirmed by PET. Inclusion criteria included MMSE score between 24-30 and Clinical Dementia Rating Scale (CDR) global score of 0.5. The primary outcome measure for both studies was the CDR-sum of boxes (CSR-SB) score. Study arms included titrating to both low-dose and high-dose Aducanumab and were stratified by APOE status; low-dose Aducanumab was titrated to 3 mg/kg in APOE4 carriers and 6 mg/kg in APOE4 non-carriers, while high-dose Aducanumab was titrated to 6 mg/kg in APOE4 carriers (subsequently revised to 10 mg/kg) and 10 mg/kg in APOE4 non-carriers. Both trials were terminated based upon findings of a prespecified futility analysis performed after approximately 50% of the study subjects completed (or had the opportunity to complete) week 78 of the trials. The results of the trials were published by Biogen [33], which contended that some of the assumptions on which the futility analysis was based had been violated. Biogen announced that their analysis of a larger data set indicated that in EMERGE, the primary end point had been met with high-dose Aducanumab. A difference of -0.39 between high-dose Aducanumab and placebo in the mean change from baseline in CDR-SB score at week 78 had been found (p = 0.012), indicating a 22% reduction in the rate of cognitive decline. Positive results were also reported for the EMERGE high-dose arm on the three secondary end points, namely mean change from baseline at week 78 for MMSE (p = 0.049), ADAS-Cog13 (p = 0.010), and Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI) scores (p < 0.001). In contrast, in the ENGAGE trial, high-dose Aducanumab did not meet its primary or secondary end points. PET data from both studies showed “dose- and time-dependent reduction” in PET-detectable Aβ; the effect was statistically significant in both studies although the effect for high-dose Aducanumab at 78 weeks was 16.5% less in ENGAGE than in EMERGE. For patients treated with high-dose Aducanumab, a decrease in PET-detectable Aβ to the threshold level suggested to distinguish between Aβ-positive and Aβ-negative patients was reached by week 78 in 48% of EMERGE patients and 31% of ENGAGE patients. The incidence of ARIA-E for high-dose Aducanumab was 35% in EMERGE and 36% in ENGAGE, versus 2% and 3% for placebo-treated subjects, respectively. In both studies the incidence of ARIA-E was higher with high-dose Aducanumab than with low-dose Aducanumab, and higher in APOE4 carriers than in APOE4 non-carriers. (In pooled data from both studies the incidence of ARIA-E with high-dose Aducanumab was 65% in APOE4 homozygotes and 35% in APOE4 heterozygotes.) Subjects with ARIA-E were more likely than those without ARIA-E to have brain microhemorrhages and localized superficial siderosis (ARIA-H). The incidence of brain microhemorrhage for subjects treated with high-dose Aducanumab was 20% in EMERGE and 19% in ENGAGE, versus 7% and 6% for placebo-treated subjects. Localized superficial siderosis was noted for high-dose Aducanumab in 13% of EMERGE subjects and 16% of ENGAGE subjects, versus 3% and 2% for placebo-treated subjects.

A phase IIb trial, BAN2401-G000-201, was performed with Lecanemab. The effects of three doses of the antibody were evaluated across two regimens (administration monthly and bi-weekly) in patients with mild AD, including MCI attributable to AD. The findings were published by Eisai [35]. The primary end point, Bayesian analysis of change at 12 months on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, was not met, but because conditions were not satisfied for terminating the trial based on futility analysis the trial continued for the full 18 months. A dose-dependent reduction of PET-detectable Aβ was found at 18 months, and in the study cohort receiving the highest dose of Lecanemab (10 mg/kg) twice monthly, statistically significant slowing of cognitive impairment (based on ADCOMS and ADAS-Cog14 scores; 30% and 47% slowing, respectively) was detected at 18 months.

An 18-month phase III trial with Lecanemab, Clarity AD, was subsequently performed, with the primary end point the change from baseline at 18 months in the CDR-SB score. Study subjects had MCI due to AD, or mild AD based on NIA-Alzheimer’s Association criteria [228]. The results were published in November 2022 by van Dyck et al. [36]. The primary end point was met; 27% slowing of cognitive decline was achieved in Lecanemab-treated versus placebo-treated subjects (p < 0.001). van Dyck et al. noted that while there was no established definition for “clinically meaningful” effects in the CDR-SB score, the prospectively defined target had been exceeded. (Whether Lecanemab’s effect in this study was clinically meaningful has been questioned [229]). Significant differences between Lecanemab-treated and placebo-treated subjects were also found for PET-detectable Aβ. Mean PET-Aβ at baseline for Lecanemab-treated and placebo-treated subjects were 77.92 centiloids (CTL) and 75.03 CTL, respectively; the adjusted mean change from baseline at 18 months was -55.48 CTL for Lecanemab-treated subjects versus 3.64 CTL for placebo-treated subjects (p < 0.001). (In a study comparing PET-detectable and neuropathologically detectable Aβ in AD patients, CTL values greater than 20 were found to indicate at least moderate plaque density, while CTL < 10 reflected absence of neuritic plaques [230], so the mean detectable PET-Aβ in Lecanemab-treated subjects at 18 months approached the lower level of detection of moderate plaque density. The paper by van Dyck et al. [36] in which the Clarity AD results were published cited an older PET study, by Fleisher et al. [231], in which > 30 CTL was considered to represent elevated brain amyloid levels.) Secondary end points were also met in Clarity AD for measures of cognition, namely ADAS-cog14, ADCOMS, and ADCS-MCI-ADL (all p < 0.001). The incidence of ARIA-E in Lecanemab-treated and placebo-treated subjects was 12.6% and 1.7%, respectively, and the incidence of ARIA-H in Lecanemab-treated and placebo-treated subjects was 17.3% and 9.0%, respectively.

In Donanemab’s phase II study TRAILBLAZER-ALZ, the primary end point was change from baseline at 76 weeks in the Integrated Alzheimer’s Disease Rating Scale (iADRS), which assesses both cognitive and functional abilities [232]. Secondary measures included PET detection of Aβ and tau (the latter measured via ¹⁸F-flortaucipir) and multiple measures of cognitive functioning. Findings were reported by Mintun et al. [233]. The primary end point was achieved, with 32% slowing of decline in Donanemab-treated versus placebo-treated subjects as measured by iADRS (p = 0.04), although no statistically significant differences between treatment and placebo groups were found for CDR-SB scores, a secondary measure of cognition. Topline results were released by Lilly on May 3, 2023 for Donanemab’s phase III trial TRAILBLAZER-ALZ 2 [37], whose study subjects were individuals with MCI or early AD. The selection process for study participants included cognitive testing and PET screening for brain levels of insoluble Aβ and tau. The primary end point in TRAILBLAZER-ALZ 2 was change from baseline to 18 months on the iADRS. Subjects included in the primary analysis had intermediate levels of insoluble tau. As stated earlier the primary end point was met, as were all secondary end points (CDR-SB, Alzheimer’s Disease Cooperative Study - instrumental Activities of Daily Living Inventory [ADCS-iADL], and the ADAS-Cog13). Relative slowing on the iADRS of Donanemab-treated subjects with intermediate tau levels was 40% based on one statistical analysis and 35% based on another analysis. Slowing of disease progression in the “intermediate tau level” subjects based upon the scales assessed in the secondary end points was similar to that for the iADRS. When the analysis included subjects with high tau levels as well as those with intermediate tau levels, Donanemab was less effective at slowing AD progression, based upon iADRS scores (23% and 22% relative slowing as assessed by the two statistical procedures) although the differences versus placebo were still highly statistically significant (p values < 0.00004 and < 0.00006). Donanemab was effective at lowering brain levels of PET-detectable Aβ, with 34% of subjects in the primary analysis reported to achieve plaque clearance by 6 months and 71% achieving this goal by 12 months. ARIA-E and ARIA-H were detected in 24% and 31% of Donanemab-treated subjects, respectively. (The topline results did not include the incidence of ARIA-E in placebo-treated subjects; the incidence of ARIA-H in these subjects was reported to be 13.6%). Although most cases of ARIA were rated as mild-to-moderate, two deaths in TRAILBLAZER-ALZ 2 were attributed to ARIA, and another subject died after an incident of serious ARIA. Lilly’s announcement of its topline results included a statement that the company will proceed with submissions of regulatory approval for Donanemab in the United States and globally.

SIGNIFICANCE OF ANTI-Aβ MONOCLONAL ANTIBODY-ASSOCIATED ARIA

As discussed above, treatment of AD patients with Aducanumab, Lecanemab, and Donanemab increased the incidence of ARIA, and other monoclonal antibodies targeting Aβ’s N-terminal amino acids, including Bapineuzumab and Gantenerumab, also increased the incidence of ARIA [234 –239]. The mechanisms underlying ARIA are incompletely understood. The development of ARIA in the anti-Aβ monoclonal antibody trials was suggested to be due to increased production of inflammatory cytokines secondary to antibody-induced activation of microglia [217 , 241]. The Alzheimer’s Association Research Roundtable Workgroup [242] suggested that the increased incidence of ARIA in Bapineuzumab-treated subjects might be related to increased clearance of plaque-associated Aβ, causing a transient elevation in the cerebrovascular level of Aβ, which could increase vascular fragility and permeability.

Treatment-associated ARIA-E is usually short-lived and may be clinically asymptomatic [234, 235]. Spontaneous development of ARIA-E is rare, although its incidence increases in individuals with CAA and in APOE4 carriers [239, 242]. ARIA-H indicates the presence of cerebral microhemorrhages (microbleeds), which are classified according to their location as either lobar or deep microbleeds. Lobar microbleeds may be located in the cortex (“lobar cerebral microbleeds”), gray-white matter junction, subcortical white matter, or cerebellum (“lobar cerebellar microbleeds”), while deep microbleeds are present in basal ganglia gray matter, internal/external capsules, thalamus, or brain stem [221]. A community-based study found that cerebral microbleeds may be present by middle age and their incidence increases with age [243]. Lobar microbleeds have been reported to be an indicator of CAA [244], whereas combined lobar and deep microbleeds may be due to hypertensive angiopathy or atherosclerosis [221, 245]. The incidence of lobar microbleeds is increased in APOE4 carriers [245, 246].

It is not clear if microbleeds adversely affect cognitive performance [247]. Studies of community-based individuals without dementia have associated an increased incidence of microbleeds with lower cognitive functioning and increased risk for dementia [248 –251]. Conflicting reports have been published as to the association between microbleeds and cognitive performance in AD patients. Some studies have not found associations between these factors [247 , 253], but a study comparing MMSE scores between AD patients with multiple cerebral microbleeds and AD patients without microbleeds found that the patients with multiple microbleeds had lower MMSE scores despite similar duration of clinical disease [254].

In three Bapineuzumab phase II trials, 49% of the patients who developed ARIA-E also developed ARIA-H, suggesting a common mechanism for the two types of ARIA [255]. In those trials, although some patients with ARIA-E were asymptomatic, in other patients ARIA-E was associated with headache, confusion, visual disturbances, and gait abnormalities [242]. Similar adverse effects, plus nausea, were reported in subjects in the Aducanumab phase III trials who developed ARIA-E [256]. The increased risk for ARIA is a concern with regard to the use of N-terminal targeting anti-Aβ monoclonal antibodies for treatment of AD.

Some of the anti-Aβ monoclonal antibodies evaluated in clinical trials were designed to limit the development of ARIA. Crenezumab’s isotype is IgG4, which binds less avidly than IgG1 to the microglial FcR and does not induce microglial activation [241]. Ponezumab contains two mutations in its Fc region, inactivating this part of the antibody and preventing it from activating complement or triggering antibody-dependent cell-mediated cytotoxicity [206]. Deglycosylation of anti-Aβ antibodies has also been suggested as an approach to limit antibody-driven inflammation, because deglycosylation reduces the affinity of antibody binding to the FcR and to complement [257].

DOWNSTREAM EFFECTS OF ANTI-Aβ ANTIBODIES IN CLINICAL TRIALS

According to the amyloid hypothesis a number of pathological conditions occur between increased Aβ aggregation (or, in the revised hypothesis, the formation of Aβ oligomers) and the development of dementia. These include tau pathology, cell loss, and vascular damage [5], and possibly other conditions including oxidative stress, inflammation, mitochondrial dysfunction, and impaired autophagy. It is unclear which if any of these downstream processes are appropriate therapeutic targets. Even if some monoclonal anti-Aβ antibodies are able to slow AD progression (as Lecanemab and Donanemab have been shown to do), targeting of other factors in addition to Aβ may be required to further slow the disease [258].

Biomarkers for downstream events that have been evaluated in AD trials involving Aβ vaccination, IVIG, and monoclonal anti-Aβ antibodies include CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), neurofilament light chain (NfL), neurogranin, interleukin-6 (IL-6), α-synuclein, glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and chitinase-3-like protein 1 (YKL-40), as well as tau PET imaging. In some of the clinical trials statistically significant differences in the levels of these biomarkers were found between the treatment and placebo groups despite no evidence of lowering of PET-detectable Aβ; in those trials the mechanism responsible for the changes in the downstream markers is unknown. The significance of CSF t-tau measurements in AD is controversial. CSF t-tau levels are increased in some, but not all, AD patients [259, 260]; increased CSF t-tau was reported to be associated with dysregulation of neuronal plasticity, whereas AD subjects lacking evidence for dysregulated neuronal plasticity (i.e., AD subjects with lower CSF levels of neuronal plasticity proteins) had normal CSF concentrations of t-tau [261]. CSF p-tau, including p-tau-181, p-tau-217, and p-tau-231, is also increased in AD patients [262], although CSF p-tau-181 was reported to decrease in later stages of AD [263]. Hyperphosphorylation of tau causes sequestering of normal tau, leading to microtubule disassembly. This compromises axoplasmic flow, initially causing synaptic loss and ultimately resulting in neurodegeneration [264, 265]. NfL is a scaffolding protein of the neuronal exoskeleton whose CSF concentration increases with axonal damage [266], so it is considered to be a biomarker for axonal damage and neurodegeneration [267, 268]. CSF NfL increases during normal aging and AD [266] and is positively associated with AD progression [269 –271], increased ventricular volume [270], and hippocampal atrophy [272]. Neurogranin is a postsynaptic protein involved in long-term potentiation signaling [273] and is thought to play a major role in regulating hippocampal synaptic plasticity and synaptic function [274]. Neurogranin concentrations are decreased in AD brain and increased in AD CSF, and it has been suggested to be a marker for synaptic dysfunction or synaptic loss [275 –277]. IL-6, a pro-inflammatory cytokine, is a biomarker for inflammation [278]. α-synuclein is the main component of Lewy bodies and is a biomarker for Parkinson’s disease and other synucleinopathies [279]. GFAP is a cytoskeletal component of reactive astrocytes [280]. S100B is another astrocytic protein which has been used as a biomarker for neurodegeneration [281]. sTREM2 is the soluble form of TREM2, which is expressed in the CNS mainly on microglia [282] and is a biomarker for microglial activation [283]. YKL-40 is an astrocyte-derived biomarker involved in inflammation, proliferation, and angiogenesis [284].

In the AN1792 vaccination trial, CSF t-tau was measured in a small subset of the study subjects. It was significantly decreased (p < 0.001) in antibody responders (n = 11) compared to placebo (saline) - treated patients (n = 10) [23]. The significance of this finding was uncertain because postmortem studies on some of the study subjects indicated that tau pathology did not appear to be affected by Aβ vaccination [177 , 184–186].

In the phase II trial with the IVIG preparation Octagam [28], no significant changes versus placebo were found for CSF t-tau or p-tau-181. A similar result was found in the phase III trial with the IVIG product Gammagard [29]. Interestingly, in a study of the effects of Gammagard in 3xTg mice, hippocampal neurofibrillary tangle pathology was found to be decreased by 25-30% [285]. It was unclear if this was a downstream effect of Gammagard’s anti-Aβ antibodies, because as stated above some IVIG products also contain antibodies to non-phosphorylated tau and p-tau (p-tau-199 and p-tau-202) [154, 155]. Gammagard was found in another study to impair in vitro tau aggregation [286].

Two phase III trials, one with APOE4 carriers and the other with APOE4 non-carriers, were performed with Bapineuzumab in AD patients, because of the finding in a phase II trial of possible differences in antibody efficacy and the incidence of vasogenic edema between APOE4 carriers and non-carriers in Bapineuzumab-treated subjects [287]. CSF p-tau (phosphorylation site not stated) was measured in both trials. The results of the trials were published by Salloway et al. [32]. A significant difference for CSF p-tau concentration between Bapineuzumab-treated and placebo-treated subjects (reflecting decreased CSF p-tau in Bapineuzumab-treated subjects) was found in the APOE4 carrier study. In the APOE4 non-carrier study, no significant difference was found for CSF p-tau between the pooled 0.5 mg/kg Bapineuzumab and 1.0 mg/kg Bapineuzumab groups, although a pre-specified exploratory analysis found lower p-tau in the 1.0 mg/kg Bapineuzumab-treated group than in the placebo group. The decrease in CSF p-tau in Bapineuzumab-treated APOE4 carriers could have been a downstream effect of reduced cerebral Aβ because in that study, the mean change in PET-detectable Aβ was significantly different between treated and placebo subjects (p = 0.004) for the 0.5 mg/kg Bapineuzumab dose. In contrast, no significant differences were seen for PET-detectable Aβ between Bapineuzumab-treated and placebo-treated subjects in the non-APOE4 carrier trial.

In the first two phase III trials with Solanezumab, CSF t-tau and p-tau-181 were measured in a subset of the study subjects. No significant changes in these biomarkers were found in either Solanezumab-treated or placebo-treated patients in either study [31]. The effects of Solanezumab, together with those of the anti-Aβ monoclonal antibody Gantenerumab (discussed below), were also evaluated in a prevention study, DIAN-TU-001, performed by the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU). Study subjects carried mutations associated with early-onset AD and were asymptomatic or mildly symptomatic. The study evolved from a phase II biomarker trial to a phase III cognitive end point trial. Solanezumab treatment did not change CSF t-tau or p-tau concentrations in the study subjects; however, it produced an unexpected, statistically significant increase in CSF NfL concentrations at year 4 of the study. Whether this was due to an increase in disease progression, a problem with the study design, or some other factor was not determined [288, 289].

Several clinical trials have been performed with Gantenerumab. Scarlet RoAD was a phase II study in patients with prodromal AD (MCI thought to be due to AD [290, 291]) and Marguerite RoAD was a phase III trial in patients with mild AD [292]. Both trials were terminated based on findings from futility analyses. Downstream biomarkers examined in a subset of patients in Scarlet RoAD included CSF t-tau, p-tau-181, and neurogranin. Exploratory analyses suggested dose-related lowering of all three biomarkers [237]. In Marguerite RoAD, CSF t-tau and p-tau-181 decreased from baseline in Gantenerumab-treated subjects compared to placebo-treated subjects at 52 and 104 weeks (p = 0.053 for p-tau-181 at week 104) [293]. In year 4 of the DIAN-TU-001 preventative trial, CSF t-tau and p-tau-181 were lower in Gantenerumab-treated subjects than in placebo-treated subjects (both p < 0.001), and the increase in CSF NfL concentration was less in Gantenerumab- treated subjects than in placebo-treated subjects (p < 0.05) [289].

Ponezumab was intended to bind to, and sequester, Aβ in peripheral blood, with the hope that it would lower cerebral Aβ via the peripheral sink mechanism [206]. But as discussed above, phase II studies with Ponezumab found no effects on CSF Aβ, and CSF t-tau and p-tau (phosphorylation site not stated) were also unchanged [207, 294].

Crenezumab’s efficacy in AD patients was examined in two phase II trials, BLAZE and ABBY [295, 296]. Crenezumab failed to meet primary end points, and it did not appear to influence CSF t-tau or p-tau-181 levels, in either trial. Crenezumab was further evaluated in two phase III trials, CREAD and CREAD2, both of which were terminated due to futility analysis [297]. Similar to the phase II trials, no evidence was found in Crenezumab’s phase III trials for treatment-related changes in CSF t-tau or p-tau-181. In CREAD2, PET-detectable tau was measured at baseline and 53 weeks. An unexpected increase in PET tau (p = 0.03) was found in the Crenezumab-treated subgroup at 53 weeks. Exploratory analyses of changes from baseline were performed on other CSF biomarkers (pooled data from CREAD and CREAD2) including Aβ oligomers, neurogranin, NfL, IL-6, α-synuclein, GFAP, S100B, sTREM2, and YKL-40. These analyses suggested lowering of neurogranin, NfL, α-synuclein, GFAP, sTREM2, and YKL-40 at week 105 in Crenezumab-treated subjects compared to placebo-treated subjects. However, the only biomarker which achieved clear separation (as indicated by no overlapping of standard error bars) was neurogranin, whose CSF concentration was unchanged at weeks 53 and 105 in placebo-treated subjects but decreased in Crenezumab-treated subjects at week 53, with a further decrease at week 105.

Crenezumab was also administered to subjects in the Alzheimer’s Prevention Initiative (API) Colombian trial, a phase II trial which investigated its safety and efficacy in non-cognitively impaired carriers of the E280Q presenilin 1 mutation. The study also included a placebo-treated non-carrier cohort. Topline results revealed no evidence of a significant clinical benefit in either of the study’s primary end points, which assessed the rate of change in cognitive abilities and episodic memory function [298]. CSF t-tau, p-tau (phosphorylation site not stated), and NfL levels were lowered in Crenezumab-treated subjects by 29%, 37%, and 18% compared to placebo-treated subjects, but these differences were not statistically significant [299, 300].

CSF and PET studies performed on subsets of study subjects in Aducanumab’s two phase III trials [33] suggested that the highest dose of Aducanumab slowed the development of tau pathology. CSF t-tau and p-tau-181 were measured at baseline and week 78, and tau PET imaging was performed at screening and week 78. Dose-dependent reductions in CSF total and p-tau-181 were found in one study, while in the other study these measures decreased only in the high-dose group. Pooled results from the two studies indicated that the highest dose of Aducanumab reduced PET-detectable tau in medial temporal, temporal, and frontal lobes.

In Lecanemab’s phase IIb trial [35], CSF studies (collected at baseline, 12 months, and 18 months) included measurements of t-tau, p-tau (phosphorylation site not stated; probably p-tau-181, because Lecanemab’s phase III trial, discussed below, measured p-tau-181), neurogranin, and NfL. The least squares mean difference for p-tau was decreased in Lecanemab- versus placebo-treated subjects, but findings for t-tau were inconsistent. Neurogranin was significantly decreased in Lecanemab-treated versus placebo-treated subjects at 12 months but not at 18 months, while differences for NfL between Lecanemab-treated and placebo-treated patients were not significant at either time point. Lecanemab’s phase III trial [36] included measurements of PET-detectable tau and CSF t-tau, p-tau-181, neurogranin, and NfL. Prespecified analyses found “numerical improvements” between Lecanemab-treated and placebo-treated subjects for the CSF biomarkers other than NfL. The tau PET results were reported to have not been fully analyzed, although topline results mentioned that Lecanemab treatment slowed the development of tau pathology (based on PET detection of tau) in the temporal lobe [301].

In Donanemab’s phase II study TRAILBLAZER-ALZ, prespecified analyses presented at the International Conference on Alzheimer’s and Parkinson’s Diseases 2021 [302] and the Alzheimer’s Association International Conference 2021 [303] indicated that Donanemab reduced development of tau pathology in frontal, parietal, and lateral temporal lobes. Lilly’s announcement in May 2023 of topline results for Donanemab’s phase III trial TRAILBLAZER-ALZ 2 [37] did not mention downstream effects. The ClinicalTrials.gov posting for TRAILBLAZER-ALZ 2 [304] states that one of the secondary outcome measures in the study is change from baseline in PET-detectable tau. This result will likely be reported at the Alzheimer’s Association International Conference in July 2023.

Some of the antibodies which produced detectable downstream effects targeted Aβ conformations other than oligomers (Donanemab targeted Aβ fibrils) or other Aβ conformations in addition to oligomers (Bapineuzumab bound to Aβ monomers, oligomers, and fibrils, Gantanerumab bound to Aβ oligomers and fibrils, Aducanumab bound to oligomers and fibrils, and Lecanemab bound to protofibrils and fibrils as well as oligomers). This suggests that while antibody targeting of oligomeric Aβ may be optimal, because oligomers are thought to be the most neurotoxic Aβ conformation [305], effective targeting of other Aβ conformations can also decrease downstream pathological processes, even if significant slowing of cognitive decline is not achieved. An unanswered question is whether AD’s clinical progression can slowed by directly targeting downstream pathological mechanisms. The first clinical trials of anti-tau monoclonal antibodies in AD failed to meet their primary end points [306 –309]. Nonsteroidal anti-inflammatory agents (NSAIDs) [310 –314] and the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists rosiglitazone [315, 316] and pioglitazone [317] also failed to meet primary end points in large-scale clinical trials, while trials with antioxidants produced mixed results [318 –321]. Future AD trials with anti-Aβ monoclonal antibodies should assess treatment-associated changes in CSF levels of Aβ oligomers, as well as changes in downstream biomarkers including PET-detectable tau and CSF t-tau, p-tau, and inflammatory and oxidative stress proteins. Determining the downstream effects of anti-Aβ monoclonals is important because the ability of these antibodies to slow AD progression may depend on the extent to which they reduce downstream pathological processes.

POTENTIAL APPROACHES TO INCREASE THE ABILITY OF MONOCLONAL ANTI-Aβ ANTIBODIES TO SLOW AD PROGRESSION

The results for the phase III trials with Aducanumab, Lecanemab, and Donanemab indicate that treatment of AD patients with these antibodies can efficiently reduce brain levels of PET-detectable (insoluble) Aβ. High-dose Aducanumab reduced PET-Aβ to threshold levels in 48% of subjects in EMERGE and 31% of patients in ENGAGE [33], while in Lecanemab’s Clarity AD trial the mean detectable level of PET-Aβ in antibody-treated subjects approached the lower limit for detection of moderate plaque density [36], and in Donanemab’s TRAILBLAZER-ALZ 2, PET-Aβ was cleared in 71% of subjects in the primary analysis group (subjects with intermediate brain levels of insoluble tau) [37]. The finding that this lowering of insoluble Aβ was associated with slowing of disease progression (high-dose Aducanumab slowed cognitive decline by 22% in EMERGE, Lecanemab slowed cognitive decline by 27% in Clarity AD, and Donanemab slowed cognitive decline by 35-40% in TRAILBLAZER-ALZ 2) provides the strongest support yet for the amyloid hypothesis. As mentioned above, the question has been raised for Lecanemab as to whether its slowing of cognitive decline (a mean difference of 0.45 points on CDR-SB) is clinically meaningful [229]. The same question can be asked for Donanemab. Given that the antibodies (particularly Lecanemab and Donanemab) are effective at reducing PET-detectable Aβ, are the rates of slowing of cognitive decline achieved in their phase III trials the maximum that can obtained by antibody targeting of Aβ alone?

Several approaches could be considered in an effort to increase the ability of these antibodies to slow AD progression. Antibody-facilitated microglial degradation of Aβ might be increased by preventing, or at least decreasing, the shift in microglial activation phenotype from M2 (anti-inflammatory) to M1 (pro-inflammatory) which is thought to occur during AD progression [54 –57]. NSAIDs, pioglitazone, rosiglitazone, and curcumin are agents which have been suggested to promote glial cell M2-type activation [322 –326]. Increasing the expression and/or activity of microglial enzymes which degrade Aβ such as neprilysin, insulin-degrading enzyme, tissue plasminogen activator, cathepsin B, and matrix metalloproteinases [327] might also increase antibody-facilitated clearance of Aβ by microglia. In addition, enhancing the other mechanisms by which antibodies promote cerebral clearance of Aβ might enhance the ability of monoclonal antibodies to lower brain Aβ. For example, increasing the expression of LRP1 or the neonatal FcR on BBB endothelial cells might increase efflux of antibody-Aβ complexes from the brain through binding of antibody-Aβ complexes to these receptors. Increasing the ability of the monoclonal antibodies to enter the brain (possibly through the use of focused ultrasound, as was used in an experimental study with IVIG [163]) might also improve the antibodies’ Aβ-clearing ability. Finally, administration of an antibody such as Lecanemab, which targets soluble Aβ (protofibrils are large soluble oligomeric species [328, 329]), combined with an intervention designed to increase peripheral sink efflux of Aβ from the brain, is another approach that could be considered. Approaches that may increase peripheral sink efflux of brain Aβ include plasmapheresis with albumin replacement as was done in the AMBAR study [38, 39], administration of a monoclonal antibody designed to sequester peripheral blood Aβ by binding to its C-terminal residues (although the Aβ C-terminal-binding antibody Ponezumab failed to lower brain Aβ in phase II trials [207], and increasing peripheral blood levels of sLRP1. LRP1 is the main receptor mediating Aβ efflux from the brain into the peripheral circulation via the BBB [330, 331]; cleavage of LRP1 on cell surfaces results in shedding of sLRP1 into plasma [112]. sLRP1 binds 70% of plasma Aβ₄₀ and 90% of plasma Aβ₄₂ in neurologically normal subjects, with lower binding in AD patients [111].

As discussed above, the development of ARIA is a concern when AD patients are treated with approaches which mobilize brain Aβ. In the anti-Aβ monoclonal antibody trials, many of the cases of ARIA were asymptomatic. In Aducanumab’s phase III trials EMERGE and ENGAGE, approximately one-third of Aducanumab-treated patients developed ARIA-E, with only a quarter of these being symptomatic [332] and in Donanemab’s phase III trial TRAILBLAZER-ALZ 2, ARIA-E developed in 24% of Donanemab-treated patients, but it was symptomatic in only 6.1% of the Donanemab-treated patients [37]. However, ARIA can have serious clinical consequences. It would be worthwhile to determine if either Lecanemab or Donanemab can be modified to reduce its ability to induce ARIA, while retaining its ability to slow AD progression. The development of microhemorrhages and microglial activation can be prevented when anti-Aβ antibodies targeting N-terminal epitopes of Aβ are deglycosylated [333].

Finally, while recent clinical trials with AD patients have been limited to individuals with early AD (including MCI attributed to AD), there is an urgent need to develop therapies which can slow progression of patients who are in later stages of the disease. Even if targeting of Aβ by some monoclonal antibodies is effective at slowing the progression of early AD, it is unclear if this approach will be beneficial in later stages of AD. At some point in the disease process, downstream pathological processes may continue irrespective of treatment-induced reductions in brain Aβ.

CONCLUSIONS

To date, the only anti-Aβ monoclonal antibodies which have unequivocally been shown to slow AD progression are Lecanemab and Donanemab. Whether the effects of these antibodies on AD progression are also clinically meaningful is unclear. Antibodies promote clearance of Aβ from the brain by multiple mechanisms, offering possibilities for increasing this process. The extent to which antibodies which target Aβ are able to slow the progression of early AD may depend not only on their ability to reduce brain levels of Aβ aggregates, but also on their ability to decrease downstream pathological processes. Designing of future anti-Aβ monoclonal antibodies should include efforts to minimize the ability of these antibodies to induce ARIA.

Footnotes

ACKNOWLEDGMENTS

The author has no acknowledgements to report.

FUNDING

Funding was provided by donations to the Beaumont Foundation to support Alzheimer’s research in the Beaumont Research Institute.

CONFLICT OF INTEREST

The author has no conflict of interest to report.

References

Alzheimer’s Association (2022) Alzheimer’s Disease Facts and Figures, 19.

Abner

, Neltner

, Jicha

, Patel

, Anderson

, Wilcock

, Van Eldik

, Nelson

(2018) Diffuse Amyloid-β plaques, neurofibrillary tangles, and the impact of APOE in elderly persons’ brains lacking neuritic amyloid plaques. J Alzheimers Dis 64, 1307–1324.

Rahman

, Lendel

(2021) Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology. Mol Neurodegener 16, 59.

Hardy

, Allsop

(1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12, 383–388.

Hardy

, Higgins

(1992) Alzheimer’s disease: The amyloid cascade hypothesis. Science 256, 184–185.

Morris

, Storandt

, McKeel

Jr , Rubin

, Price

, Grant

, Berg

(1996) Cerebral amyloid deposition and diffuse plaques in “normal” aging: Evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 46, 707–719.

Arriagada

, Growdon

, Hedley-Whyte

, Hyman

(1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639.

Berg

, McKeel

Jr , Miller

, Baty

, Morris

(1993) Neuropathological indexes of Alzheimer’s disease in demented and nondemented persons aged 80 years and older. Arch Neurol 50, 349–358.

Lue

, Kuo

, Roher

, Brachova

, Shen

, Sue

, Beach

, Kurth

, Rydel

, Rogers

(1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155, 853–862.

10.

McLean

, Cherny

, Fraser

, Fuller

, Smith

, Beyreuther

, Bush

, Masters

(1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46, 860–866.

11.

Morris

, Clark

, Vissel

(2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2, 135.

12.

Mehta

, Jackson

, Paul

, Shi

, Sabbagh

(2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 26, 735–739.

13.

Mullane

, Williams

(2020) Alzheimer’s disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery? Biochem Pharmacol 177, 113945.

14.

Walsh

, Selkoe

(2007) A beta oligomers - a decade of discovery. J Neurochem 101, 1172–1184.

15.

Viola

, Velasco

, Klein

(2008) Why Alzheimer’s is a disease of memory: The attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 12, 51S–57S.

16.

Nixon

(2017) Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: Inseparable partners in a multifactorial disease. FASEB J 31, 2729–2743.

17.

Hong

, Huang

, Jiang

(2014) Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer’s disease. Neurol Res 36, 276–282.

18.

Cho

, Cho

, Kang

, Jeon

, Kim

, Kwon

, Kim

, Yoon

(2014) Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy 10, 1761–1775.

19.

Deane

, Bell

, Sagare

, Zlokovic

(2009) Clearance of amyloid-beta peptide across the blood-brain barrier: Implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 8, 16–30.

20.

Pascale

, Miller

, Chiu

, Boylan

, Caralopoulos

, Gonzalez

, Johanson

, Silverberg

(2011) Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent. Fluids Barriers CNS 8, 21.

21.

Iliff

, Wang

, Zeppenfeld

, Venkataraman

, Plog

, Liao

, Deane

, Nedergaard

(2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33, 18190–18199.

22.

Weller

, Subash

, Preston

, Mazanti

, Carare

(2008) Perivascular drainage of amyloid-beta peptides fromthe brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18, 253–266.

23.

Gilman

, Koller

, Black

, Jenkins

, Griffith

, Fox

, Eisner

, Kirby

, Rovira

, Forette

, Orgogozo

; AN1792(QS-21)-201 Study Team (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562.

24.

Aisen

, Gauthier

, Ferris

, Saumier

, Haine

, Garceau

, Duong

, Suhy

, Oh

, Lau

, Sampalis

(2011) Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 7, 102–111.

25.

Moussa-Pacha

, Abdin

, Omar

, Alniss

, Al-Tel

(2020) BACE1 inhibitors: Current status and future directions in treating Alzheimer’s disease. Med Res Rev 40,, 339–384.

26.

Green

, Schneider

, Amato

, Beelen

, Wilcock

, Swabb

, Zavitz

; Tarenflurbil Phase 3 Study Group (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 302, 2557–2564.

27.

Imbimbo

, Panza

, Frisardi

, Solfrizzi

, D’Onofrio

, Logroscino

, Seripa

, Pilotto

(2011) Therapeutic intervention for Alzheimer’s disease with γ-secretase inhibitors: Still a viable option? Expert Opin Investig Drugs 20, 325–341.

28.

Dodel

, Rominger

, Bartenstein

, Barkhof

, Blennow

, Förster

, Winter

, Bach

, Popp

, Alferink

, Wiltfang

, Buerger

, Otto

, Antuono

, Jacoby

, Richter

, Stevens

, Melamed

, Goldstein

, Haag

, Wietek

, Farlow

, Jessen

(2013) Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 12, 233–243.

29.

Relkin

, Thomas

, Rissman

, Brewer

, Rafii

, van Dyck

, Jack

, Sano

, Knopman

, Raman

, Szabo

, Gelmont

, Fritsch

, Aisen

; Alzheimer’s Disease Cooperative Study (2017) A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 88, 1768–1775.

30.

Panza

, Solfrizzi

, Imbimbo

, Giannini

, Santamato

, Seripa

, Logroscino

(2014) Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease. Expert Rev Neurother 14, 973–986.

31.

Doody

, Thomas

, Farlow

, Iwatsubo

, Vellas

, Joffe

, Kieburtz

, Raman

, Sun

, Aisen

, Siemers

, Liu-Seifert

, Mohs

; Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370, 311–321.

32.

Salloway

, Sperling

, Fox

, Blennow

, Klunk

, Raskind

, Sabbagh

, Honig

, Porsteinsson

, Ferris

, Reichert

, Ketter

, Nejadnik

, Guenzler

, Miloslavsky

, Wang

, Lu

, Lull

, Tudor

, Liu

, Grundman

, Yuen

, Black

, Brashear

; Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370, 322–333.

33.

Budd Haeberlein

, Aisen

, Barkhof

, Chalkias

, Chen

, Cohen

, Dent

, Hansson

, Harrison

, von Hehn

, Iwatsubo

, Mallinckrodt

, Mummery

, Muralidharan

, Nestorov

, Nisenbaum

, Rajagovindan

, Skordos

, Tian

, van Dyck

, Vellas

, Wu

, Zhu

, Sandrock

(2022) Two randomized phase 3 studies of Aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis 9, 197–210.

34.

Vaz

, Silva

, Monteiro

, Silvestre

(2022) Role of Aducanumab in the treatment of Alzheimer’s disease: Challenges and opportunities. Clin Interv Aging 17, 797–810.

35.

Swanson

, Zhang

, Dhadda

, Wang

, Kaplow

, Lai

RYK

, Lannfelt

, Bradley

, Rabe

, Koyama

, Reyderman

, Berry

, Gordon

, Kramer

, Cummings

(2021) A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther 13, 80.

36.

van Dyck

, Swanson

, Aisen

, Bateman

, Chen

, Gee

, Kanekiyo

, Li

, Reyderman

, Cohen

, Froelich

, Katayama

, Sabbagh

, Vellas

, Watson

, Dhadda

, Irizarry

, Kramer

, Iwatsubo

(2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388, 9–21.

37.

Lilly.com. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease (May 3, 2023) https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional. Accessed May 21, 2023.

38.

Boada

, López

, Olazarán

, Núñez

, Pfeffer

, Paricio

, Lorites

, Piñol-Ripoll

, Gámez

, Anaya

, Kiprov

, Lima

, Grifols

, Torres

, Costa

, Bozzo

, Szczepiorkowski

, Hendrix

, Páez

(2020) A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: Primary results of the AMBAR Study. Alzheimers Dement 16, 1412–1425.

39.

Cuberas-Borrós

, Roca

, Castell-Conesa

, Núñez

, Boada

, López

, Grifols

, Barceló

, Pareto

, Páez

(2022) Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer’s disease: Additional results from the AMBAR study. Eur J Nucl Med Mol Imaging 49, 4589–4600.

40.

ClinicalTrials.Gov. A Study to Evaluate Albumin and Immunoglobulin in Alzheimer’s Disease (AMBAR). (ClinicalTrials.gov Identifier: NCT01561053). First posted March 22, 2012.

41.

Yiannopoulou

, Anastasiou

, Zachariou

, Pelidou

(2019) Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicines 7, 97.

42.

Nemirovsky

, Shapiro

, Baron

, Kompaniets

, Monsonego

(2012) Active Aβ vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer’s disease with Aβ42-driven pathology. J Neuroimmunol 247, 95–99.

43.

Castellani

, Lee

, Zhu

, Nunomura

, Perry

, Smith

(2006) Neuropathology of Alzheimer disease: Pathognomonic but not pathogenic. Acta Neuropathol 111, 503–509.

44.

Hardy

, Mayer

(2011) The amyloid cascade hypothesis has misled the pharmaceutical industry. Biochem Soc Trans 39, 920–923.

45.

Castillo-Carranza

, Guerrero-Muñoz

, Kayed

(2013) Immunotherapy for the treatment of Alzheimer’s disease: Amyloid-β or tau, which is the right target? Immunotargets Ther 3, 19–28.

46.

Castellani

, Plascencia-Villa

, Perry

(2019) The amyloid cascade and Alzheimer’s disease therapeutics: Theory versus observation. Lab Invest 99, 958–970.

47.

Solito

, Sastre

(2012) Microglia function in Alzheimer’s disease. Front Pharmacol 3, 14.

48.

Minter

, Taylor

, Crack

(2016) The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J Neurochem 136, 457–474.

49.

Wilcock

, Munireddy

, Rosenthal

, Ugen

, Gordon

, Morgan

(2004) Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15, 11–20.

50.

Fuller

, Stavenhagen

, Teeling

(2014) New roles for Fc receptors in neurodegeneration-the impact on immunotherapy for Alzheimer’s disease. Front Neurosci 8, 235.

51.

Wilcock

, Zhao

, Morgan

, Gordon

, Everhart

, Wilson

, Lee

, Colton

(2011) Diverse inflammatory responses in transgenic mouse models of Alzheimer’s disease and the effect of immunotherapy on these responses. ASN Neuro 3, 249–258.

52.

Heneka

, Carson

, El Khoury

, Landreth

, Brosseron

, Feinstein

, Jacobs

, Wyss-Coray

, Vitorica

, Ransohoff

, Herrup

, Frautschy

, Finsen

, Brown

, Verkhratsky

, Yamanaka

, Koistinaho

, Latz

, Halle

, Petzold

, Town

, Morgan

, Shinohara

, Perry

, Holmes

, Bazan

, Brooks

, Hunot

, Joseph

, Deigendesch

, Garaschuk

, Boddeke

, Dinarello

, Breitner

, Cole

, Golenbock

, Kummer

(2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14, 388–405.

53.

Tang

, Le

(2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53, 1181–1194.

54.

Jimenez

, Baglietto-Vargas

, Caballero

, Moreno-Gonzalez

, Torres

, Sanchez-Varo

, Ruano

, Vizuete

, Gutierrez

, Vitorica

(2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: Age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28, 11650–11661.

55.

Hickman

, Allison

, El Khoury

(2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28, 8354–8360.

56.

Bell

, Zlokovic

(2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118, 103–113.

57.

Polazzi

, Monti

(2010) Microglia and neuroprotection: From in vitro studies to therapeutic applications. Prog Neurobiol 92, 293–315.

58.

Ries

, Sastre

(2016) Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci 8, 160.

59.

N’Songo

, Kanekiyo

, Bu

(2013) LRP1 plays a major role in the amyloid-β clearance in microglia. Mol Neurodegener 8, 33.

60.

Webster

, Galvan

, Ferran

, Garzon-Rodriguez

, Glabe

, Tenner

(2001) Antibody-mediated phagocytosis of the amyloid beta-peptide in microglia is differentially modulated by C1q. J Immunol 166, 7496–7503.

61.

Weinstein

, Quan

, Hanson

, Colonna

, Iorga

, Honda

, Shibuya

, Elkon

, Möller

(2015) IgM-dependent phagocytosis in microglia is mediated by complement receptor 3, not Fcα/μ receptor. J Immunol 195, 5309–5317.

62.

Iribarren

, Zhou

, Hu

, Le

, Wang

(2005) Role of formyl peptide receptor-like 1 (FPRL1/FPR2) in mononuclear phagocyte responses in Alzheimer disease. Immunol Res 31, 165–176.

63.

Husemann

, Loike

, Anankov R

, Febbraio

, Silverstein

(2002) Scavenger receptors in neurobiology and neuropathology: Their role on microglia and other cells of the nervous system. Glia 40, 195–205.

64.

Carty

, Bowie

(2011) Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol 81, 825–837.

65.

Zuroff

, Daley

, Black

, Koronyo-Hamaoui

(2017) Clearance of cerebral Aβ in Alzheimer’s disease: Reassessing the role of microglia and monocytes. Cell Mol Life Sci 74, 2167–2201.

66.

Pan

, Zhu

, Lin

, Zhang

, Ye

, Huang

, Chen

(2011) Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: Implications for Alzheimer’s disease. Mol Neurodegener 6, 45.

67.

Okun

, Mattson

, Arumugam

(2010) Involvement of Fc receptors in disorders of the central nervous system. Neuromolecular Med 12, 164–178.

68.

Andoh

, Kuraishi

(2004) Expression of Fc epsilon receptor I on primary sensory neurons in mice. Neuroreport 15, 2029–2031.

69.

Nitta

, Yagita

, Sato

, Okumura

(1992) Expression of Fc gamma receptors on astroglial cell lines and theirrole in the central nervous system. Neurosurgery 31, 83–87.

70.

, Qin

, Kuang

, Wu

, Duan

, Ju

, Wang

(2008) Alterations of Fc gamma receptor I and Toll-like receptor 4 mediate the antiinflammatory actions of microglia and astrocytes after adrenaline-induced blood-brain barrier opening in rats. J Neurosci Res 86, 3556–3565.

71.

Nakahara

, Tan-Takeuchi

, Seiwa

, Gotoh

, Kaifu

, Ujike

, Inui

, Yagi

, Ogawa

, Aiso

, Takai

, Asou

(2003) Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. Dev Cell 4, 841–52.

72.

Fanger

, Guyre

, Graziano

(2001) Uptake of antigen-antibody complexes by human dendritic cells. Methods Mol Med 64, 377–386.

73.

Tampellini

, Magrané

, Takahashi

, Li

, Lin

, Almeida

, Gouras

(2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 282, 18895–18906.

74.

Goldwaser

, Acharya

, Wu

, Godsey

, Sarkar

, DeMarshall

, Kosciuk

, Nagele

(2020) Evidence that brain-reactive autoantibodies contribute to chronic neuronal internalization of exogenous amyloid-β1-42 and key cell surface proteins during Alzheimer’s disease pathogenesis. J Alzheimers Dis 74, 345–361.

75.

Congdon

, Gu

, Sait

, Sigurdsson

(2013) Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem 288, 35452–35465.

76.

Collin

, Bohrmann

, Göpfert

, Oroszlan-Szovik

, Ozmen

, Grüninger

(2014) Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137, 2834–2846.

77.

Cunningham

, McGonigal

, Meehan

, Barrie

, Yao

, Halstead

, Willison

(2016) Anti-ganglioside antibodies are removed from circulation in mice by neuronal endocytosis. Brain 139, 1657–1665.

78.

Yamaguchi

, Sugihara

, Ogawa

, Saido

, Ihara

(1998) Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol 95, 217–222.

79.

Jones

, Minogue

, Connor

, Lynch

(2013) Amyloid-β-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J Neuroimmune Pharmacol 8, 301–311.

80.

Lee

, Seo

, Koh

(2015) Metallothionein-3 modulates the amyloid β endocytosis of astrocytes through its effects on actin polymerization. Mol Brain 8, 84.

81.

Koistinaho

, Lin

, Wu

, Esterman

, Koger

, Hanson

, Higgs

, Liu

, Malkani

, Bales

, Paul

(2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10, 719–726.

82.

Konishi

, Koizumi

, Kiyama

(2022) Phagocytic astrocytes: Emerging from the shadows of microglia. Glia 70, 1009–1026.

83.

Söllvander

, Nikitidou

, Brolin

, Söderberg

, Sehlin

, Lannfelt

, Erlandsson

(2016) Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener 11, 38.

84.

, Chen

, Ahmed

, Chen

, Ku

, Goldberg

, Hsu

(2001) Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neurosci 21, RC118.

85.

Rogers

, Cooper

, Webster

, Schultz

, McGeer

, Styren

, Civin

, Brachova

, Bradt

, Ward

(1992) Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 89, 10016–10020.

86.

Diebolder

, Beurskens

, de Jong

, Koning

, Strumane

, Lindorfer

, Voorhorst

, Ugurlar

, Rosati

, Heck

, van de Winkel

, Wilson

, Koster

, Taylor

, Saphire

, Burton

, Schuurman

, Gros

, Parren

(2014) Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260–1263.

87.

Sharp

, Boyle

, Diebolder

, Kros

, Koster

, Gros

(2019) Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b. Proc Natl Acad Sci U S A 116, 11900–11905.

88.

Velazquez

, Cribbs

, Poulos

, Tenner

(1997) Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: Implications for Alzheimer’s disease pathogenesis. Nat Med 3, 77–79.

89.

Bradt

, Kolb

, NR

Cooper

(1998) Complement-dependent proinflammatory properties of the Alzheimer’s disease beta-peptide. J Exp Med 188, 431–438.

90.

Wyss-Coray

, Mucke

(2002) Inflammation in neurodegenerative disease–a double-edged sword. Neuron 35, 419–432.

91.

Kolev

, Ruseva

, Harris

, Morgan

, Donev

(2009) Implication of complement system and its regulators in Alzheimer’s disease. Curr Neuropharmacol 7, 1–8.

92.

Morgan

(2011) Immunotherapy for Alzheimer’s disease. J Intern Med 269, 54–63.

93.

Garcia-Alloza

, Ferrara

, Dodwell

, Hickey

, Hyman

, Bacskai

(2007) A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28, 286–292.

94.

Bacskai

, Kajdasz

, McLellan

, Games

, Seubert

, Schenk

, Hyman

(2002) Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci 22, 7873–7878.

95.

Das

, Howard

, Loosbrock

, Dickson

, Murphy

, Golde

(2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci 23, 8532–8538.

96.

Solomon

, Koppel

, Frankel

, Hanan-Aharon

(1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A 94, 4109–4112.

97.

Taguchi

, Planque

, Nishiyama

, Symersky

, Boivin

, Szabo

, Friedland

, Ramsland

, Edmundson

, Weksler

, Paul

(2008) Autoantibody-catalyzed hydrolysis of amyloid beta peptide. J Biol Chem 283, 4714–4722.

98.

Solomon

, Koppel

, Hanan

, Katzav

(1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 93, 452–455.

99.

Deane

, Sagare

, Hamm

, Parisi

, LaRue

, Guo

, Wu

, Holtzman

, Zlokovic

(2005) IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J Neurosci 25, 11495–11503.

100.

, Zhong

, Jiang

, Du

, Dodel

, Farlow

, Zheng

, Du

(2014) The role of choroid plexus in IVIG-induced beta-amyloid clearance. Neuroscience 270, 168–176.

101.

Shibata

, Yamada

, Kumar

, Calero

, Bading

, Frangione

, Holtzman

, Miller

, Strickland

, Ghiso

, Zlokovic

(2000) Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106, 1489–1499.

102.

Osgood

, Miller

, Messier

, Gonzalez

, Silverberg

(2017) Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. Neurobiol Aging 57, 178–185.

103.

Kang

, Pietrzik

, Baum

, Chevallier

, Merriam

, Kounnas

, Wagner

, Troncoso

, Kawas

, Katzman

, Koo

(2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest 106, 1159–1166.

104.

Shinohara

, Fujioka

, Murray

, Wojtas

, Baker

, Rovelet-Lecrux

, Rademakers

, Das

, Parisi

J.E

, Graff-Radford

(2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137, 1533–1549.

105.

Qiu

, Strickland

, Hyman

, Rebeck

(2001) Elevation of LDL receptor-related protein levels via ligand interactions in Alzheimer disease and in vitro. J Neuropathol Exp Neurol 60, 430–440.

106.

Matsui

, Ingelsson

, Fukumoto

, Ramasamy

, Kowa

, Frosch

, Irizarry

, Hyman

(2007) Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res 1161, 116–123.

107.

DeMattos

, Bales

, Cummins

, Dodart

, Paul

, Holtzman

(2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 98, 8850–8855.

108.

DeMattos

, Bales

, Cummins

, Paul

, Holtzman

(2002) Brain to plasma amyloid-beta efflux: A measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295, 2264–2267.

109.

Deane

, Wu

, Sagare

, Davis

, Du Yan

, Hamm

, Xu

, Parisi

, LaRue

, Hu

, Spijkers

, Guo

, Song

, Lenting

, Van Nostrand

, Zlokovic

(2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 333–344.

110.

Biere

, Ostaszewski

, Stimson

, Hyman

, Maggio

, Selkoe

(1996) Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem 271, 32916–32922.

111.

Sagare

, Deane

, Bell

, Johnson

, Hamm

, Pendu

, Marky

, Lenting

, Wu

, Zarcone

, Goate

, Mayo

, Perlmutter

, Coma

, Zhong

, Zlokovic

(2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 13, 1029–1031.

112.

Quinn

, Grimsley

, Dai

, Tapner

, Chesterman

, Owensby

(1997) Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. J Biol Chem 272, 23946–23951.

113.

Henderson

, Andersson

, Narwal

, Janson

, Goldschmidt

, Appelkvist

, Bogstedt

, Steffen

, Haupts

, Tebbe

, Freskgård

, Jermutus

, Burrell

, Fowler

, Webster

(2014) Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β. Brain 137, 553–564.

114.

Georgievska

, Gustavsson

, Lundkvist

, Neelissen

, Eketjäll

, Ramberg

, Bueters

, Agerman

, Juréus

, Svensson

, Berg

, Fälting

, Lendahl

(2015) Revisiting the peripheral sink hypothesis: Inhibiting BACE1 activity in the periphery does not alter β-amyloid levels in the CNS. J Neurochem 132, 477–486.

115.

Szabo

, Relkin

, Weksler

(2008) Natural human antibodies to amyloid beta peptide. Autoimmun Rev 7, 415–420.

116.

Bach

, Dodel

(2012) Naturally occurring autoantibodies against β-Amyloid. Adv Exp Med Biol 750, 91–99.

117.

Liu

, Wang

, Li

, Fowler

, Zeng

, Deng

, Xu

, Zhou

, Doecke

, Villemagne

, Lim

, Masters

, Wang

(2021) Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease. Sci Adv 7, eabb0457.

118.

Avrameas

(1991) Natural autoantibodies: From ‘horror autotoxicus’ to ‘gnothi seauton’. Immunol Today 12, 154–159.

119.

Holodick

, Rodríguez-Zhurbenko

, Hernández

(2017) Defining natural antibodies. Front Immunol 8, 872.

120.

Kappler

, Hennet

(2020) Emergence and significance of carbohydrate-specific antibodies. Genes Immun 21, 224–239.

121.

, Dodel

, Hampel

, Buerger

, Lin

, Eastwood

, Bales

, Gao

, Moeller

, Oertel

, Farlow

, Paul

(2001) Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 57, 801–805.

122.

Weksler

, Relkin

, Turkenich

(2002) Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol 37, 943–948.

123.

Brettschneider

, Morgenthaler

, Teipel

, Fischer-Schulz

, Bürger

, Dodel

, Du

, Moller

, Bergmann

, Hampel

(2005) Decreased serum amyloid β1–42 autoantibody levels in Alzheimer’s disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid β1–42 peptide. Biol Psychiatry 57, 813–816.

124.

Moir

, Tseitlin

, Soscia

, Hyman

, Irizarry

, Tanzi

(2005) Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer’s disease patients. J Biol Chem 280, 17458–17463.

125.

Song

, Mook-Jung

, Lee

, Min

, Park

(2007) Serum anti amyloid-beta antibodies and Alzheimer’s disease in elderly Korean patients. J Int Med Res 35, 301–306.

126.

, Gong

, Moore

, Fu

, German

, Chang

, Rosenberg

, Diaz-Arrastia

(2014) Beta-amyloid auto-antibodies are reduced in Alzheimer’s disease. J Neuroimmunol 274, 168–173.

127.

Britschgi

, Olin

, Johns

, Takeda-Uchimura

, LeMieux

, Rufibach

, Rajadas

, Zhang

, Tomooka

, Robinson

, Clark

, Fagan

, Galasko

, Holtzman

, Jutel

, Kaye

, Lemere

, Leszek

, Li

, Peskind

, Quinn

, Yesavage

, Ghiso

, Wyss-Coray

(2009) Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer’s disease. Proc Natl Acad Sci U S A 106, 12145–12150.

128.

Klaver

, Coffey

, Smith

, Bennett

, Finke

, Dang

, Loeffler

(2011) ELISA measurement of specific non-antigen-bound antibodies to Aβ1-42 monomer and soluble oligomers in sera from Alzheimer’s disease, mild cognitively impaired, and noncognitively impaired subjects. J Neuroinflammation 8, 93.

129.

Nath

, Hall

, Tuzova

, Dobbs

, Jons

, Anderson

, Woodward

, Guo

, Fu

, Kryscio

, Wekstein

, Smith

, Markesbery

, Mattson

(2003) Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer’sdisease patients and Abeta antibodies can enhance Abeta neurotoxicity: Implications for disease pathogenesis andvaccine development. Neuromolecular Med 3, 29–39.

130.

Gruden

, Davidova

, Malisauskas

, Sewell

, Voskresenskaya

, Wilhelm

, Elistratova

, Sherstnev

, Morozova-Roche

(2007) Differential neuroimmune markers to the onset of Alzheimer’s disease neurodegeneration and dementia: Autoantibodies to Abeta((25-35)) oligomers, S100b and neurotransmitters. J Neuroimmunol 186, 181–192.

131.

Bard

, Cannon

, Barbour

, Burke

, Games

, Grajeda

, Guido

, Hu

, Huang

, Johnson-Wood

, Khan

, Kholodenko

, Lee

, Lieberburg

, Motter

, Nguyen

, Soriano

, Vasquez

, Weiss

, Welch

, Seubert

, Schenk

, Yednock

(2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6, 916–919.

132.

Banks

, Terrell

, Farr

, Robinson

, Nonaka

, Morley

(2002) Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer’s disease. Peptides 23, 2223–2226.

133.

Montagne

, Nation

, Pa

, Sweeney

, Toga

, Zlokovic

(2016) Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol 131, 687–707.

134.

van de Haar

, Burgmans

, Jansen

, van Osch

, van Buchem

, Muller

, Hofman

, Verhey

, Backes

(2016) Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology 281, 527–535.

135.

Sweeney

, Sagare

, Zlokovic

(2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14, 133–150.

136.

D’Andrea

(2003) Evidence linking neuronal cell death to autoimmunity in Alzheimer’s disease. Brain Res 982, 19–30.

137.

Farrall

, Wardlaw

(2009) Blood-brain barrier: Ageing and microvascular disease–systematic review and meta-analysis. Neurobiol Aging 30, 337–352.

138.

Halliday

, Rege

, Ma

, Zhao

, Miller

, Winkler

, Zlokovic

(2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 36, 216–227.

139.

Kellner

, Matschke

, Bernreuther

, Moch

, Ferrer

, Glatzel

(2009) Autoantibodies against beta-amyloid are common in Alzheimer’s disease and help control plaque burden. Ann Neurol 65, 24–31.

140.

Ishii

, Haga

(1976) Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques. Acta Neuropathol 36, 243–249.

141.

Ihara

, Kurizaki

, Nukina

, Sugita

, Toyokura

, Ebara

(1981) Presence of immunoglobulin light chain in the cores of senile plaques - an unlabelled antibody peroxidase-antiperoxidase (PA) study. Neurol Med (Japan) 15, 292–295.

142.

Eikelenboom

, Stam

(1982) Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 57, 239–242.

143.

Licandro

, Ferla

, Tavolato

(1983) Alzheimer’s disease and senile brains: An immunofluorescence study. Riv Patol Nerv Ment 104, 75–87.

144.

Kimura

, Takemura

, Saito

, Yoshikura

, Hayashi

, Inuzuka

(2017) Association between naturally occurring anti-amyloid β autoantibodies and medial temporal lobe atrophy in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 88, 126–131.

145.

Carmona-Iragui

, Fernández-Arcos

, Alcolea

, Piazza

, Morenas-Rodriguez

, Antón-Aguirre

, Sala

, Clarimon

, Dols-Icardo

, Camacho

, Sampedro

, Munuera

, Nuñez-Marin

, Lleó

, Fortea

, Gómez-Ansón

, Blesa

(2016) Cerebrospinal fluid anti-amyloid-β autoantibodies and amyloid PET in Cerebral amyloid angiopathy-related inflammation. J Alzheimers Dis 50, 1–7.

146.

Thal

, Ronisz

, Tousseyn

, Rijal Upadhaya

, Balakrishnan

, Vandenberghe

, Vandenbulcke

, von Arnim

CAF

, Otto

, Beach

, Lilja

, Heurling

, Chakrabarty

, Ismail

, Buckley

, Smith

APL

, Kumar

, Farrar

, Walter

(2019) Different aspects of Alzheimer’s disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia. Acta Neuropathol Commun 7, 178.

147.

Carrano

, Hoozemans

, van der Vies

, Rozemuller

, van Horssen

, de Vries

(2016) Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal 15, 1167–1178.

148.

Hartz

, Bauer

, Soldner

, Wolf

, Boy

, Backhaus

, Mihaljevic

, Bogdahn

, Klünemann

, Schuierer

, Schlachetzki

(2012) Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 43, 514–523.

149.

Dodel

, Hampel

, Depboylu

, Lin

, Gao

, Schock

, Jäckel

, Wei

, Buerger

, Höft

, Hemmer

, Möller

, Farlow

, Oertel

, Sommer

, Du

(2002) Human antibodies against amyloid beta peptide: Apotential treatment for Alzheimer’s disease. Ann Neurol 52, 253–225.

150.

Balakrishnan

, Andrei-Selmer

, Selmer

, Bacher

, Dodel

(2010) Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against amyloid-beta. J Alzheimers Dis 20, 135–143.

151.

Klaver

, Finke

, Digambaranath

, Balasubramaniam

, Loeffler

(2010) Antibody concentrations to Abeta1-42 monomer and soluble oligomers in untreated and antibody-antigen-dissociated intravenous immunoglobulin preparations. Int Immunopharmacol 10, 115–119.

152.

Istrin

, Bosis

, Solomon

(2006) Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res 84, 434–443.

153.

Dodel

, Balakrishnan

, Keyvani

, Deuster

, Neff

, Andrei-Selmer

, Röskam

, Stüer

, Al-Abed

, Noelker

, Balzer-Geldsetzer

, Oertel

, Du

, Bacher

(2011) Naturally occurring autoantibodies against beta-amyloid: Investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci 31, 5847–5854.

154.

Smith

, Coffey

, Klaver

, Loeffler

(2013) Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein. Int Immunopharmacol 16, 424–428.

155.

Loeffler

, Klaver

, Coffey

(2015) ELISA measurement of specific antibodies to phosphorylated tau in intravenous immunoglobulin products. Int Immunopharmacol 28, 1108–1112.

156.

Svenson

, Hansen

, Bendtzen

(1993) Binding of cytokines to pharmaceutically prepared human immunoglobulin. J Clin Invest 92, 2533–2539.

157.

Svenson

, Hansen

, Ross

, Diamant

, Rieneck

, Nielsen

, Bendtzen

(1998) Antibody to granulocyte-macrophage colony-stimulating factor is a dominant anti-cytokine activity in human IgG preparations. Blood 91, 2054–2061.

158.

Nimmerjahn

, Ravetch

(2007) The antiinflammatory activity of IgG: The intravenous IgG paradox. J Exp Med 204, 11–15.

159.

Anthony

, Nimmerjahn

, Ashline

, Reinhold

, Paulson

, Ravetch

(2008) Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. . Science 320, 373–376.

160.

Counts

, Ray

, Mufson

, Perez

, He

, Lahiri

(2014) Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer’s disease. J Clin Immunol 34, S80–S85.

161.

Magga

, Puli

, Pihlaja

, Kanninen

, Neulamaa

, Malm

, Härtig

, Grosche

, Goldsteins

, Tanila

, Koistinaho

(2010) Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease. J Neuroinflammation 7, 90.

162.

Puli

, Pomeshchik

, Olas

, Malm

, Koistinaho

, Tanila

(2012) Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflammation 9, 105.

163.

Dubey

, Heinen

, Krantic

, McLaurin

, Branch

, Hynynen

, Aubert

(2020) Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease. Proc Natl Acad Sci U S A 117, 32691–32700.

164.

Games

, Adams

, Alessandrini

, Barbour

, Berthelette

, Blackwell

, Carr

, Clemens

, Donaldson

, Gillespie

, Guido

, Hagopian

, Johnson-Wood

, Khan

, Lee

, Leibowitz

, Lieberburg

, Little

, Masliah

, McConlogue

, Montoya-Zavala

, Mucke

, Paganini

, Penniman

, Power

, Schenk

, Seubert

, Snyder

, Soriano

, Tan

, Vitale

, Wadsworth

, Wolozin

, Zhao

(1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523–527.

165.

Hsiao

, Chapman

, Nilsen

, Eckman

, Harigaya

, Younkin

, Yang

, Cole

(1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.

166.

Sturchler-Pierrat

, Abramowski

, Duke

, Wiederhold

, Mistl

, Rothacher

, Ledermann

, Bürki

, Frey

, Paganetti

, Waridel

, Calhoun

, Jucker

, Probst

, Staufenbiel

, Sommer

(1997) Two amyloid precursorprotein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94, 13287–13292.

167.

Duff

, Eckman

, Zehr

, Yu

, Prada

, Perez-tur

, Hutton

, Buee

, Harigaya

, Yager

, Morgan

, Gordon

, Holcomb

, Refolo

, Zenk

, Hardy

, Younkin

(1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.

168.

Oakley

, Cole

, Logan

, Maus

, Shao

, Craft

, Guillozet-Bongaarts

, Ohno

, Disterhoft

, Van

, Berry

, Vassar

(2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci 26, 10129–10140.

169.

Wisniewski

, Sigurdsson

(2010) Murine models of Alzheimer’s disease and their use in developing immunotherapies. Biochim Biophys Acta 1802, 847–859.

170.

Schenk

, Barbour

, Dunn

, Gordon

, Grajeda

, Guido

, Hu

, Huang

, Johnson-Wood

, Khan

, Kholodenko

, Lee

, Liao

, Lieberburg

, Motter

, Mutter

, Soriano

, Shopp

, Vasquez

, Vandevert

, Walker

, Wogulis

, Yednock

, Games

, Seubert

(1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177.

171.

Games

, Bard

, Grajeda

, Guido

, Khan

, Soriano

, Vasquez

, Wehner

, Johnson-Wood

, Yednock

, Seubert

, Schenk

(2000) Prevention and reduction of AD-type pathology in PDAPP mice immunized with A beta 1-42. Ann N Y Acad Sci 920, 274–284.

172.

Vehmas

, Borchelt

, Price

, McCarthy

, Wills-Karp

, Peper

, Rudow

, Luyinbazi

, Siew

, Troncoso

(2001) Beta-Amyloid peptide vaccination results in marked changes in serum and brain Abeta levels in APPswe/PS1DeltaE9 mice, as detected by SELDI-TOF-based ProteinChip technology. DNA Cell Biol 20, 713–721.

173.

Wilcock

, Gordon

, Ugen

, Gottschall

, DiCarlo

, Dickey

, Boyett

, Jantzen

, Connor

, Melachrino

, Hardy

, Morgan

(2001) Number of Abeta inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol 20, 731–736.

174.

Lemere

, Spooner

, LaFrancois

, Malester

, Mori

, Leverone

, Matsuoka

, Taylor

, DeMattos

, Holtzman

, Clements

, Selkoe

, Duff

(2003) Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis 14, 10–18.

175.

Check

(2002) Nerve inflammation halts trial for Alzheimer’s drug. Nature 415, 462.

176.

Imbimbo

(2002) Toxicity of beta-amyloid vaccination in patients with Alzheimer’s disease. Ann Neurol 51, 794.

177.

Nicoll

, Wilkinson

, Holmes

, Steart

, Markham

, Weller

(2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: A case report. Nat Med 9, 448–452.

178.

Orgogozo

, Gilman

, Dartigues

, Laurent

, Puel

, Kirby

, Jouanny

, Dubois

, Eisner

, Flitman

, Michel

, Boada

, Frank

, Hock

(2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46–54.

179.

Wisniewski

, Konietzko

(2008) Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol 7, 805–811.

180.

Pride

, Seubert

, Grundman

, Hagen

, Eldridge

, Black

(2008) Progress in the active immunofherapeutic approach to Alzheimer’s disease: Clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5, 194–196.

181.

Monsonego

, Imitola

, Petrovic

, Zota

, Nemirovsky

, Baron

, Fisher

, Owens

, Weiner

(2006) Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 103, 5048–5053.

182.

Fukuchi

, Accavitti-Loper

, Kim

, Tahara

, Cao

, Lewis

, Caughey

, Kim

, Lalonde

(2006) Amelioration of amyloid load by anti-Abeta single-chain antibody in Alzheimer mouse model. Biochem Biophys Res Commun 344, 79–86.

183.

Lee

, Bard

, Johnson-Wood

, Lee

, Hu

, Griffith

, Black

, Schenk

, Seubert

(2005) Abeta42 immunization in Alzheimer’s disease generates Abeta N-terminal antibodies. Ann Neurol 58, 430–435.

184.

Nicoll

, Barton

, Boche

, Neal

, Ferrer

, Thompson

, Vlachouli

, Wilkinson

, Bayer

, Games

, Seubert

, Schenk

, Holmes

(2006) Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65, 1040–1048.

185.

Nicoll

JAR

, Buckland

, Harrison

, Page

, Harris

, Love

, Neal

, Holmes

, Boche

(2019) Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain 142, 2113–2126.

186.

Wisniewski

(2019) Follow-up of active Aβ immunization in Alzheimer disease. Nat Rev Neurol 15, 495–496.

187.

Holmes

, Boche

, Wilkinson

, Yadegarfar

, Hopkins

, Bayer

, Jones

, Bullock

, Love

, Neal

, Zotova

, Nicoll

(2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised,placebo-controlled phase I trial. Lancet 372, 216–223.

188.

Dodart

, Bales

, Gannon

, Greene

, DeMattos

, Mathis

, DeLong

, Wu

, Holtzman

, Paul

(2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5, 452–457.

189.

McLaurin

, Cecal

, Kierstead

, Tian

, Phinney

, Manea

, French

, Lambermon

, Darabie

, Brown

, Janus

, Chishti

, Horne

, Westaway

, Fraser

, Mount

, Przybylski

, St George-Hyslop

(2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8, 1263–1269.

190.

Schiltz

, Salzer

, Mohajeri

, Franke

, Heinrich

, Pavlovic

, Wollmer

, Nitsch

, Moelling

(2004) Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease. J Mol Med (Berl) 82, 706–714.

191.

Maier

, Seabrook

, Lazo

, Jiang

, Das

, Janus

, Lemere

(2006) Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci 26, 4717–4728.

192.

, Li

, Zong

, Xing

, Zhang

, Cao

(2011) Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Aβ3-10 repeat fragment plasmid by reducing Aβ deposition and inflammatory response. Brain Res 1400, 112–124.

193.

, Ma

, Zong

, Xing

, Guo

, Jiang

, Sha

, Liu

, Cao

(2012) Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Aβ3-10 reduces AD-like pathology and cognitive impairment in Tg-APPswe/PSEN1dE9 mice. J Neuroimmunol 249, 16–26.

194.

Chauhan

, Siegel

(2002) Reversal of amyloid beta toxicity in Alzheimer’s disease model Tg2576 by intraventricular antiamyloid beta antibody. J Neurosci Res 69, 10–23.

195.

Wilcock

, DiCarlo

, Henderson

, Jackson

, Clarke

, Ugen

, Gordon

, Morgan

(2003) Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23, 3745–3751.

196.

Wilcock

, Alamed

, Gottschall

, Grimm

, Rosenthal

, Pons

, Ronan

, Symmonds

, Gordon

, Morgan

(2006) Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci 26, 5340–5346.

197.

Banks

, Farr

, Morley

, Wolf

, Geylis

, Steinitz

(2007) Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer’s disease: An age-related selective uptake with reversal of learning impairment. Exp Neurol 206, 248–256.

198.

Seubert

, Barbour

, Khan

, Motter

, Tang

, Kholodenko

, Kling

, Schenk

, Johnson-Wood

, Schroeter

, Gill

, Jacobsen

, Pangalos

, Basi

, Games

(2008) Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis 5, 65–71.

199.

Rasool

, Martinez-Coria

, Wu

, Laferla

, Glabe

(2013) Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice. J Neurochem 126, 473–482.

200.

Dong

, Li

, Cheng

, Hou

(2019) Drug Development for Alzheimer’s disease: Microglia induced neuroinflammation as a target? Int J Mol Sci 20, 558.

201.

Tian Hui Kwan

, Arfaie

, Therriault

, Rosa-Neto

, Gauthier

(2020) Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord 49, 334–348.

202.

Söldner

, Sticht

, Horn

AHC

(2017) Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry. PLoS One 12, e0186347.

203.

Petkova

, Ishii

, Balbach

, Antzutkin

, Leapman

, Delaglio

, Tycko

(2002) A structural model for Alzheimer’s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A 99, 16742–16747.

204.

Colletier

, Laganowsky

, Landau

, Zhao

, Soriaga

, Goldschmidt

, Flot

, Cascio

, Sawaya

, Eisenberg

(2011) Molecular basis for amyloid-beta polymorphism. Proc Natl Acad Sci U S A 108, 16938–16943.

205.

Liu

, Bu

, Liang

, Wang

, Zhang

, Jiao

, Zeng

, Yao

, Zhou

, Deng

, Wang

(2015) An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: The dust-raising effect. J Neuroinflammation 12, 153.

206.

La Porte

, Bollini

, Lanz

, Abdiche

, Rusnak

, Ho

, Kobayashi

, Harrabi

, Pappas

, Mina

, Milici

, Kawabe

, Bales

, Lin

, Pons

(2012) Structural basis of C-terminal β-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer’s disease. J Mol Biol 421, 525–536.

207.

Landen

, Andreasen

, Cronenberger

, Schwartz

, Börjesson-Hanson

, Östlund

, Sattler

, Binneman

, Bednar

(2017) Ponezumab in mild-to-moderate Alzheimer’s disease: Randomized phase II PET-PIB study. Alzheimers Dement (N Y) 3, 393–401.

208.

Sullivan

, Berg

, Elliott-Bryant

, Fishman

, McKee

, Morin

, Shia

, Fine

(2011) Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer’s disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core. Neurosci Lett 505, 109–112.

209.

DeMattos

, Lu

, Tang

, Racke

, Delong

, Tzaferis

, Hole

, Forster

, McDonnell

, Liu

, Kinley

, Jordan

, Hutton

(2012) A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron 76, 908–920.

210.

Perchiacca

, Ladiwala

, Bhattacharya

, Tessier

(2012) Structure-based design of conformation- and sequence-specific antibodies against amyloid β. Proc Natl Acad Sci U S A 109, 84–89.

211.

Desai

, Smith

, Zhang

, Makowski

, Gerson

, Ionescu

, Starr

, Zupancic

, Moore

, Sutter

, Ivanova

, Murphy

, Paulson

, Tessier

(2021) Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity. J Biol Chem 296, 100508.

212.

Sevigny

, Chiao

, Bussière

, Weinreb

, Williams

, Maier

, Dunstan

, Salloway

, Chen

, Ling

, O’Gorman

, Qian

, Arastu

, Li

, Chollate

, Brennan

, Quintero-Monzon

, Scannevin

, Arnold

, Engber

, Rhodes

, Ferrero

, Hang

, Mikulskis

, Grimm

, Hock

, Nitsch

, Sandrock

(2016) The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56.

213.

Arndt

, Qian

, Smith

, Quan

, Kilambi

, Bush

, Walz

, Pepinsky

, Bussière

, Hamann

, Cameron

, Weinreb

(2018) Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep 8, 6412.

214.

Wilcock

, Rojiani

, Rosenthal

, Levkowitz

, Subbarao

, Alamed

, Wilson

, Freeman

, Gordon

, Morgan

(2004) Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 24, 6144–6151.

215.

Hartman

, Izumi

, Bales

, Paul

, Wozniak

, Holtzman

(2005) Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. J Neurosci 25, 6213–6220.

216.

Bohrmann

, Baumann

, Benz

, Gerber

, Huber

, Knoflach

, Messer

, Oroszlan

, Rauchenberger

, Richter

, Rothe

, Urban

, Bardroff

, Winter

, Nordstedt

, Loetscher

(2012) Gantenerumab: A novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis 28, 49–69.

217.

Adolfsson

, Pihlgren

, Toni

, Varisco

, Buccarello

, Antoniello

, Lohmann

, Piorkowska

, Gafner

, Atwal

, Maloney

, Chen

, Gogineni

, Weimer

, Mortensen

, Friesenhahn

, Ho

, Paul

, Pfeifer

, Muhs

, Watts

(2012) An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ . J Neurosci 32, 9677–9689.

218.

, Deng

, Hou

, Tian

, Giunta

, Wang

, Sawmiller

, Smith

, Sanberg

, Obregon

, Mori

, Tan

(2014) Specific antibody binding to the APP672-699 region shifts APP processing from α- to β-cleavage. Cell Death Dis 5, e1374.

219.

Deng

, Hou

, Giunta

, Mori

, Wang

, Fernandez

, Weggen

, Araki

, Obregon

, Tan

(2012) Autoreactive-Aβ antibodies promote APP β-secretase processing. J Neurochem 120, 732–740.

220.

Ikonomovic

, Buckley

, Heurling

, Sherwin

, Jones

, Zanette

, Mathis

, Klunk

, Chakrabarty

, Ironside

, Ismail

, Smith

, Thal

, Beach

, Farrar

, Smith

(2016) Post-mortem histopathology underlyingβ-amyloid PET imaging following flutemetamol F 18 injection. Acta Neuropathol Commun 4, 130.

221.

Jung

, Jang

, Park

, Choe

, Park

, Kang

, Lee

, Kim

, Na

, Seo

(2020) Strictly lobar microbleeds reflect amyloid angiopathy regardless of cerebral and cerebellar compartments. Stroke 51, 3600–3607.

222.

Alzheimer Research Forum, Topline Results: 18 Months of BAN2401 Might Work (July 7, 2018), https://www.alzforum.org/news/research-news/topline-results-18-months-ban2401-might-work. Accessed March 13, 2023.

223.

Clark

, Schneider

, Bedell

, Beach

, Bilker

, Mintun

, Pontecorvo

, Hefti

, Carpenter

, Flitter

, Krautkramer

, Kung

, Coleman

, Doraiswamy

, Fleisher

, Sabbagh

, Sadowsky

, Reiman

, Zehntner

, Skovronsky

; AV45-A07 Study Group (2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305, 275–283.

224.

Fang

, Hultqvist

, Meier

, Antoni

, Sehlin

, Syvänen

(2019) High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain. Neuroimage 184, 881–888.

225.

Yang

, Dang

, Ostaszewski

, Mengel

, Steffen

, Rabe

, Bittner

, Walsh

, Selkoe

(2019) Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann Neurol 86, 215–224.

226.

Honig

, Vellas

, Woodward

, Boada

, Bullock

, Borrie

, Hager

, Andreasen

, Scarpini

, Liu-Seifert

, Case

, Dean

, Hake

, Sundell

, Poole Hoffmann

, Carlson

, Khanna

, Mintun

, DeMattos

, Selzler

, Siemers

(2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378, 321–330.

227.

Doggrell

(2018) Grasping at straws: The failure of solanezumab to modify mild Alzheimer’s disease. Expert Opin Biol Ther 18, 1189–1192.

228.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

Jr , Kawas

, Klunk

, Koroshetz

, Manly

, Mayeux

, Mohs

, Morris

, Rossor

, Scheltens

, Carrillo

, Thies

, Weintraub

, Phelps

(2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.

229.

Prillaman

(2022) Alzheimer’s drug slows mental decline in trial - but is it a breakthrough? Nature 610, 15–16.

230.

Amadoru

, Doré

, McLean

, Hinton

, Shepherd

, Halliday

, Leyton

, Yates

, Hodges

, Masters

, Villemagne

, Rowe

(2020) Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s disease. Alzheimers Res Ther 12, 22.

231.

Fleisher

, Chen

, Liu

, Roontiva

, Thiyyagura

, Ayutyanont

, Joshi

, Clark

, Mintun

, Pontecorvo

, Doraiswamy

, Johnson

, Skovronsky

, Reiman

(2011) Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 68, 1404–1411.

232.

Wessels

, Andersen

, Dowsett

, Siemers

(2018) The integrated Alzheimer’s Disease Rating Scale (iADRS) findings from the EXPEDITION3 trial. J Prev Alzheimers Dis 5, 134–136.

233.

Mintun

, Lo

, Duggan Evans

, Wessels

, Ardayfio

, Andersen

, Shcherbinin

, Sparks

, Sims

, Brys

, Apostolova

, Salloway

, Skovronsky

(2021) Donanemab in early Alzheimer’s disease. N Engl J Med 384, 1691–1704.

234.

Sperling

, Salloway

, Brooks

, Tampieri

, Barakos

, Fox

, Raskind

, Sabbagh

, Honig

, Porsteinsson

, Lieberburg

, Arrighi

, Morris

, Lu

, Liu

, Gregg

, Brashear

, Kinney

, Black

, Grundman

(2012) Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: A retrospective analysis. Lancet Neurol 11, 241–249.

235.

Carlson

, Siemers

, Hake

, Case

, Hayduk

, Suhy

, Oh

, Barakos

(2016) Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer’s disease. Alzheimers Dement (Amst) 2, 75–85.

236.

Piazza

, Winblad

(2016) Amyloid-Related Imaging Abnormalities (ARIA) in immunotherapy trials for Alzheimer’s disease: Need for prognostic biomarkers? J Alzheimers Dis 52, 417–420.

237.

Ostrowitzki

, Lasser

, Dorflinger

, Scheltens

, Barkhof

, Nikolcheva

, Ashford

, Retout

, Hofmann

, Delmar

, Klein

, Andjelkovic

, Dubois

, Boada

, Blennow

, Santarelli

, Fontoura

; SCarlet RoAD Investigators (2017) A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 9, 95.

238.

Swanson

, Zhang

, Dhadda

, Wang

, Kaplow

, Lai

, Lannfelt

, Kramer

, Luthman

(2018) Treatment of early AD subjects with BAN2401, an anti-Aβ protofibril monoclonal antibody, significantly clears amyloid plaque and reduces clinical decline. Alzheimers Dement 14, P1668.

239.

Withington

, Turner

(2022) Amyloid-related imaging abnormalities with anti-amyloid antibodies for the treatment of dementia due to Alzheimer’s disease. Front Neurol 13, 862369.

240.

Racke

, Boone

, Hepburn

, Parsadainian

, Bryan

, Ness

, Piroozi

, Jordan

, Brown

, Hoffman

, Holtzman

, Bales

, Gitter

, May

, Paul

, DeMattos

(2005) Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci 25, 629–636.

241.

Gibbs

, Silverman

, Zhao

, Peng

, Wang

, Wellington

, Mackenzie

, Plotkin

, Kaplan

, Cashman

(2019) A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer’s disease. Sci Rep 9, 9870.

242.

Sperling

, Jack

Jr , Black

, Frosch

, Greenberg

, Hyman

, Scheltens

, Carrillo

, Thies

, Bednar

, Black

, Brashear

, Grundman

, Siemers

, Feldman

, Schindler

(2011) Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 7, 367–385.

243.

Poels

, Vernooij

, Ikram

, Hofman

, Krestin

, van der Lugt

, Breteler

(2010) Prevalence and risk factors of cerebral microbleeds: An update of the Rotterdam scan study. Stroke 41, S103–S106.

244.

Banerjee

, Carare

, Cordonnier

, Greenberg

, Schneider

, Smith

, Buchem

, Grond

, Verbeek

, Werring

(2017) The increasing impact of cerebral amyloid angiopathy: Essential new insights for clinical practice. J Neurol Neurosurg Psychiatry 88, 982–994.

245.

Vernooij

, van der Lugt

, Ikram

, Wielopolski

, Niessen

, Hofman

, Krestin

, Breteler

(2008) Prevalence and risk factors of cerebral microbleeds: The Rotterdam Scan Study. Neurology 70, 1208–1214.

246.

Sveinbjornsdottir

, Sigurdsson

, Aspelund

, Kjartansson

, Eiriksdottir

, Valtysdottir

, Lopez

, van Buchem

, Jonsson

, Gudnason

, Launer

(2008) Cerebral microbleeds in the population based AGES-Reykjavik study: Prevalence and location. J Neurol Neurosurg Psychiatry 79, 1002–1006.

247.

Pettersen

, Sathiyamoorthy

, Gao

, Szilagyi

, Nadkarni

, St George-Hyslop

, Rogaeva

, Black

(2008) Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 65, 790–795.

248.

Qiu

, Cotch

, Sigurdsson

, Jonsson

, Jonsdottir

, Sveinbjrnsdottir

, Eiriksdottir

, Klein

, Harris

, van Buchem

, Gudnason

, Launer

(2010) Cerebral microbleeds, retinopathy, and dementia: The AGES-Reykjavik Study. Neurology 75, 2221–2228.

249.

Takashima

, Mori

, Hashimoto

, Kinukawa

, Uchino

, Yuzuriha

, Yao

(2011) Clinical correlating factors and cognitive function in community-dwelling healthy subjects with cerebral microbleeds. J Stroke Cerebrovasc Dis 20, 105–110.

250.

Poels

, Ikram

, van der Lugt

, Hofman

, Niessen

, Krestin

, Breteler

, Vernooij

(2012) Cerebral microbleeds are associated with worse cognitive function: The Rotterdam Scan Study. Neurology 78, 326–333.

251.

Akoudad

, Wolters

, Viswanathan

, de Bruijn

, van der Lugt

, Hofman

, Koudstaal

, Ikram

, Vernooij

(2016) Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol 73, 934–943.

252.

van der Vlies

, Goos

, Barkhof

, Scheltens

, van der Flier

(2012) Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology 79, 763–769.

253.

Heringa

, Reijmer

, Leemans

, Koek

, Kappelle

, Biessels

; Utrecht Vascular Cognitive Impairment (VCI) Study Group (2014) Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer’s disease. J Alzheimers Dis 38, 211–221.

254.

Goos

, Kester

, Barkhof

, Klein

, Blankenstein

, Scheltens

, van der Flier

(2009) Patients with Alzheimer disease with multiple microbleeds: Relation with cerebrospinal fluid biomarkers and cognition. Stroke 40, 3455–3460.

255.

Barakos

, Sperling

, Salloway

, Jack

, Gass

, Fiebach

, Tampieri

, Melançon

, Miaux

, Rippon

, Black

, Lu

, Brashear

, Arrighi

, Morris

, Grundman

(2013) MR imaging features of amyloid-related imaging abnormalities. AJNR Am J Neuroradiol 34, 1958–1965.

256.

Salloway

, Chalkias

, Barkhof

, Burkett

, Barakos

, Purcell

, Suhy

, Forrestal

, Tian

, Umans

, Wang

, Singhal

, Budd Haeberlein

, Smirnakis

(2022) Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating Aducanumab in patients with early Alzheimer disease. JAMA Neurol 79, 13–21.

257.

Karlnoski

, Rosenthal

, Alamed

, Ronan

, Gordon

, Gottschall

, Grimm

, Pons

, Morgan

(2008) Deglycosylated anti-Abeta antibody dose-response effects on pathology and memory in APP transgenic mice. J Neuroimmune Pharmacol 3, 187–197.

258.

Musiek

, Holtzman

(2015) Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nat Neurosci 18, 800–806.

259.

Andreasen

, Minthon

, Davidsson

, Vanmechelen

, Vanderstichele

, Winblad

, Blennow

(2001) Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 58, 373–379.

260.

Bos

, Vos

, Verhey

, Scheltens

, Teunissen

, Engelborghs

, Sleegers

, Frisoni

, Blin

, Richardson

, Bordet

, Tsolaki

, Popp

, Peyratout

, Martinez-Lage

, Tainta

, Lleó

, Johannsen

, Freund-Levi

, Frölich

, Vandenberghe

, Westwood

, Dobricic

, Barkhof

, Legido-Quigley

, Bertram

, Lovestone

, Streffer

, Andreasson

, Blennow

, Zetterberg

, Visser

(2019) Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer’s disease spectrum. Alzheimers Dement 15, 644–654.

261.

Visser

, Reus

, Gobom

, Jansen

, Dicks

, van der Lee

, Tsolaki

, Verhey

FRJ

, Popp

, Martinez-Lage

, Vandenberghe

, Lleó

, Molinuevo

, Engelborghs

, Freund-Levi

, Froelich

, Sleegers

, Dobricic

, Lovestone

, Streffer

, Vos

SJB

, Bos I; ADNI; Smit

, Blennow

, Scheltens

, Teunissen

, Bertram

, Zetterberg

, Tijms

(2022) Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease. Mol Neurodegener 17, 27.

262.

Ashton

, Benedet

, Pascoal

, Karikari

, Lantero-Rodriguez

, Brum

, Mathotaarachchi

, Therriault

, Savard

, Chamoun

, Stoops

, Francois

, Vanmechelen

, Gauthier

, Zimmer

, Zetterberg

, Blennow

, Rosa-Neto

(2022) Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease. EBioMedicine 76, 103836.

263.

Seppälä

, Koivisto

, Hartikainen

, Helisalmi

, Soininen

, Herukka

(2011) Longitudinal changes of CSF biomarkers in Alzheimer’s disease. J Alzheimers Dis 25, 583–594.

264.

Alonso

, Grundke-Iqbal

, Iqbal

(1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2, 783–787.

265.

Iqbal

, Alonso Adel

, Chen

, Chohan

, El-Akkad

, Gong

, Khatoon

, Li

, Liu

, Rahman

, Tanimukai

, Grundke-Iqbal

(2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739, 198–210.

266.

Meeker

, Butt

, Gordon

, Fagan

, Schindler

, Morris

, Benzinger

TLS

, Ances

(2022) Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage. Neurobiol Dis 166, 105662.

267.

Verberk

IMW

, Thijssen

, Koelewijn

, Mauroo

, Vanbrabant

, de Wilde

, Zwan

, Verfaillie

SCJ

, Ossenkoppele

, Barkhof

, van Berckel

BNM

, Scheltens

, van der Flier

, Stoops

, Vanderstichele

, Teunissen

(2020) Combination of plasma amyloid beta(1-42/1-40) and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology. Alzheimers Res Ther 12, 118.

268.

Dhiman

, Gupta

, Villemagne

, Eratne

, Graham

, Fowler

, Bourgeat

, Li

, Collins

, Bush

, Rowe

, Masters

, Ames

, Hone

, Blennow

, Zetterberg

, Martins

(2020) Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer’s disease. Alzheimers Dement (Amst) 12, e12005.

269.

Mattsson

, Andreasson

, Zetterberg

, Blennow

; Alzheimer’s Disease Neuroimaging Initiative (2017) Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 74, 557–566.

270.

Zetterberg

, Skillbäck

, Mattsson

, Trojanowski

, Portelius

, Shaw

, Weiner

, Blennow

; Alzheimer’s Disease Neuroimaging Initiative (2016) Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression. JAMA Neurol 73, 60–67.

271.

Pereira

, Westman

, Hansson

; Alzheimer’s Disease Neuroimaging Initiative (2017) Association between cerebrospinal fluid and plasma neurodegeneration biomarkers with brain atrophy in Alzheimer’s disease. Neurobiol Aging 58, 14–29.

272.

Idland

, Sala-Llonch

, Borza

, Watne

, Wyller

, Brækhus

, Zetterberg

, Blennow

, Walhovd

, Fjell

(2017) CSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults. Neurobiol Aging 49, 138–144.

273.

Casaletto

, Elahi

, Bettcher

, Neuhaus

, Bendlin

, Asthana

, Johnson

, Yaffe

, Carlsson

, Blennow

, Zetterberg

, Kramer

(2017) Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers. Neurology 89, 1782–1788.

274.

Zhong

, Gerges

(2010) Neurogranin and synaptic plasticity balance. Commun Integr Biol 3, 340–342.

275.

Thorsell

, Bjerke

, Gobom

, Brunhage

, Vanmechelen

, Andreasen

, Hansson

, Minthon

, Zetterberg

, Blennow

(2010) Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer’s disease. Brain Res 1362, 13–22.

276.

Kester

, Teunissen

, Crimmins

, Herries

, Ladenson

, Scheltens

, van der Flier

, Morris

, Holtzman

, Fagan

(2015) Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol 72, 1275–1280.

277.

Wellington

, Paterson

, Portelius

, Törnqvist

, Magdalinou

, Fox

, Blennow

, Schott

, Zetterberg

(2016) Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835.

278.

Slaats

, Ten Oever

, van de Veerdonk

, Netea

(2016) IL-1β/IL-6/CRP and IL-18/ferritin: Distinct inflammatoryrograms in infections. PLoS Pathog 12, e100597.

279.

Magalhães

, Lashuel

(2022) Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies. NPJ Parkinsons Dis 8, 93.

280.

Verberk

IMW

, Laarhuis

, van den Bosch

, Ebenau

, van Leeuwenstijn

, Prins

, Scheltens

, Teunissen

, van der Flier

(2021) Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: A prospective memory clinic-based cohort study. Lancet Healthy Longev 2, e87–e95.

281.

Michetti

, D’Ambrosi

, Toesca

, Puglisi

, Serrano

, Marchese

, Corvino

, Geloso

(2019) The S100B story: From biomarker to active factor in neural injury. J Neurochem 148, 168–187.

282.

Jiahuan

, Ying

, Hongyu

, Zhijing

, Shibo

, Chengyue

, Liangyu

, Fan

, Wei

(2022) Serum sTREM2: A potential biomarker for mild cognitive impairment in patients with obstructive sleep apnea. Front Aging Neurosci 14, 843828.

283.

Park

, Lee

, Kim

, Jo

, Lee

, Seo

, Park

, Koh

, Lee

(2021) The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer’s disease. Sci Rep 11, 13050.

284.

Salomon

, Matusiak

, Nowicka-Suszko

, Szepietowski

(2017) Chitinase-3-like Protein 1 (YKL-40) is a new biomarker of inflammation in psoriasis. Mediators Inflamm 2017, 9538451.

285.

Counts

, Perez

, He

, Mufson

(2014) Intravenous immunoglobulin reduces tau pathology and preserves neuroplastic gene expression in the 3xTg mouse model of Alzheimer’s disease. Curr Alzheimer Res 11, 655–663.

286.

Esteves-Villanueva

, Trzeciakiewicz

, Loeffler

, Martić

(2015) Effects of tau domain-specific antibodies and intravenous immunoglobulin on tau aggregation and aggregate degradation. Biochemistry 54, 293–302.

287.

Salloway

, Sperling

, Gilman

, Fox

, Blennow

, Raskind

, Sabbagh

, Honig

, Doody

, van Dyck

, Mulnard

, Barakos

, Gregg

, Liu

, Lieberburg

, Schenk

, Black

, Grundman

; Bapineuzumab 201 Clinical Trial Investigators (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061–2070.

288.

Alzheimer Research Forum, In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned (10 April 2020), https://www.alzforum.org/news/conference-coverage/dian-tu-gantenerumab-brings-down-tau-lot-open-extension-planned. Accessed November 23, 2022.

289.

Salloway

, Farlow

, McDade

, Clifford

, Wang

, Llibre-Guerra

, Hitchcock

, Mills

, Santacruz

, Aschenbrenner

, Hassenstab

, Benzinger

TLS

, Gordon

, Fagan

, Coalier

, Cruchaga

, Goate

, Perrin

, Xiong

, Li

, Morris

, Snider

, Mummery

, Surti

, Hannequin

, Wallon

, Berman

, Lah

, Jimenez-Velazquez

, Roberson

, van Dyck

, Honig

, Sánchez-Valle

, Brooks

, Gauthier

, Galasko

, Masters

, Brosch

, Hsiung

, Jayadev

, Formaglio

, Masellis

, Clarnette

, Pariente

, Dubois

, Pasquier

, Jack

Jr , Koeppe

, Snyder

, Aisen

, Thomas

, Berry

, Wendelberger

, Andersen

, Holdridge

, Mintun

, Yaari

, Sims

, Baudler

, Delmar

, Doody

, Fontoura

, Giacobino

, Kerchner

, Bateman

; Dominantly Inherited Alzheimer Network–Trials Unit (2021) A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med 27, 1187–1196.

290.

Scharre

(2019) Preclinical, prodromal, and dementia stages of Alzheimer’s disease. Practical Neurology, pp. 36-47. https://practicalneurology.com/articles/2019-june/preclinical-prodromal-and-dementia-stages-ofalzheimers-disease.

291.

Albert

, DeKosky

, Dickson

, Dubois

, Feldman

, Fox

, Gamst

, Holtzman

, Jagust

, Petersen

, Snyder

, Carrillo

, Thies

, Phelps

(2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 270–279.

292.

Abi-Saab

, Andjelkovic

, Pross

, Delmar

, Voyle

, Esau

(2017) MRI findings in the open label extension ofthe Marguerite RoAD study in patients with mild Alzheimer’s disease. J Prev Alzheimers Dis 4, 339.

293.

Voyle

, Abi-Saab

, Klein

, Hofmann

, Delmar

, Pross

, Andjelkovic

, Milosavljevic-Ristic

, Marteny

, Fontoura

, Doody

(2018) O1-09-02: The effect of low doses of gantenerumab on amyloid and tau biomarkers in cerebrospinal fluid (CSF) in the Marguerite Road Study. Alzheimer Dement 14, 240.

294.

Landen

, Cohen

, Billing

Jr , Cronenberger

, Styren

, Burstein

, Sattler

, Lee

, Jack

Jr , Kantarci

, Schwartz

, Duggan

, Zhao

, Sprenger

, Bednar

, Binneman

(2017) Multiple-dose ponezumab for mild-to-moderate Alzheimer’s disease: Safety and efficacy. Alzheimers Dement (N Y) 3, 339–347.

295.

Salloway

, Honigberg

, Cho

, Ward

, Friesenhahn

, Brunstein

, Quartino

, Clayton

, Mortensen

, Bittner

, Ho

, Rabe

, Schauer

, Wildsmith

, Fuji

, Suliman

, Reiman

, Chen

, Paul

(2018) Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 10, 96.

296.

Cummings

, Cohen

, van Dyck

, Brody

, Curtis

, Cho

, Ward

, Friesenhahn

, Rabe

, Brunstein

, Quartino

, Honigberg

, Fuji

, Clayton

, Mortensen

, Ho

, Paul

(2018) ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 90, e1889–e1897.

297.

Ostrowitzki

, Bittner

, Sink

, Mackey

, Rabe

, Honig

, Cassetta

, Woodward

, Boada

, van Dyck

, Grimmer

, Selkoe

, Schneider

, Blondeau

, Hu

, Quartino

, Clayton

, Dolton

, Dang

, Ostaszewski

, Sanabria-Bohórquez

, Rabbia

, Toth

, Eichenlaub

, Smith

, Honigberg

, Doody

(2022) Evaluating the safety and efficacy of Crenezumab vs placebo in adults with early Alzheimer disease: Two phase 3 randomized placebo-controlled trials. JAMA Neurol 79, 1113–1121.

298.

Banner Health, Landmark Alzheimer’s prevention trial unable to show significantly slower cognitive decline ininherited form of disease (June 15, 2022), https://www.bannerhealth.com/newsroom/press-releases/alzheimers-trial-unable-to-show-significantly-slower-cognitive-dec-line-in-inherited-form-of-disease. Accessed March 13, 2023.

299.

Alzheimer Research Forum, Crenezumab Secondaries Negative; Gantenerumab OLE Hints at Efficacy (August 12, 2022), https://www.alzforum.org/news/conference-coverage/crenezumab-secondaries-negative-gantenerum-ab-ole-hints-efficacy. Accessed March 13, 2023.

300.

NeurologyLive. Crenezumab Fails to Meet Primary End Points in API ADAD Colombia Trial. (August 2, 2022) https://www.neurologylive.com/view/crenezumab-fails-meet-primary-end-points-api-adad-colombia-trial. Accessed June 20, 2023.

301.

Eisai, Eisai Presents Full Results of Lecanemab Phase 3 Confirmatory Clarity AD Study for Early Alzheimer’s Disease at Clinical Trials on Alzheimer’s Disease (CTAD) Conference (November 29, 2022), https://www.eisai.com/news/2022/news202285.html. Accessed March 13, 2023.

302.

Alzheimer Research Forum. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit (March 19, 2021), https://www.alzforum.org/news/conference-coverage/donanemab-confirms-clearing-plaques-slows-decline-bit. Accessed March 13, 2023.

303.

prnewswire.com. Lilly releases Donanemab data that demonstrated relationship between reduction of amyloid plaqueand slowing of cognitive decline (July 29, 2021), https://www.prnewswire.com/news-releases/lilly-releas-es-donanemab-data-that-demonstrated-relationship-bet-ween-reduction-of-amyloid-plaque-and-slowing-of-cog-nitive-decline-301344633.html. Accessed March 13, 2023.

304.

ClinicalTrials.gov. A Study of Donanemab (LY3002813) in Participants with Early Alzheimer’s Disease(TRAILBLAZER-ALZ 2). (ClinicalTrials.gov Identifier: NCT04437511), https://clinicaltrials.gov/ct2/show/NCT0443751. Accessed May 24, 2023.

305.

Goure

, Krafft

, Jerecic

, Hefti

(2014) Targeting the proper amyloid-beta neuronal toxins: A path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther 6, 42.

306.

Shulman

, Rajagovindan

, Kong

, O’gorman

, Viollet

, Huang

, Hering

, Ratti

, Graham

, Haeberlein

(2021) Top-line results from TANGO, a phase 2 study of gosuranemab in participants with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease. J Prev Alzheimers Dis 8, S65.

307.

Teng

, Manser

, Pickthorn

, Brunstein

, Blendstrup

, Sanabria Bohorquez

, Wildsmith

, Toth

, Dolton

, Ramakrishnan

, Bobbala

, Sikkes

SAM

, Ward

, Fuji

, Kerchner

; Tauriel Investigators (2022) Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: A randomized clinical trial. JAMA Neurol 79, 758–767.

308.

Imbimbo

, Balducci

, Ippati

, Watling

(2023) Initial failures of anti-tau antibodies in Alzheimer’s disease are reminiscent of the amyloid-β story. Neural Regen Res 18, 117–118.

309.

Florian

, Wang

, Arnold

, Boada

, Guo

, Jin

, Zheng

, Fisseha

, Kalluri

, Rendenbach-Mueller

, Budur

, Gold

(2023) Tilavonemab in early Alzheimer’s disease: Results from a phase 2, randomized, double-blind study. Brain 146, 2275–2284.

310.

Aisen

, Schafer

, Grundman

, Pfeiffer

, Sano

, Davis

, Farlow

, Jin

, Thomas

, Thal

; Alzheimer’s Disease Cooperative Study (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: A randomized controlled trial. JAMA 289, 2819–2826.

311.

Reines

, Block

, Morris

, Liu

, Nessly

, Lines

, Norman

, Baranak

; Rofecoxib Protocol 091 Study Group (2004) Rofecoxib: No effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 62, 66–71.

312.

Soininen

, West

, Robbins

, Niculescu

(2007) Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Dement Geriatr Cogn Disord 23, 8–21.

313.

Wilcock

, Black

, Hendrix

, Zavitz

, Swabb

, Laughlin

; Tarenflurbil Phase II Study investigators (2008) Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: A randomised phase II trial. Lancet Neurol 7, 483–493.

314.

Pasqualetti

, Bonomini

, Dal Forno

, Paulon

, Sinforiani

, Marra

, Zanetti

, Rossini

(2009) A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging Clin Exp Res 21, 102–110.

315.

Gold

, Alderton

, Zvartau-Hind

, Egginton

, Saunders

, Irizarry

, Craft

, Landreth

, Linnamägi

, Sawchak

(2010) Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: Results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 30, 131–146.

316.

Harrington

, Sawchak

, Chiang

, Davies

, Donovan

, Saunders

, Irizarry

, Jeter

, Zvartau-Hind

, van Dyck

, Gold

(2011) Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: Two phase 3 studies. Curr Alzheimer Res 8, 592–606.

317.

Alzheimer’s News Today, Poor Results Prompt Takeda and Zinfandel to End Phase 3 Alzheimer’s Therapy Trial Early(January 31, 2018), https://alzheimersnewstoday.com/news/takeda-and-zinfandel-bring-early-end-to-pha-se-3-trial-of-alzheimers-therapy-pioglitazone/ Accessed March 13, 2023.

318.

Sano

, Ernesto

, Thomas

, Klauber

, Schafer

, Grundman

, Woodbury

, Growdon

, Cotman

, Pfeiffer

, Schneider

, Thal

(1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 336, 1216–1222.

319.

Filip

, Kolibás

(1999) Selegiline in the treatment of Alzheimer’s disease: A long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group. J Psychiatry Neurosci 24, 234–243.

320.

Galasko

, Peskind

, Clark

, Quinn

, Ringman

, Jicha

, Cotman

, Cottrell

, Montine

, Thomas

, Aisen

; Alzheimer’s Disease Cooperative Study (2012) Antioxidants for Alzheimer disease: A randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69, 836–841.

321.

Pritam

, Deka

, Bhardwaj

, Srivastava

, Kumar

, Jha

, Villa

, Jha

(2022) Antioxidants in Alzheimer’s disease: Current therapeutic significance and future prospects. Biology (Basel) 11, 212.

322.

Cuzzocrea

, Pisano

, Dugo

, Ianaro

, Maffia

, Patel

, Di Paola

, Ialenti

, Genovese

, Chatterjee

, Di Rosa

, Caputi

, Thiemermann

(2004) Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol 483, 79–93.

323.

Wang

, Zhao

, Zhang

, Liu

, Kang

, Tang

, Ding

, Chen

(2010) PPARγ agonist curcumin reduces the amyloid-β-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis 20, 1189–1199.

324.

Mandrekar-Colucci

, Karlo

, Landreth

(2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 32, 10117–10128.

325.

Yamanaka

, Ishikawa

, Griep

, Axt

, Kummer

, Heneka

(2012) PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32, 17321–17331.

326.

Bolós

, Perea

, Avila

(2017) Alzheimer’s disease as an inflammatory disease. Biomol Concepts 8, 37–43.

327.

Loeffler

(2023) Experimental approaches for altering the expression of Abeta-degrading enzymes. J Neurochem 164, 725–763.

328.

Walsh

, Lomakin

, Benedek

, Condron

, Teplow

(1997) Amyloid β-protein fibrillogenesis. J Biol Chem 272, 22364–22372.

329.

Lannfelt

, Möller

, Basun

, Osswald

, Sehlin

, Satlin

, Logovinsky

, Gellerfors

(2014) Perspectives on future Alzheimer therapies: Amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6, 16.

330.

Sagare

, Deane

, Zlokovic

(2012) Low-density lipoprotein receptor-related protein 1: A physiological Aβ homeostatic mechanism with multiple therapeutic opportunities. Pharmacol Ther 136, 94–105.

331.

Ramanathan

, Nelson

, Sagare

, Zlokovic

(2015) Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: The role, regulation and restoration of LRP1. Front Aging Neurosci 7, 136.

332.

Alzheimer Research Forum, Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious (December 14, 2021), https://www.alzforum.org/news/research-news/aduhelm-phase-3-data-aria-common-sometimes-serious. Accessed June 7, 2023.

333.

Sumner

, Edwards

, Asuni

, Teeling

(2018) Antibody engineering for optimized immunotherapy in Alzheimer’s disease. Front Neurosci 12, 254.