Alzheimer's Disease-related Neuropathology Research Articles

Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease.

Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson's disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer's disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson's disease and Alzheimer's disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson's disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer's disease co-pathology. In an ordinal logistic regression model, the Alzheimer's disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson's disease risk score and specific to the subset of samples without significant concomitant Alzheimer's disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson's and Alzheimer's disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer's disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

Association of Neighborhood-Level Disadvantage With Alzheimer Disease Neuropathology

Social determinants of health, such as income, education, housing quality, and employment, are associated with disparities in Alzheimer disease and health generally, yet these determinants are rarely incorporated within neuropathology research. To establish the feasibility of linking neuropathology data to social determinants of health exposures using neighborhood disadvantage metrics (the validated Area Deprivation Index) and to evaluate the association between neighborhood disadvantage and Alzheimer disease-related neuropathology. This cross-sectional study consisted of decedents with a known home address who donated their brains to 1 of 2 Alzheimer disease research center brain banks in California and Wisconsin between January 1, 1990, and December 31, 2016. Neither site had preexisting social metrics available for their decedents. Neuropathologic features were obtained from each site for data collected using the standardized Neuropathology Data Set form and from autopsy reports. Data were analyzed from June 7 to October 10, 2019. Geocoded decedent addresses linked to neighborhood disadvantage as measured by the Area Deprivation Index calculated for the year of death. Presence of Alzheimer disease neuropathology. The association between neighborhood disadvantage and Alzheimer disease neuropathology was evaluated via logistic regression, adjusting for age, sex, and year of death. The sample consisted of 447 decedents (249 men [56%]; mean [SD] age, 80.3 [9.5] years; median year of death, 2011) spanning 24 years of donation. Fewer decedents (n = 24 [5.4%]) originated from the top 20% most disadvantaged neighborhood contexts. Increasing neighborhood disadvantage was associated with an 8.1% increase in the odds of Alzheimer disease neuropathology for every decile change on the Area Deprivation Index (adjusted odds ratio, 1.08; 95% CI, 1.07-1.09). As such, living in the most disadvantaged neighborhood decile was associated with a 2.18 increased odds of Alzheimer disease neuropathology (adjusted odds ratio, 2.18; 95% CI, 1.99-2.39). The findings of this cross-sectional study suggest that social determinants of health data can be linked to preexisting autopsy samples as a means to study sociobiological mechanisms involved in neuropathology. This novel technique has the potential to be applied to any brain bank within the United States. To our knowledge, this is the first time Alzheimer disease neuropathology has been associated with neighborhood disadvantage.

LESS CONVERSION TO AD AND FEWER NEUROFIBRILLARY TANGLES IN MCI PATIENTS TAKING CERTAIN ANTIHYPERTENSIVES

With the projected increase in Alzheimer's disease (AD) prevalence, repurposing existing drugs generally recognized as safe, and show promise in AD studies, shortens the time to provide urgently needed treatment options. The renin-angiotensin system (RAS) regulates blood pressure, fluid homeostasis, and has been implicated in memory consolidation. Research suggests that antihypertensives that act via the RAS, may decrease AD risk, possibly via Aβ and/or tau. We previously reported that individuals taking RAS acting medications (ACE-Is or A2RBs), particularly those that are centrally acting, show slower cognitive decline and are less likely to progress from mild cognitive impairment (MCI) to AD over three years. However, the potential mechanism was unclear, due to the absence of neuropathological findings on these individuals. Here we test the hypothesis that individuals taking RAS acting antihypertensives may exhibit slower clinical disease progression and less AD related neuropathology than individuals taking non-RAS acting antihypertensives. Participants were older (M=83.1 years), 32% male, well educated (M=15.7 years) and 9.2% identified as Black. Males comprised a larger proportion of RAS users vs non-users (45% vs 20% for RAS users vs. non-RAS users, respectively). Groups did not differ in percent of ApoE4 positive individuals (28%) or Baseline MMSE score (M=26). While there were no group differences in blood pressure (M=138/72 mmHg), HDL (M=59mg/dL) or LDL (M=101 mg/dL), RAS users were more likely to be diabetic than non-RAS users (p=.01). Participants with MCI at Baseline who were taking a RAS medication were less likely to progress to AD than non-RAS users (p=.02). There were no group differences in brain weight, amyloid level, diffuse plaques, or NIA Reagan, Braak or CERAD scores. However, individuals taking RAS acting medications exhibited significantly fewer neurofibrillary tangles (NFT) than non-RAS users in brain regions including the hippocampal CA1 region (p<.01), entorhinal cortex (p=.04), and the average of tangles in the angular gyrus, inferior temporal, mid-frontal cortex and superior frontal (p=.03). Results suggest that prevention or clearance of NFTs via abnormal tau hyperphosphorylation represents a plausible mechanism by which RAS acting medications aid in slowing the progression from MCI to AD.

Clinical Assessment of Cognitive Decline in Adults with Down Syndrome.

Down syndrome is an intellectual disability requiring periodic monitoring of cognition given the near universal presence of Alzheimer's Disease related neuropathology and high rates of dementia in middle adulthood. We review current approaches to detecting decline in this population, including informant-based measures, dementia screening tools, and neuroimaging techniques. The challenges for detecting decline in this group are discussed, including the need to take into account premorbid cognitive function as well as medical comorbidity.

Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study

We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI). Participants included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex. Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002). Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease-related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury-PET abnormality findings in those with MCI.

African ancestry protects against Alzheimer's disease-related neuropathology.

Previous studies in dementia epidemiology have reported higher Alzheimer's disease rates in African-Americans when compared with White Americans. To determine whether genetically determined African ancestry is associated with neuropathological changes commonly associated with dementia, we analyzed a population-based brain bank in the highly admixed city of São Paulo, Brazil. African ancestry was estimated through the use of previously described ancestry-informative markers. Risk of presence of neuritic plaques, neurofibrillary tangles, small vessel disease, brain infarcts and Lewy bodies in subjects with significant African ancestry versus those without was determined. Results were adjusted for multiple environmental risk factors, demographic variables and apolipoprotein E genotype. African ancestry was inversely correlated with neuritic plaques (P=0.03). Subjects with significant African ancestry (n=112, 55.4%) showed lower prevalence of neuritic plaques in the univariate analysis (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.55–0.95, P=0.01) and when adjusted for age, sex, APOE genotype and environmental risk factors (OR 0.43, 95% CI 0.21–0.89, P=0.02). There were no significant differences for the presence of other neuropathological alterations. We show for the first time, using genetically determined ancestry, that African ancestry may be highly protective of Alzheimer's disease neuropathology, functioning through either genetic variants or unknown environmental factors. Epidemiological studies correlating African-American race/ethnicity with increased Alzheimer's disease rates should not be interpreted as surrogates of genetic ancestry or considered to represent African-derived populations from the developing nations such as Brazil.

RNA Oxidation Adducts 8-OHG and 8-OHA Change with Aβ42 Levels in Late-Stage Alzheimer's Disease

While research supports amyloid-β (Aβ) as the etiologic agent of Alzheimer's disease (AD), the mechanism of action remains unclear. Evidence indicates that adducts of RNA caused by oxidation also represent an early phenomenon in AD. It is currently unknown what type of influence these two observations have on each other, if any. We quantified five RNA adducts by gas chromatography/mass spectroscopy across five brain regions from AD cases and age-matched controls. We then used a reductive directed analysis to compare the RNA adducts to common indices of AD neuropathology and various pools of Aβ. Using data from four disease-affected brain regions (Brodmann's Area 9, hippocampus, inferior parietal lobule, and the superior and middle temporal gyri), we found that the RNA adduct 8-hydroxyguanine (8-OHG) decreased, while 8-hydroxyadenine (8-OHA) increased in AD. The cerebellum, which is generally spared in AD, did not show disease related changes, and no RNA adducts correlated with the number of plaques or tangles. Multiple regression analysis revealed that SDS-soluble Aβ42 was the best predictor of changes in 8-OHG, while formic acid-soluble Aβ42 was the best predictor of changes in 8-OHA. This study indicates that although there is a connection between AD related neuropathology and RNA oxidation, this relationship is not straightforward.

Investigation of Alzheimer's disease-related pathology in community dwelling older subjects who committed suicide

Background Older people have a higher risk of completed suicide than any other age group worldwide. The contribution of neurodegenerative disease to this risk remains controversial. Aims To investigate prevalence of Alzheimer's disease-related (AD) pathology in older suicide victims. Methods Ratings of AD pathology using Braak and CERAD protocols were compared in 143 community-dwelling suicide victims aged 65 years or more and 59 motor vehicle accident victims autopsied at the request of an Australian Coroner's Court. Results There were no significant differences in plaque score or neurofibrillary tangle staging between suicide and control groups. None of the subjects with a history of dementia had neuropathologically confirmed AD. Conclusions Our study is the second and largest investigation of the prevalence of AD neuropathology in the elderly suicide population. Unlike the previous study, we did not find an increased prevalence of AD neuropathology despite a history of dementia in 6.3%, implicating other pathologies such as Lewy Body or Vascular dementia in the aetiology of dementia in elderly suicide victims.

Age-dependent association between butyrylcholinesterase K-variant and Alzheimer disease-related neuropathology in human brains

The association between the K-variant of the butyrylcholinesterase gene (BCHE-K) and Alzheimer disease (AD) or AD-related neuropathology has been reported to date with conflicting results. Here, we determined in a sample of 521 cases the severity of AD-related neuropathology and the polymorphisms of both BCHE-K and apolipoprotein E (ApoE). Histopathologically, all brains were classified according to procedures permitting differentiation of the evolutionary stages of neurofibrillary tangles (NFTs) and amyloid-β-protein deposition (Aβ-deposits). The results show that the association between BCHE-K and AD-related neuropathology only was limited to homozygotes for the K allele ( P=0.036 for NFTs, and P=0.045 for Aβ-deposits) at ages ≥70 years but not 50–69 years. Furthermore, no interaction was apparent between BCHE-K and ApoE.

Neuropathology in the Down's syndrome brain

The presence of a specific amyloid β-protein in the brains of Down's syndrome patients suggests a common etiological pathway with the development of Alzheimer's disease-related neuropathology (pages 93–95).

Effects of intrahippocampal colchicine administration on the levels and localization of microtubule-associated proteins, tau and MAP2

Colchicine, a microtubule disrupting agent, has been used to model several aspects of Alzheimer's disease-related neuropathology. The formation of neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, involves the loss of tau (a low mol. wt. microtubule-associated protein) from axons and accumulation of abnormally phosphorylated tau in somatodendritic compartments. Other cytoskeletal proteins, such as microtubule-associated protein 2 (MAP2), disappear as tau accumulates. The present study was directed at evaluating the effects of colchicine on tau and MAP2, to determine if changes in their levels or distribution might be similar to those which precede the formation of neurofibrillary tangles in Alzheimer's disease. Six hours following intrahippocampal colchicine injection (3.5 μg injected into two rostro-caudal locations) tau-1 immunostaining was enhanced in CA1 s. radiatum and decreased in the outer molecular layer of the dentate gyrus. In addition, a shift in the relative abundance of tau isoforms was observed in Western blots. Both the immunocytochemical and immunoblot results are consistent with a dephosphorylation of tau. Loss of MAP2 was evident 3 days postinjection which coincided with a loss of Cresyl violet staining in granule cell, CA3, subicular and entorhinal neurons. Accumulation of tau or MAP2 in neuronal perikarya was not observed at any postinjection time points. Thus, intrahippocampal colchicine administration does not model the shift in tau localization, excessive tau phosphorylation, or other cytoskeletal alterations that are suggested to precede or accompany the formation of neurofibrillary pathology in Alzheimer's disease.