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Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome.

TitleCausal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome.
Publication TypeJournal Article
Year of Publication2021
AuthorsAndrews SJ, Fulton-Howard B, O'Reilly P, Marcora E, Goate AM
Corporate Authorscollaborators of the Alzheimer's Disease Genetics Consortium
JournalAnn Neurol
Date Published2021 01
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Brain, Cholesterol, Cognition, Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles, Peptide Fragments, Risk Factors, Sleep

OBJECTIVE: The purpose of this study was to infer causal relationships between 22 previously reported risk factors for Alzheimer's disease (AD) and the "AD phenome": AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of amyloid-β (Aβ ), tau, and ptau , and the neuropathological burden of neuritic plaques, neurofibrillary tangles (NFTs), and vascular brain injury (VBI).
METHODS: Polygenic risk scores (PRS) for the 22 risk factors were computed in 26,431 AD cases/controls and the association with AD was evaluated using logistic regression. Two-sample Mendelian randomization (MR) was used to infer the causal effect of risk factors on the AD phenome.
RESULTS: PRS for increased education and diastolic blood pressure were associated with reduced risk for AD. MR indicated that only education was causally associated with reduced risk of AD, delayed AAOS, and increased cortical surface area and thickness. Total- and LDL-cholesterol levels were causally associated with increased neuritic plaque burden, although the effects were driven by single nucleotide polymorphisms (SNPs) within the APOE locus. Diastolic blood pressure and pulse pressure are causally associated with increased risk of VBI. Furthermore, total cholesterol was associated with decreased hippocampal volume; smoking initiation with decreased cortical thickness; type 2 diabetes with an earlier AAOS; and sleep duration with increased cortical thickness.
INTERPRETATION: Our comprehensive examination of the genetic evidence for the causal relationships between previously reported risk factors in AD using PRS and MR supports a causal role for education, blood pressure, cholesterol levels, smoking, and diabetes with the AD phenome. ANN NEUROL 2021;89:54-65.

Pubmed Link
Alternate JournalAnn Neurol
PubMed ID32996171
PubMed Central IDPMC8088901
Grant ListRC2 AG036528 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
K99 AG070109 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
R01 MH122866 / MH / NIMH NIH HHS / United States
MR/N015746/1 / MRC_ / Medical Research Council / United Kingdom
U01 AG058635 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States

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