Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.
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ABSTRACT: Introduction
Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes.Methods
We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI).Results
The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants.Discussion
The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.
SUBMITTER: Deming Y
PROVIDER: S-EPMC10427737 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Publications
Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.
Deming Yuetiva Y Vasiljevic Eva E Morrow Autumn A Miao Jiacheng J Van Hulle Carol C Jonaitis Erin E Ma Yue Y Whitenack Vanessa V Kollmorgen Gwendlyn G Wild Norbert N Suridjan Ivonne I Shaw Leslie M LM Asthana Sanjay S Carlsson Cynthia M CM Johnson Sterling C SC Zetterberg Henrik H Blennow Kaj K Bendlin Barbara B BB Lu Qiongshi Q Engelman Corinne D CD
Alzheimer's & dementia : the journal of the Alzheimer's Association 20230216 8
<h4>Introduction</h4>Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes.<h4>Methods</h4>We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE va ...[more]
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Project description:The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor of Alzheimer's disease (AD) but does not account for the entirety of genetic risk. Genetic risk scores (GRSs) incorporating additional genetic variants have been developed to determine the genetic risk for AD, yet there is no systematic review assessing the contribution of GRSs for AD beyond the effect of APOE ε4. The purpose of this systematic PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses)-based review was to summarize original research studies that have developed and validated a GRS for AD utilizing associated single nucleotide polymorphisms (SNPs). The PubMed and Web of Science databases were searched on April 6, 2018 and screening was completed on 2018 citations by two independent reviewers. Eighteen studies published between 2010 and 2018 were included in the review. All GRSs expressed significant associations or discrimination capability of AD when compared to clinically normal controls; however, GRS prediction of MCI to AD conversion was mixed. APOE ε4 status was more predictive of AD than the GRSs, although the GRSs did add to AD prediction accuracy beyond APOE ε4. GRSs might contribute to identifying genetic risk of AD beyond APOE. However, additional studies are warranted to assess the performance of GRSs in independent longitudinal cohorts.
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Project description: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 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, β-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 ε4 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 ε4, one where β-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between APOE ε4 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 β-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.
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