Journal of Alzheimer's Disease Reports

It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta-analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients.

Alzheimer’s disease (AD) is the most common form of dementia and there is no successful treatment available. Evidence suggests that fibril formation of the amyloid β-peptide (Aβ) is a major underlying cause of AD, and treatment strategies that reduce the toxic effects of Aβ amyloid are sought for. The BRICHOS domain is found in several proteins, including Bri2 (also called integral membrane protein 2B (ITM2B)), mutants of which are associated with amyloid and neurodegeneration, and Bri3 (ITM2C). We have used mouse hippocampal neurons and brain tissues from mice and humans and show Bri3 deposits dispersed on AD plaques. In contrast to what has been shown for Bri2, Bri3 immunoreactivity is decreased in AD brain homogenates compared to controls. Both Bri2 and Bri3 BRICHOS domains interact with Aβ₄₀ and Aβ₄₂ present in neurons and reduce Aβ₄₂ amyloid fibril formation in vitro, but Bri3 BRICHOS is less efficient. These results indicate that Bri2 and Bri3 BRICHOS have different roles in relation to Aβ aggregation.

Amyloid-β (Aβ) peptides can be aggregated into β-sheet rich fibrils or plaques and deposited on the extracellular matrix of brain tissues, which is a hallmark of Alzheimer’s disease. Several drug candidates have been designed to retard the progression of the neurodegenerative disorder or to eliminate toxic Aβ aggregates. Recently, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) has emerged as a promising drug candidates for elimination of toxic Aβ aggregates. However, the effect of EPPS on the degradation of Aβ aggregates such as fibrils has not yet been fully elucidated. In this article, we investigate the EPPS-driven degradative behavior of Aβ aggregates at the molecular level by using high-resolution atomic force microscopy. We synthesized Aβ fibrils and observed degradation of fibrils following treatment with various concentrations (1–50 mM) of EPPS for various time periods. We found that degradation of Aβ fibrils by EPPS increased as a function of concentration and treatment duration. Intriguingly, we also found regeneration of Aβ aggregates with larger sizes than original aggregates at high concentrations (10 and 50 mM) of EPPS. This might be attributed to a shorter lag phase that facilitates reformation of Aβ aggregates in the absence of clearance system.

A 66-year-old woman presented with slowly progressive cognitive decline. MRI showed bi-frontotemporal atrophy, but the 14.3.3 protein was not present in cerebrospinal fluid. Electroencephalogram was irrelevant. Interview with relatives led doctors to search for a genetic cause and confirmed the diagnosis of Gerstmann–Sträussler–Scheinker syndrome.

There is evidence demonstrating that 5-mg of fast-release melatonin significantly reduces nocturnal sleep onset in patients with mild-to-moderate Alzheimer’s disease (AD). However, the physiological mechanism that could promote sleep installation by melatonin in patients with AD is still poorly understood. The present pilot study was designed to analyze the effects of melatonin on cortical activity during the sleep onset period (SOP) in eight mild-to-moderate AD patients treated with 5-mg of fast-release melatonin. Electroencephalographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4, and O1-O2. The relative power (RP), interhemispheric, intrahemispheric, and fronto-posterior correlations of six electroencephalographic bands were calculated and compared between two conditions: placebo and melatonin. Results show that at F7-T3, F3-F4, and C3-A1, melatonin induced an increase of the RP of the delta band. Likewise, in F7-T3, melatonin induced a decrease of the RP in the alpha1 band. Similarly, results show a lower interhemispheric correlation between the F7-T3 and F8-T4 derivations in the alpha1 band compared to the placebo condition. We conclude that the short sleep onset related to melatonin intake in AD patients was associated with a lower RP of the alpha1, a higher RP of the delta band (mainly in the left hemisphere) and a decreased interhemispheric EEG coupling in the alpha1 band. The possible role of the GABAergic neurotransmission as well as of the cascade of neurochemical events that melatonin triggers on sleep onset are discussed.

Alzheimer’s disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro. We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable.

Older adults engaging in regular physical activity can help create a buffer toward cognitive decline. The main aim of this study was to assess the effects of physical activity and cognitive functioning on a sample of young-old and old-old physically active adults and young-old and old-old sedentary adults. Cognitive functioning was examined using the digit span test, Wisconsin card sorting task. The National Task Group-Early Detection Screen for Dementia measure was used explore the relationship between scores and physical activity and sedentary adults. Findings from the study showed partial support for physical activity has a positive relationship with cognitive functioning. The results found Young-old adults did better on the DST than all other groups regardless of being sedentary or physically active. Young-old physically active adults, however, did better on the DST latency measure than sedentary adults while old-old physically active adults did worse on the DST latency measure compared with old-old sedentary adults. The results also found that Physically active adults had a better score on the NTG-EDSD measure compared to the sedentary adults. Findings showed no significant differences for the WCST. Future research exploring the relationship between physical activity and cognitive functioning should do so by having more control over the extraneous variables.

Genetic factors may be involved in the onset of neurodegenerative diseases like Alzheimer’s disease. In the case of the familial type, the disease is due to an inherited mutation at specific sites in three genes. Also, there are some genetic risk factors that facilitate the development of sporadic Alzheimer’s disease. All of these genetic analyses were performed using blood samples as a source of DNA. However, the presence of somatic mutations in the brain can be identified only using brain samples. In this review, we comment on a method that correctly identifies single nucleotide variations in the human brain and that can be used to validate high-through sequencing techniques. This method involves selective enrichment of the DNA population bearing the nucleotide variations, thereby facilitating posterior validation of the data by Sanger’s sequencing.

Although inappropriate sexual behavior in dementia is not common, it can be extremely troublesome for healthcare professionals and caregivers as well as patients themselves. There is paucity of data in the literature for the management of these behaviors, but the limited available data suggest efficiency of some commonly used treatment modalities. Herein, we present a 74-year old Alzheimer’s disease (AD) patient, known to be heterosexual throughout her past life, presenting with a recent display of same-sex inappropriate sexual behavior six years after the initial diagnosis of her disease. This new clinical picture of hypersexuality responded well to aripiprazole and her symptoms gradually diminished and eventually disappeared after onset of medication. This report also constitutes the first reported case of an AD patient in the published literature presenting with hypersexuality of shifted sexual orientation during the course of the disease.

Various fungi and bacteria can colonize in the brain and produce physical alterations seen in Alzheimer’s disease (AD). Environmental and genetic factors affect the occurrence of fungal colonization, and how fungi can grow, enter the brain, and interact with the innate immune system. The essence of AD development is the defeat of the innate immune system, whether through vulnerable patient health status or treatment that suppresses inflammation by suppressing the innate immune system. External and mechanical factors that lead to inflammation are a door for pathogenic opportunity. Current research associates the presence of fungi in the etiology of AD and is shown in cerebral tissue at autopsy. From the time of the discovery of AD, much speculation exists for an infective cause. Identifying any AD disease organism is obscured by processes that can take place over years. Amyloid protein deposits are generally considered to be evidence of an intrinsic response to stress or imbalance, but instead amyloid may be evidence of the innate immune response which exists to destroy fungal colonization through structural interference and cytotoxicity. Fungi can remain ensconced for a long time in niches or inside cells, and it is the harboring of fungi that leads to repeated reinfection and slow wider colonization that eventually leads to a grave outcome. Although many fungi and bacteria are associated with AD affected tissues, discussion here focuses on Candida albicans as the archetype of human fungal pathology because of its wide proliferation as a commensal fungus, extensive published research, numerous fungal morphologies, and majority proliferation in AD tissues.

In spite of compelling evidence linking amyloid-β (Aβ) disturbances to the pathophysiology of Alzheimer’s disease (AD), Aβ-based treatments have consistently failed to produce any beneficial effects both in mild cognitive impairment (MCI) and AD, even with successful reductions of toxic aggregated and soluble Aβ species. Before abandoning both the hypothesis and approach, there is a need to examine some overlooked factors that may have contributed to the lack of efficacy, such as the potential drug-induced increases in neuronal hyperactivity leading to adverse cognitive effects. In particular, we posit that selective cholinergic and noradrenergic pathways will be especially vulnerable to this adverse effect. If confirmed, this idea could help identify a potentially preventable and treatable obstacle for enhancing the efficacy of therapeutic agents in MCI and AD.

Strategies to achieve a therapy for Alzheimer’s disease (AD) aimed at reducing the effects of amyloid-β (Aβ) have largely involved inhibiting or modifying the activities of the β- or γ-secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Aβ in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-β protein precursor (AβPP) and did not affect the catalytic activities of β- or γ-secretase, or the level of AβPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate.

Aβ₄₀ and Aβ₄₂ peptides are believed to be associated with Alzheimer’s disease. Aggregates (plaques) of Aβ fibrils are found in the brains of humans affected with this disease. The mechanism of formation of Aβ fibrils has not been studied completely, which hinders the development of a correct strategy for therapeutic prevention of this neurodegenerative disorder. It has been found that the most toxic samples upon generation of fibrils are different oligomeric formations. Based on different research methods used for studying amyloidogenesis of Aβ₄₀ and Aβ₄₂ peptides and its amyloidogenic fragments, we have proposed a new mechanism of formation of amyloid fibrils. In accord with this mechanism, the main building unit for fibril generation is a ring-like oligomer. Association of ring-like oligomers results in the formation of fibrils of different morphologies. Our model implies that to prevent development of Alzheimer’s disease a therapeutic intervention is required at the earliest stages of amyloidogenesis—at the stage of formation of ring-like oligomers. Therefore, the possibility of a personified approach for prevention not only of Alzheimer’s disease development but also of other neurodegenerative diseases associated with the formation of fibrils is argued.

Executive function was assayed following a nutritional supplementation in healthy adults using the Trail Making Test. Comparison with published normative scores demonstrated that cohorts from 35–74 years of age displayed similar relative improvement compared to their own baseline performance. These findings support early, pro-active lifestyle modifications to maintain cognitive performance during aging and further demonstrate the persistence of cognitive reserve in healthy older adults.

We set out to investigate the insights general practitioners (GPs) have into the early signs and symptoms of Alzheimer’s disease (AD), factors that may be responsible for the late diagnosis, as well as their recommendations for early diagnosis of AD. This was a semi-structured, qualitative and audio-recorded interview of seven GPs, from five GP surgeries in Milton Keynes and Luton, using the framework analysis. GPs reported challenges with the current patient’s consultation time, a lack of continuity of care, inadequate training, limited support for patients after diagnosis, and poor treatment of the UK’s aging population. The study highlights important changes that would facilitate the earlier diagnosis of AD.

Our research into Alzheimer’s disease (AD) focuses on the oral cavity and the brain, from which key evaluations of prospective and retrospective population-based data have shown that chronic periodontal disease existing for ten-years or over doubles the risk for the sporadic form of AD. Furthermore, Porphyromonas gingivalis (P. gingivalis) mono-infections in established periodontal lesions, or introducing its lipopolysachharide (LPS), as demonstrated in in vivo studies, show hallmark pathology inclusive of extracellular amyloid plaques and phospho-tau bound neurofibrillary tangles with AD-like phenotype. Other studies have shown that if periodontitis remains untreated in human AD patients, cognitive decline ensues. This is a bi-directional relationship meaning that the converse is also true; treating periodontal disease in AD patients improves memory. Bacterial cultures and established oral biofilms generate vast numbers of microvesicles and P. gingivalis outer membrane vesicles encase key virulence factors (LPS, gingipains, capsule, fimbriae) as though they are complete destructive “microbullets” when shed in the host. This provides P. gingivalis additional arsenal to manipulate its entry into disparate organs, hijack phagocytosis, destroy tissues, and affect complement related genes while transducing the onset of proinflammatory signaling cascades. The resulting inflammatory mediators may be the cause of disease defining lesions and cognitive decline typical of clinical AD.

Plaque formation due to amyloid-β oligomerization and fibrillation is a key issue for its deposition in the brains of dementia and Alzheimer’s disease patients. Related drugs preventing this peptide fibril accumulation bear the potential of considerable medical and social value. In this study, we performed in vitro fibrillation inhibition tests with eight different medical plant extracts and nutraceuticals using fluorescence spectroscopy. Successful inhibition of the following plant extracts and nutraceuticals were obtained: Withania somnifera, Centella asiatica, Bacopa monnieri, and Convolvulus pluricaulis, providing new drug candidates for the prevention and treatment of Alzheimer’s disease.