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Assessment of the contribution of common genetic variants associated with Alzheimer’s disease on neuropathological burden and clinical characteristics in the Brains for Dementia Research cohort
Author(s) -
Han Eilis,
Brookes Keeley J.,
Shireby Gemma,
Attems Johannes,
Sims Rebecca,
Cairns Nigel J.,
Morgan Kevin,
Thomas Alan J.,
Francis Paul T.,
Mill Jonathan
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042868
Subject(s) - neuropathology , apolipoprotein e , dementia , tauopathy , cohort , oncology , genetic epidemiology , alzheimer's disease , genome wide association study , cerebral amyloid angiopathy , epidemiology , medicine , psychology , disease , genotype , biology , genetics , single nucleotide polymorphism , neurodegeneration , gene
Background 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 (AD). Individually these variants confer only a small increase on an individual’s overall risk; however, combined into a polygenic risk score (PRS), they represent a powerful tool in genetic epidemiology for the investigation of correlates of high genetic risk. We investigated the clinical and neuropathological outcomes associated with high PRS for AD in the Brains for Dementia Research (BDR) cohort. Method 693 individuals in the BDR cohort with high quality genetic data and neuropathology measurements, including staging assessments (Braak and Thal) and established diagnostic criteria were included in this study. PRS were calculated for each individual as the number of genetic risk alleles, weighted by the log odds ratio, using the results of the largest available GWAS of AD. Statistical analysis was performed using regression models whilst controlling for age at death, sex and brain bank. Result We report statistically significant associations between APOE genotype and Braak neurofibrillary tangle stage, a measure of tauopathy, and Thal stage, a measure of Aβ plaque propagation. We also found significant associations between AD PRS and multiple measures of neuropathology (Braak stage, Thal stage, Lewy body stage, and severe cerebral amyloid angiopathy). In order to determine if APOE and AD PRS represent independent predictors of tauopathy (Braak stage) and b‐amyloidosis (Thal stage), we performed a joint analysis finding that APOE and PRS combine in an additive manner to influence both measures of neuropathology. Conclusion The results from this study characterise how genetic risk for AD influence both the clinical and pathological features of dementia and increases our understanding of the interaction between APOE status and other genetic risk factors.