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Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

ABSTRACT: Alzheimer's disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of ?-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research study to understand how genetic risk factors for Alzheimer's disease influence the development of neuropathology and clinical performance. Six hundred and ninety-three donors in the Brains for Dementia Research cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of APOE genotype and Alzheimer's disease polygenic risk score-a quantitative measure of genetic burden-with survival, four common neuropathological features in Alzheimer's disease brains (neurofibrillary tangles, ?-amyloid plaques, Lewy bodies and transactive response DNA-binding protein 43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The APOE ?4 allele was significantly associated with younger age of death in the Brains for Dementia Research cohort. Our analyses of neuropathology highlighted two independent pathways from APOE ?4, one where ?-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of ?-amyloidosis. Although we also detected association between APOE ?4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and ?-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer's disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer's disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between APOE genotype and other genetic risk factors.

SUBMITTER: Hannon E

PROVIDER: S-EPMC7750986 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

Hannon Eilis E Shireby Gemma L GL Brookes Keeley K Attems Johannes J Sims Rebecca R Cairns Nigel J NJ Love Seth S Thomas Alan J AJ Morgan Kevin K Francis Paul T PT Mill Jonathan J

Brain communications 20201012 2

Alzheimer's disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the <i>APOE</i> locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clin ...[more]

PMID: 33376986

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Project description:BackgroundMitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function.ObjectiveThe objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.MethodsWe employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions.ResultsUsing the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ).ConclusionsOur results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

Publications

Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

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