Modifiable,Non-Modifiable,and Clinical Factors Associated with Progression of Alzheimer’s Disease

Abstract

There is an extensive literature relating to factors associated with the development of Alzheimer’s disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.

Keywords

Alzheimer’s disease baseline cognition extrapyramidal signs genetic factors malnutrition neuropsychiatric symptoms progression

Alzheimer’s disease (AD) accounts for 60–80%of cases of dementia. An estimated 5.8 million Americans are presently afflicted with this disorder [1]. Currently available therapeutic options provide temporary symptomatic benefits to some patients but do not influence neuropathological progression of the disease [2].

There is an extensive literature relating to factors associated with the development of AD; a systematic review published in 2017 identified 136 systematic reviews and 432 primary studies on this subject [3]. Less is known about factors which may contribute to AD progression. A literature review published in 2013 [4] found trends for more rapid decline among younger AD patients, more highly educated AD patients, and AD patients with more severe cognitive impairment at baseline, while the systematic review from 2017 [3] also suggested that higher educational level might be associated with more rapid cognitive decline in AD patients. The objectives of the present manuscript were to present an updated review of factors suggested in the literature to be associated with AD progression, and to compare these findings with those in previous reviews. Although the development of AD in patients previously diagnosed with mild cognitive impairment (MCI) is also disease progression, in this review “AD progression” was limited to the worsening of symptoms or AD-type neuropathology in individuals already diagnosed with AD. This review was based upon citations found on PubMed in November 2019, initially using the search term “Alzheimer’s progression” (which produced 15,107 citations) and then narrowing the search to “rapid Alzheimer’s progression” (which produced 576 citations). 15 factors suggested to be positively associated with the progression of AD were selected. These factors were divided into modifiable, non-modifiable, and clinical factors, as shown in Table 1. PubMed searches of these factors were performed between November 2019 and April 2020 using as search terms the name of each factor plus “Alzheimer’s” and “progression.” Only manuscripts in English were considered for inclusion. Both primary studies and reviews were considered. The numbers of citations found for each factor are shown in Table 2. Because there is no consensus as to the definition of rapid cognitive decline [5], the review focused on factors associated with AD progression; when a factor was suggested to be associated with rapid cognitive decline, this was indicated in the manuscript.

Table 1

Factors suggested in the literature to be associated with cognitive and/or neuropathological progression of Alzheimer’s disease

Potentially modifiable factors

Vascular risk factors

Comorbidities

Malnutrition

Educational level

Inflammation

Oxidative stress

Non-modifiable factors

Age at clinical onset

Family history of dementia

Gender

APOE ɛ4

Genetic variants

Altered gene regulation

Clinical factors

Baseline cognitive level

Neuropsychiatric symptoms

Extrapyramidal signs

Based on a PubMed search, the literature was reviewed for 15 factors which had been suggested to be positively associated with the clinical and/or neuropathological progression of AD. These were divided into modifiable, non-modifiable, and clinical factors.

Table 2

Results of PubMed searches for terms associated with Alzheimer’s disease progression

Search term	Citations
APOE ɛ4	599
Baseline cognition	868
Comorbidities	284
Education	988
Extrapyramidal signs	66
Family history	120
Gender	305
Genes	948
Inflammation	1,320
Malnutrition	70
Neuropsychiatric symptoms	316
Onset age	1,052
Oxidative stress	1,186
Vascular risk factors	384

PubMed searches of each factor were performed between November 2019 and April 2020, using as search terms the name of each factor plus “Alzheimer’s” and “progression.” The citations found in the PubMed search of “genes and Alzheimer’s and progression” were divided into “genetic variants” and “alterations in gene regulation,” each of which was reviewed separately.

POTENTIALLY MODIFIABLE FACTORS SUGGESTED TO BE ASSOCIATED WITH AD PROGRESSION

Vascular risk factors (VRF)

VRF include coronary heart disease, cardiac arr-hythmia, hypertension, cerebrovascular disease, diabetes mellitus, obesity, smoking, and physical inactivity [6]. Some studies have reported faster rates of cognitive decline in AD patients with VRF than in AD patients lacking these risk factors [6 –10]. VRF-induced lowering of cerebral perfusion has been suggested to contribute to AD progression [11 –16], perhaps by reducing brain amyloid-β (Aβ) clearance [17] and/or promoting Aβ deposition [18]. Among participants in The Nun Study [19] with postmortem confirmation of AD, the presence of brain infarcts was associated with lower cognitive functioning [20]. Hypertension may also promote more rapid AD progression [8 , 21–26]. Some studies have suggested that interactions between VRF and the Apolipoprotein E ɛ4 (APOE ɛ4) allele may increase the risk for rapid disease progression [6, 27]. Conflicting results have been reported for the associations of diabetes [22 , 28–31] and hypercholesterolemia [24 , 31] with AD progression. In contrast to these findings, other investigators found no association between VRF and AD progression [29 , 32–36]. Similarly, Bergland et al. [37] reported that smoking was the only VRF significantly associated with more rapid cognitive decline in AD patients.

Conclusion

Despite the presence of VRF in many AD patients and the possibility that these factors could increase the concentration of Aβ in the brain, conflicting results have been found for associations between VRF and the rate of progression of AD.

Comorbidities

“Comorbidity” refers to any co-existing ailment in a patient with a particular disease [38]. Medical comorbidity is measured with the Cumulative Illness Rating Scale-Geriatric (CIRS-G) [39] or the Charlson Comorbidity Index [40]. The CIRS-G includes 14 organ systems which are rated from 0 to 4 (0 = no problem; 4 = severe problems). Non-psychiatric (somatic) medical comorbidity is more prevalent in patients with AD than in non-demented individuals [41 –43]. The ear-nose-and-throat, vascular, urogenital, musculoskeletal, and neurological systems are the most common comorbidities in AD patients [44, 45]. A recent systematic review [46] concluded that “somatic comorbidity burden” was associated with both cognitive and functional progression in patients with late onset Alzheimer’s disease (LOAD). In that review, comorbidity burden was found to be associated with decreased cognitive status in seven of ten studies [10 , 47–50] and with decreased ability to perform activities of daily living in five of seven studies [44 , 52].

In conflict with these reports, a few studies have not found significant associations between comorbidity burden and cognitive progression [53, 54], functional progression [45, 53], or time to death [55] in AD patients.

Conclusion

Despite the increased prevalence of comorbities in AD patients compared to non-demented individuals, the association between comorbidity burden and AD progression is unclear.

Malnutrition

Malnutrition is frequently present in older individuals, particularly those who are homebound, institutionalized, or hospitalized [56, 57]. The Mini Nutritional Assessment [58] is commonly used to assess nutritional status. A total score of 30 points is possible with the MNA, which categorizes subjects as well-nourished (MNA score 24–30), at risk for malnutrition (MNA score 17–23.5), or malnourished (MNA score <17). Malnutrition and the risk of malnutrition are often present in patients with AD, although differing prevalence rates have been reported [59 –62]. Some studies have found higher rates of malnutrition in female than in male AD patients [59 , 64].

Many studies have found that malnutrition or being at risk for it is associated with more rapid disease progression in patients with dementia [59 , 62–67]. Brüggenjürgen et al. [68] found that malnutrition significantly increased the risk of AD patients for needing nursing care (defined as requiring more than 1.5 h per day of care), and neuropsychiatric abnormalities have been reported to be more severe in AD patients at risk for malnutrition than in adequately nourished AD patients [63, 67].

Conclusion

Malnutrition and the risk for it appear to be associated with more rapid progression of AD.

Educational level

Educational level has been considered as a potentially modifiable risk factor by some authors [69 –71], but not others [72, 73]. Although the level of education of an individual with AD will not change, increased education may lower the risk for the disorder [74]. Higher educational attainment has been associated with more rapid cognitive and functional decline in AD patients in many studies [4 , 75–85]. Similarly, Seo et al. [86] and Cho et al. [87] detected more rapid cortical atrophy in highly-educated than in lower-educated patients with early-stage AD. However, other studies have found no association between educational level and AD progression or suggested that a lower level of education may be associated with more rapid disease progression [34 , 88–95]. A possible association between higher education and more rapid disease progression has been suggested by the cognitive reserve hypothesis, which postulates that AD’s early symptoms may be less obvious in more highly-educated individuals, thus resulting in a delay in their diagnosis until neurodegeneration is more advanced [96]. Supporting this possibility, Amieva et al. [97] found that in more highly educated individuals, subtle signs of cognitive impairment could be detected 15 to 16 years before dementia, although global cognition did not decline until 7 years before being diagnosed with dementia; in contrast, subjects with lower education had only one period of cognitive decrease, which lasted approximately 7 years.

Conclusion

The association between educational level and the rate of AD progression is unclear.

Inflammation

Inflammatory mechanisms in the brain increase during the development of AD [98] and may precede it [99]. Retrospective studies have found that individuals taking anti-inflammatory drugs including steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) on a long-term basis have a lower risk for AD [100], suggesting that inflammation may play a role in the development of AD. However, an alternative explanation for these findings is possible, namely that NSAID-mediated decrease in the production of Aβ could have reduced the risk for AD [101].

The amyloid hypothesis [102] considers Aβ deposition in the brain to be the initial event in AD pathogenesis, while local inflammation is considered to be a secondary event. But systemic inflammation has also been associated with an increased risk for AD [103, 104] and may activate brain inflammatory mechanisms [105]. Sources of this systemic inflammation may include oral infections [106] or alterations in the gut biome [107].

Many studies have reported activation of plaque-associated microglia in AD brain (reviewed by Mrak [108]). These cells produce a variety of neurotoxic species including inflammatory cytokines and chemokines, reactive oxygen species (ROS), reactive nitrogen species (RNS), and glutamate [109 –113]. They also produce Aβ-degrading enzymes such as insulin degrading enzyme, neprilysin, and matrix metalloprotease 9 [114, 115]. The role of activated microglia in AD pathogenesis is unclear because they exert both neuroprotective and neurotoxic effects [116 –118]. Studies of changes in microglial activation during AD progression have produced conflicting results. Xiang et al. [119] found that microglial activation in AD entorhinal cortex and hippocampus increased during disease progression. Conversely, Lee et al. [120] reported decreased brain concentrations for some inflammatory cytokines and chemokines in mid- and/or late-stage AD specimens, and Lanzrein et al. [121] found lower brain concentrations of TNF-α in AD patients than in control subjects.

Less is known about the role of astrocytes in AD. While believed to exert primarily neuroprotective effects [122], they also secrete mediators of neurotoxicity including interleukin-1β, tumor necrosis factor-α, and S100β [123, 124]. Promotion of neurite growth by S100β may contribute to development of dystrophic neurites in neuritic plaques [125]. Astrocytosis develops early in AD [126] and increases during disease progression [127, 128].

In addition to glial cell activation, a second inflammatory mechanism, complement activation, is also increased in AD brain (reviewed by Shen et al.) [129]. The complement system consists of more than 30 plasma and membrane-associated proteins [130], and may be activated via the classical, alternative, or lectin-mediated pathways [131]. Early-stage complement activation generates anaphylatoxins and opsonins, while complete activation produces the membrane attack complex (MAC), C5b-9 [132]. Although the anaphylatoxins and opsonins may facilitate clearance of Aβ by chemotactic attraction of microglia and promotion of Aβ phagocytosis, the MAC is neurotoxic [133, 134]. Immunoreactivity to both early-stage and late-stage complement proteins is present on plaques and neurofibrillary tangles in AD brain [135 –137] and increases in association with plaque density during neuropathological progression of AD [138, 139]. Whether complement deposition on neurofibrillary tangles increases during AD progression is unclear.

With regard to associations between systemic inflammation and AD progression, conflicting results have been found [105 , 140–142], possibly due to peripheral immunosuppressive effects of IL-1 produced in the brain [143].

Conclusion

Inflammatory mechanisms may differ with respect to changes in their activation during AD progression. Astrocytosis and complement activation (at least on plaques) appear to increase, but whether microglial activation and systemic inflammation also increase is unclear.

Oxidative stress

Oxidative stress is “an imbalance in pro-oxidants and antioxidants with associated disruption of redox circuitry and macromolecular damage” [144]. There is extensive evidence for oxidative stress in AD brain (reviewed by Butterfield et al. [145]). Oxidative stress is also increased in the brain in subjects with MCI [146 –151] suggesting that it occurs early in AD neurodegeneration. Oxidative stress in AD is thought to result from increased production of ROS and RNS, and possibly also from decreased brain antioxidant activities, although findings for changes in antioxidant levels in AD brain have been inconsistent [152 –158]. Mechanisms suggested to account for the increased production of ROS and RNS in AD brain include glial cell activation [159, 160], mitochondrial damage [161], abnormal homeostasis of transition metals [162 –165], and pathological conformations of Aβ [166, 167] and tau [168]. ROS and Aβ interact in a feed-forward cycle because Aβ species can generate further ROS [169 –171], particularly when Aβ complexes with transition metals [172 –174]. Mitochondria are the major source of cellular ROS [175, 176].

Relatively few studies were found of changes in brain or cerebrospinal fluid oxidative stress markers during AD progression. Oxidative stress was reported to plateau or decrease as the disease progresses [157 , 177–180], although one study found that lipid peroxidation in AD frontal lobe specimens increased with disease progression [120].

Conclusion

Oxidative stress in AD brain may plateau or decrease as the disease progresses, although further studies are required to examine this possibility.

NON-MODIFIABLE FACTORS SUGGESTED TO BE ASSOCIATED WITH AD PROGRESSION

Age at clinical onset

Examination of the association between the age at clinical onset of AD and the rate of its progression includes comparisons of progression rates between individuals with early onset AD (EOAD) and those with LOAD. Patients presenting with symptoms of AD before age 65 are considered to have EOAD whereas those with later onset are considered to have LOAD [181]. EOAD accounts for approximately 5%of AD cases [182]. Clinical progression has been reported to be more rapid in EOAD than in LOAD [183 –190]. Similarly, many investigations have found more rapid cognitive decline in younger AD patients [29 , 191–204] and more rapid rates of brain atrophy have been reported in younger AD patients [190 , 205–207]. However, some studies have reported similar rates of cognitive decline in AD patients regardless of age [32 , 208–213], and one study concluded that while EOAD patients may progress slightly faster than LOAD patients during the first three years after diagnosis, no differences in progression rate were found thereafter [214]. In conflict with the above findings are a few investigations which found more rapid progression in older AD patients [215 –217]. A meta-analysis performed in 2010 [218] found no association between age and cognitive performance in AD patients.

Conclusion

The association between age at clinical onset of AD and the rate of cognitive decline in AD patients is unclear, although some studies suggest that decline may be more rapid in younger AD patients.

Family history of dementia

Family history of dementia (i.e., having at least one first-degree relative who developed dementia) is a risk factor for both EOAD and LOAD [219, 220]. It has been associated with deficiencies in cognitive domains, and abnormalities in brain imaging and AD-associated biomarkers, in individuals who otherwise appear to be clinically normal [221 –223]. Some genetic variants that are risk factors for LOAD (and also some that are risk factors for EOAD) have been associated with more rapid AD progression, so overlap exists between studies examining associations between genetic variants and AD progression, and studies investigating the association between family history of dementia and AD progression. But although 948 citations were found on PubMed with the search terms “genes and Alzheimer’s and progression,” only 120 citations were found using the terms “family history and Alzheimer’s and progression.” This likely reflected the fact that family history of dementia was often not included as a covariate in studies of associations of various factors with AD progression.

Most studies investigating the association between family history of dementia and AD progression have been performed with patients with LOAD. Family history of dementia has been suggested to be associated with progression of AD [80], including in some cases with its rapid progression [2, 196]. Similarly, Romero and Kurz [224] reported a trend for more rapid decline in spontaneous language in AD patients with a family history of dementia. However, other investigators have found no evidence for associations between family history of dementia and AD progression [29 , 225–228]. In conflict with most studies is a report [34] that family history of dementia was associated with a decrease in the risk for rapid progression.

Regarding an association between family history of dementia and the rate of progression of EOAD, Jiang et al. [229] reported two PSEN1 mutations in families with EOAD, both of which were associated with progressive dementia, which in one family was rapidly progressive. Nikisch et al. [230] similarly reported the case of a patient with EOAD and family history of dementia who had a missense mutation in the PSEN2 gene and rapid disease progression.

Conclusion

The literature contains conflicting findings regarding a possible association between family history of dementia and the rate of progression of LOAD. The few studies which have examined an association between family history of dementia and the rate of disease progression in patients with EOAD suggest that progression may be more rapid in these individuals.

Gender

Approximately two-thirds of AD patients are female [231], perhaps because of longer survival of women with the disorder [232]. Underlying vascular differences may also be involved [233]. Some studies have found more rapid cognitive deterioration in female AD patients [54 , 235]. Wu et al. [236] found that increased brain Aβ was accompanied by an increase in functional connectivity between the hippocampus and the prefrontal cortex in men but not in women, possibly contributing to more rapid decline in female AD patients. Similarly, Nyarko et al. [237] suggested that amyloidogenic processes may differ in AD between males and females, and Counts et al. [238] suggested that cholinergic neurons may be at greater risk for degeneration in female AD patients. Conversely, some studies have found no significant influence of gender on the rate of AD clinical progression [24 , 239–241], and a few studies have found more rapid cognitive decline in male AD patients [22 , 188].

Conclusion

The association between gender and the rate of clinical progression in AD is unclear, although some studies have suggested more rapid progression in female patients.

APOE ɛ4

The presence of at least one APOE ɛ4 allele increases the risk for developing AD [242] although whether this risk is greater in women than in men is unclear [243]. Some studies have found APOE ɛ4 to be associated with more rapid cognitive progression [30 , 244–255], and interactions between APOE ɛ4 and VRF have been suggested [27 , 257]. Similarly, some investigations have suggested that neuropathological progression of AD may be more rapid in patients with APOE ɛ4 [258 –266] although these findings were not confirmed in other studies [205, 267]. Studies comparing rates of AD cognitive decline between APOE ɛ4 heterozygotes and APOE ɛ4 homozygotes have also produced conflicting results [246 , 269]. The increase in cerebral amyloid deposition in AD patients, monitored over 24 months via imaging with Pittsburgh Compound B-PET, was found to correlate with the number of APOE ɛ4 alleles present [266].

Conversely, many studies have found no significant association between APOE ɛ4 and AD progression [34 , 270–287], and some studies have even suggested that the presence of the A POE ɛ4 allele may slow AD progression [199 , 289]. A meta-analysis of 16 studies concluded that APOE status was not associated with the clinical progression of dementia, although the analysis was not specific for AD [290].

These conflicting results may be explained in part by the findings in a study by Belbin et al. [248] which examined single nucleotide polymorphisms (SNPs) in the APOE gene. Two SNPs in the regulatory region of the gene were found to be associated with the rate of cognitive decline. Heterogeneity for these SNPs among APOE ɛ4-positive AD patients could result in differing rates of cognitive decline.

Conclusion

The association between APOE ɛ4 and the rate of cognitive decline in AD patients is unclear.

Genetic variants

The term “genetic variant” includes polymorphisms (genetic variants present in at least 1%of the population) and mutations (an alteration in the DNA sequence in comparison to the previous state or wild type) [291]. There is an extensive literature relating to genetic variants associated with an increased risk for AD. Some of these variants, including those in the APP, presenilin 1 (PSEN1), presenilin 2 (PSEN2), APOE, and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) genes, have also been associated with AD progression. A partial list of genetic variants suggested to be associated with rapid AD progression is shown in Table 3 [229–233 , 292–305]. In a study from 1995, Farrer et al. [306] reported that Activities of Daily Living Scale scores worsened faster in male AD patients with a major genetic locus for AD than in male patients without such a genetic locus. Additionally, expression of a SNP in the LOAD risk gene for Membrane-Spanning 4-Domains, Subfamily A, Member 6A (MS4A6A, which may play a role in regulation of calcium signaling and/or immune functioning) was associated with more extensive AD brain pathology [307].

Table 3

Genetic variants associated with rapid clinical progression of AD

Gene
A Disintegrin and Metalloproteinase Domain 19 (ADAM19) [286]
Apolipoprotein E (APOE) [248]
ATP Binding Cassette Subfamily A Member 7 (ABCA7) [293]
Carbon Catabolite Repression 4-Like (CCRN4L) [286]
Cas Scaffold Protein Family Member 4 (CASS4) [286]
CD33 [293]
Clusterin (CLU) [294, 295]
Complement Receptor 1 (CR1) [293, 294]
Cystatin 3 (CST3) [285]
Ephrin Type-A Receptor 1 (EPHA1) [286]
Exocyst Complex Component 3-Like 2 (EXOC3L2) [285]
FS-7-Associated Surface Antigen (FAS) [296]
Glis Family Zinc Finger 1 (GLIS1) [297]
Interleukin-1α (IL-1α) [278]
Microtubule Associated Protein Tau (MAPT) [298]
Myocyte Enhancer Factor 2C (MEF2C) [286]
Paired Box Gene 3 (PAX3) [286]
Phosphatidylinositol Glycan Anchor Biosynthesis Class Q (PIGQ) [286]
Presenilin 1 (PSEN1) [229 , 299–302]
Presenilin 2 (PSEN2) [230]
Prion Protein (PRNP) [284]
Protein Phosphatase 2B (PP2B) [283, 298]
Purine Nucleoside Phosphorylase (PNP) [303]
Saitohin [304]
Sortilin-related receptor (SORL1) [305]
Triggering Receptor Expressed on Myeloid cells 2 (TREM2) [292]

Many genetic variants have been found to be associated with more rapid clinical progression of AD. Some of the variants, notably APOE and TREM2, are also risk factors for the development of AD. A partial list is shown.

Although not discussed further in this review, it should be noted that some gene variants have been associated with slowing of AD progression [286 , 308–310].

Conclusion

A number of genetic variants, some of which are also risk factors for the development of AD, appear to be associated with more rapid cognitive decline in AD patients.

Altered gene regulation

Although gene therapy has been suggested as a potential strategy for treatment of AD [311 –313], this approach is not presently available, so altered gene regulation in AD patients was considered in this review to be non-modifiable. Many genes are upregulated or downregulated during AD progression [314 –316]. A microarray analysis [317] concluded that upregulated genes in AD included tumor suppressors, oligodendrocyte growth factors, protein kinase A modulators, and genes involved in adhesion, apoptosis, lipid metabolism, and inflammation, while downregulated genes included those related to protein folding/metabolism/transport, energy metabolism, and some signaling pathways. A partial list of genes whose expression has been reported to be dysregulated during the progression of AD is shown in Table 4 [318 –332].

Table 4

Dysregulated genes during AD progression

Gene
Amyloid Precursor Protein (APP) [318]
Ceramide [319]
Choline Acetyltransferase (ChAT) [318]
Early and late endosomes [320]
Glial Fibrillary Acidic Protein (GFAP) [318]
Insulin [318]
Insulin-Like Growth Factor-1 (IGF-1) [318]
Ionized Calcium-Binding Adapter Molecule 1 (IBA 1) [318]
Kinesin Family Member 21b (kif21b) [321]
Micro RNAs (miRNAs) [322]
Mitochondrial Unfolded Protein Response Genes [323]
Myosin VC (MYO5C) [324]
Neuroplasticity-Related Genes [325]
Neuroprotective Proteins [326]
Neurotransmitter System Signaling Proteins [327]
Neurotrophin Receptors [320]
Phytanoyl-CoA Dioxygenase Domain Containing 1 (PHYHD1) [324]
Presenilin 2 (PSEN2) [328]
Protein Kinases [326]
Quaking (QKI) [329]
Toll-Like Receptors [330]
Transcription Factor and miRNA Regulatory Pathways [331]
Transcription Factors [326]
Translocase of Outer Mitochondrial Membrane 40 Homolog (TOMM40) [332]

The expression of many genes has been found to be upregulated or downregulated during progression of AD. A partial list of these genes is shown. Post-transcriptional gene silencing by miRNAs has been suggested to be responsible for downregulation of key regulatory genes in the AD brain.

microRNA (miRNA)-induced gene downregulation in AD is receiving increased attention. miRNAs are non-coding RNAs of approximately 22 nucleotides which downregulate genes by means of post-transcriptional gene silencing [333]. A single miRNA may downregulate hundreds of target mRNAs [334]. A review of AD-related miRNA alterations [335] concluded that “a family of pathogenically upregulated miRNAs appear(s) to be downregulating the expression (of) certain brain-essential mRNA targets, including key regulatory genes involved interactively in neuroinflammation, synaptogenesis, neurotrophic functions, and amyloidogenesis.”

Conclusion

The expression of many genes is dysregulated during AD progression. miRNAs may play an important role in this process.

CLINICAL FACTORS SUGGESTED TO BE ASSOCIATED WITH AD PROGRESSION

Baseline cognitive level

In most studies of AD patients, the initial measurements of cognitive functioning that are reported reflect the clinical stage of AD of the patients when they were diagnosed. Individuals with lower cognitive scores at the time of diagnosis (lower baseline scores) may therefore appear to progress more rapidly because they have more extensive brain pathology at the time of their diagnosis. Supporting this possibility, Velayudhan et al. [336] reported that AD subjects with lower baseline cognitive scores had thinner entorhinal cortex thickness at baseline, and experienced more rapid cognitive decline, than subjects with higher baseline cognitive scores. Many studies have found an association between lower baseline cognition and more rapid AD progression [4 , 337–344]. Conversely, Aguero-Torres et al. [54], in a study of older AD patients (≥75 years old), found that higher baseline cognitive function predicted faster decline, while Sakurai et al. [24] found no association between initial Mini-Mental State Examination score and AD cognitive decline.

Conclusion

Lower cognitive scores at baseline appear to be associated with more rapid clinical progression of AD patients.

Neuropsychiatric symptoms (NPS)

NPS are often present in AD patients and may be highly variable during the course of the disease [345 –348]. They are considered to be core features of AD rather than merely risk factors for its development [349 –351]. The Neuropsychiatric Inventory (NPI) is commonly used to measure abnormalities in 12 behavioral areas in patients with dementia. Each area is evaluated by caregivers of dementia patients with regard to frequency, severity, and caregiver distress [352]. The NPI is sometimes divided into psychotic, affective, and behavioral sub-syndromes [345]. A meta-analysis [353] reported the following prevalence rates for NPS in AD patients: apathy, 49%; depression, 42%; aggression, 40%; anxiety, 39%; sleep disorder, 39%; irritability, 36%; appetite disorder, 34%; aberrant motor behavior, 32%; delusion, 31%; disinhibition, 17%; hallucination, 16%; and euphoria, 7%. AD patients with APOE ɛ4 were reported to have a wider range of NPS than AD patients lacking the allele [354].

Many studies have found AD cognitive decline to be associated with individual NPS or with an increased NPI score [30 , 355–377]. Anxiety, depression, or delirium may increase the rate of progression of AD [378 –383]). NPS have also been associated with neuropathological progression of AD [384, 385]. The presence of NPS in AD patients has been associated with shorter survival time [371], earlier nursing home placement [386], and increased risk for death [370].

Lower baseline NPI scores, indicative of less dementia-related behavioral symptoms, were reported for EOAD patients than for LOAD patients [387], and another study found that the incidence, prevalence, and persistence of some NPS tended to be lower in EOAD than in LOAD patients [388]. However, Tanaka et al. [372] found similar patterns between EOAD and LOAD patients for the associations between AD progression and apathy, agitation, disinhibition, irritability, and aberrant motor behavior, although different patterns were reported between EOAD and LOAD patients for hallucinations, depression, and anxiety.

In contrast to the studies discussed above, a few investigations have not found associations between NPI and AD’s progression rate [389 –391].

Conclusion

NPS appear to be associated with more rapid cognitive decline in AD patients.

Extrapyramidal signs (EPS)

EPS including bradykinesia, postural instability, abnormal gait, rigidity, and tremor (referred to collectively as parkinsonism) are common in AD patients [392 –394]. EPS have been reported to be associated with lower baseline cognitive and functional scores for AD patients [395, 396]. The prevalence of EPS, with the possible exception of tremor, has been reported to increase with AD progression [393 , 397–402] and their presence is associated with a poorer prognosis for AD patients [357 , 404]. Many studies have found associations in AD patients between EPS and cognitive and/or functional decline [337 , 405–413], although a few studies have not found these associations [225 , 414–416]. Factors suggested to be responsible for the development of EPS in AD patients include subcortical Lewy bodies [417], abnormalities in dopamine and serotonin neurotransmission [418], and use of neuroleptic medications [407, 419]. Conflicting findings have been reported with regard to the influence of APOE ɛ4 on the development of EPS in AD patients [34, 270].

The loss of nigrostriatal dopaminergic neurons is the primary lesion responsible for motor deficits in Parkinson’s disease [420]. The status of midbrain dopaminergic neurotransmission in AD patients with parkinsonism has been examined in several studies. Murray et al. [421] found no reductions in dopamine transporter (DAT) sites, tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), or dopamine D2 receptors in the substantia nigra pars compacta (SNpc) in brain specimens from patients with AD or AD with parkinsonism, although decreased striatal DAT expression was found in the latter group. Chung et al. [422] similarly reported decreased DAT availability in the caudate of AD patients with parkinsonism. Horvath et al. [423] found that in brain specimens of AD patients with parkinsonism, significant neuronal loss was present in both the SNpc and the putamen, although it appeared to be unrelated to the Braak stage of AD.

Conclusion

EPS may increase during the progression of AD, and their presence appears to be associated with more rapid cognitive and functional decline in AD patients.

DISCUSSION

This review of factors which were suggested in the literature to be associated with AD progression found conflicting results for many of the factors (summarized in Table 5). Likely reasons for these conflicting findings include differences in the populations being studied, study designs, and measures of disease progression. But for six factors, nearly all of the studies that were found on PubMed reported positive associations with clinical and/or neuropathological progression of AD. These factors were malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs.

Table 5

Conflicting results reported for associations of factors with AD progression

Factor	Association with AD progression
Vascular risk factors (VRF)	More rapid cognitive decline in AD patients with VRF than in AD patients lacking VRF reported in some studies [6 –10] but not others [29 , 32–36]; conflicting results for diabetes [22 , 28–31] and hypercholesterolemia [24 , 31].
Comorbidities	Somatic comorbidity burden associated with cognitive and/or functional progression of LOAD in some studies [10 , 47–52] but not others [53, 54].
Educational level	Higher educational level associated with more rapid cognitive and functional decline in AD patients in some studies [4 , 6–85] but not others [34 , 88–95].
Inflammation	Conflicting findings for changes in microglial activation during AD progression [119 –121] and for associations between systemic inflammation and AD progression [105 , 140–142].
Oxidative stress	Conflicting findings for changes in antioxidant levels in AD brain [152 –158] and for markers of oxidative stress during disease progression [120 , 177–180].
Age at clinical onset	More rapid progression in EOAD than in LOAD reported in some studies [183 –190] but no association found in other studies between age at clinical onset of AD and rate of decline [32 , 208–213].
Family history of dementia	Family history of dementia associated with more rapid progression of LOAD in some studies [2 , 196] but not others [29 , 225–228].
Gender	More rapid cognitive deterioration in female AD patients found in some studies [54 , 235], while others found no influence of gender on rate of progression [24 , 239–241] or more rapid cognitive decline in male AD patients [22 , 188].
APOE ɛ4	Some studies reported association of APOE ɛ4 with more rapid cognitive progression [30 , 244–255] but others found no significant association [34 , 270–287]; some suggested that APOE ɛ4 may slow AD progression [199 , 289].

The conflicting results for nine factors prevented conclusions from being reached for the associations of these factors with AD progression. Possible reasons for these conflicting results include differences between studies in the populations being investigated, study designs, and measures of disease progression used in the studies.

The factors considered in this review that were also included in the review by Sona et al. [4] of factors associated with rapid progression of AD were age at onset, gender, level of education, family history of dementia, baseline cognitive level, VRF, and APOE genotype. Sona et al. searched PubMed and PsycINFO for studies published through 2010 and selected 82 citations for review. They found trends for more rapid decline in AD patients who were younger, more highly educated, or more cognitively impaired at baseline. The present review had similar findings for baseline cognition, but no conclusion could be reached for the associations of age and educational level with AD progression because of the many conflicting results. The different conclusions between the review by Sona et al. and the present one may be due to the greater number of studies reviewed in this review. The systematic review by Hersi et al. [3] focused primarily on factors associated with the development of AD. The search in that review for studies of factors associated with AD progression was limited to systematic reviews on MEDLINE and EMBASE. Twelve systematic reviews were selected for review. Among the factors evaluated for associations with AD progression in that review, only two factors, educational level and APOE genotype, were evaluated in the present review. Hersi et al. suggested that educational level might be associated with more rapid cognitive decline in AD patients. The present review found many conflicting studies for this factor, so no conclusion was reached about it.

Factors examined in this review which are presently modifiable in AD patients are vascular risk, neuropsychiatric symptoms, extrapyramidal signs, comorbidities, malnutrition, inflammation, and oxidative stress. (NPS and EPS were included as “clinical factors” despite the possibility that their severity may be reduced by treatment, as discussed below.) Therapeutic approaches which include greater attention to these factors, while still focusing on primary targets such as abnormal conformations of Aβ or tau, may be worthwhile. Admittedly, if such an approach would be found to slow AD progression, determining which intervention was responsible would be difficult, but this approach might improve the overall health of AD patients even if it does not slow their rate of decline. Such an approach could include increased attention to the following:

VRF: monitoring of blood pressure, lipid profile, glucose, and carotid blood flow, and encouraging individuals to engage in regular exercise such as walking, running, cycling, or swimming if feasible [424];

NPS (which tend to be under-recognized and under-treated in memory clinics [425]): treatment of anxiety, depression, sleep disorders, and psychoses, including interventions to try to prevent “sundowning” [426, 427] and delirium [380–383 , 428];

EPS: treatment of parkinsonian symptoms, if these symptoms are severe enough to impact on quality of life (note: deep brain stimulation is contraindicated in patients with dementia [429]);

comorbidities: neurological, musculoskeletal, urogenital, and cardiac monitoring;

malnutrition: monitoring of nutritional status, with supplementation, if necessary, with high-quality protein products such as Ensureâ (Nestle Health Science, Vevey, Switzerland).

Although inflammation and oxidative stress are also potentially modifiable, no slowing of clinical progression was found in large-scale prospective trials in which AD patients were treated with anti-inflammatory drugs or antioxidants [430, 431], so no recommendation is made for attempting to modify these factors in AD patients.

A pilot study using a similar approach was recently published by Affirmativ Health (Bellingham, WA, USA) [432]. This was a short-term study in which subjects were characterized, based on baseline Montreal Cognitive Assessment (MoCA) testing, as having subjective cognitive impairment (n = 15), MCI (n = 9), or early-stage AD (n = 4). Subsequent testing of study subjects 3–12 months later found MoCA scores to be unchanged from baseline, although these scores were improved for subjects whose baseline MoCA scores were ≤24 (p = 0.029). While no conclusions should be drawn from this study as to the effectiveness of this approach in slowing AD progression, its findings suggest that such an approach may be feasible.

Most of the studies considered in the present review lacked neuropathological confirmation of the diagnosis of AD, so incorrect clinical diagnoses may have contributed to the conflicting results found for many factors. A review of cases from the National Alzheimer’s Coordinating Center, using neuropathological confirmation of AD as the gold standard, found that diagnostic sensitivity for AD ranged from 70.9%to 87.3%and diagnostic specificity ranged from 44.3%to 70.8%[433]. A further problem with the studies examined in the present review was that Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive subscale, and Clinical Dementia Rating scale-Sum of Boxes have limited sensitivity for assessing AD progression because of their ceiling and floor effects [434 –436].

It was not possible to examine the literature with respect to every factor which was suggested to contribute to AD progression. In particular Aβ and tau were not considered separately, and excitotoxicity, autophagy, the ubiquitin proteasome system, traumatic brain injury, and changes in the gut biome were not included, although these factors may well influence the rate of AD progression.

Examination of the associations of various factors with AD progression is confounded by the heterogeneous trajectories of its progression [201 , 437–439]. This heterogeneity has been ascribed to multiple factors including differences in underlying pathology, comorbidities, genetic variants, caregivers (family members versus professionals), medications, and living situations [201]. The heterogeneous trajectories of disease progression are a major confound in clinical trials with AD patients [239 , 440]. A further difficulty with examining the associations of different factors with AD progression is that the rate of cognitive decline in AD may not be the same in all stages of the disease [338 , 441–443].

An interesting finding was that some of the factors which are known to increase the risk for developing LOAD may not be associated with AD progression. For example, APOE ɛ4 is a recognized risk factor for LOAD, but studies of its association with disease progression have produced conflicting results. Some of the more than 20 gene variants that have been identified as risk factors for LOAD have not been reported, to date, to be associated with AD progression [285 , 444]. While rare TREM2 variants confer the same risk for LOAD as one copy of APOE ɛ4 [445], insufficient studies have been done to determine if the presence of these variants is associated with AD progression, although this was suggested in one study [292]. As concluded by Hoyt et al. [280] in a study of the relationship between APOE ɛ4 and AD progression, the biological processes which contribute to the development of AD may be different from those which determine its clinical course.

This review presented a summary of factors suggested in the literature to be associated with AD progression. Unlike earlier reviews, it included inflammation and oxidative stress. A drawback to this review is that the studies which were considered were limited to those found on PubMed, and the criteria for study selection did not involve rating of studies as would be done in a systematic review [446]. The decision was made to limit the literature search to PubMed because of the large numbers of citations identified (Table 2), acknowledging that some relevant studies may have been missed by not searching additional databases. Selecting 15 factors for review necessitated providing a summary, rather than an in-depth analysis, for each factor. This review was intended to be descriptive rather than quantitative, so the evidence for an association between each factor and AD progression was not subjected to statistical analysis as would be done in a meta-analysis. Performing a meta-analysis on this literature would have been problematic because of the different populations, different measures of progression effect, and different summary statistics in the studies that were evaluated. Further, the small numbers of studies that were found for some of the factors could have led to unreliable estimates of error for those factors [447].

CONCLUSIONS

This review of 15 factors which were suggested in the literature to be associated with the progression of AD found conflicting results for the majority of factors. However, such an association was found in nearly all studies which investigated the relationship of malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs to AD progression. Whether these or other factors which have been suggested to be associated with AD progression actually influence its rate of progression is unclear. A therapeutic approach which includes addressing of modifiable factors which may contribute to AD progression should be considered.

Footnotes

ACKNOWLEDGMENTS

Funding was provided by donations to the Beaumont Foundation to support Alzheimer’s research in the Beaumont Research Institute. Thanks are expressed to Mary Coffey, PhD and Robert Mrak, MD for helpful suggestions.

Authors’ disclosures available online ().

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