Background and Objectives - With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD. Methods - We designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. Results - We identified 196 sites that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [RBFOX1], p = 0.04; 4:21788463 [KCNIP4], p < 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [KCNQ5], p = 0.01 and 13:36667102 [DCLK1], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term “vocalization behavior” and “intraspecies interaction between organisms.” Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes. Discussion - Our results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.@en

A remarkable accomplishment of human beings in recent centuries is the extension of their average lifespan, for example by improved living conditions. A downside of this achievement is that aging-related diseases, such as Alzheimer’s disease (AD), have risen, and as a consequence are impacting the lives of an increasing fraction of individuals. Although many conclude that aging is the main risk factor for AD, it might be better to say AD is one facet of aging. Indeed, the boundaries between brain aging and AD are largely fluent in the elderly. Nevertheless, dementia and AD are not inevitable. In fact, a small proportion of the population (<0.1%) reaches at least 100 years old while maintaining to have a healthy cognition. These rare but remarkable centenarians could shed light on how to escape age-related diseases. This thesis studies cognitive healthy centenarians as extreme controls in the context of aging and AD. Based on a large cohort of data, this thesis indeed shows that some centenarians escaped the buildup of some neuropathologies, indicating resistance to these neuropathologies. Contrarily, this thesis also shows that average levels of AD-associated neuropathologies increase with age in non-demented individuals, whereas these neuropathologies decrease with age in AD cases. Most intriguingly, this thesis shows that some centenarians with the highest cognitive performance, did accumulate the highest levels of some neuropathologies, yet remained cognitive healthy. This thesis then speculates that these observations point towards a resilience to these neuropathologies by these centenarians. To better understand the resilience and resistance mechanisms in centenarian brains, this thesis then continues with investigating brain proteomics in the context of the degree of AD pathology (Braak stages) as well as age. As a first characterization, clusters of Braak stage-related and age-related proteins are identified that separately are associated with specific biological processes. Some Braak stage-related proteins demonstrate a deviated abundance in centenarians compared to AD (at the Braak stage IV), indicating that these proteins may contribute to the resilient mechanisms of tau accumulation in centenarian brains. A remarkable finding regarding the age-related proteins is that centenarian brains are, in a median of, 18-years “younger" in their protein expression, when compared with non-demented controls, again hinting towards a resilience to age-related diseases. To further explore the possible role of aging behind AD, this thesis studies the extend and locations of brain somatic mutations. We show that the number of excitatory neuron specific-somatic mutations increases with age, but there is no significant difference between AD and non-demented individuals. Interestingly, certain somatic mutations occurred more frequently in the brains of AD patients. Concluding, this thesis demonstrates the value of cognitive healthy centenarians in studying brain aging and neurodegenerative diseases. In doing so, it reveals that the relationship between brain aging and neurodegeneration is extremely complex and deeply entangled. Nevertheless, basic processes that are altered during brain aging are identified, which brings targets to counteract the molecular disorder that leads to neurodegeneration, including AD, closer.@en

INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance?. METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian brains, we explored the correlations between the levels of 11 neuropathological substrates with ante mortem performance on 12 neuropsychological tests. RESULTS: Levels of neuropathological substrates varied: we observed levels up to Thal-amyloid beta phase 5, Braak-neurofibrillary tangle (NFT) stage V, Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-neuritic plaque score 3, Thal-cerebral amyloid angiopathy stage 3, Tar-DNA binding protein 43 (TDP-43) stage 3, hippocampal sclerosis stage 1, Braak-Lewy bodies stage 6, atherosclerosis stage 3, cerebral infarcts stage 1, and cerebral atrophy stage 2. Granulovacuolar degeneration occurred in all centenarians. Some high performers had the highest neuropathology scores. DISCUSSION: Only Braak-NFT stage and limbic-predominant age-related TDP-43 encephalopathy (LATE) pathology associated significantly with performance across multiple cognitive domains. Of all cognitive tests, the clock-drawing test was particularly sensitive to levels of multiple neuropathologies.

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Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD-associated neuropathologies?. Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years. Results: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16). Discussion: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates. Highlights: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.

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