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

collaborators of the Alzheimer's Disease Genetics Consortium

doi:10.1002/ana.25918

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

collaborators of the Alzheimer's Disease Genetics Consortium

NIHR Maudsley Biomedical Research Centre (BRC)

Research output: Contribution to journal › Article › peer-review

83 Citations (Scopus)

Abstract

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 (Aβ₄₂), tau, and ptau₁₈₁, 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 2020.

Original language	English
Journal	Annals of Neurology
DOIs	https://doi.org/10.1002/ana.25918
Publication status	Accepted/In press - 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/ana.25918

Cite this

@article{84e8a2c20ab446e2a9a03b53f9d50c81,

title = "Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome",

abstract = "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 (Aβ42), tau, and ptau181, 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 2020.",

author = "{collaborators of the Alzheimer's Disease Genetics Consortium} and Andrews, {Shea J.} and Brian Fulton-Howard and Paul O'Reilly and Edoardo Marcora and Goate, {Alison M.} and Farrer, {Lindsay A.} and Haines, {Jonathan L.} and Richard Mayeux and Naj, {Adam C.} and Pericak-Vance, {Margaret A.} and Schellenberg, {Gerard D.} and Wang, {Li San}",

year = "2020",

doi = "10.1002/ana.25918",

language = "English",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome

AU - collaborators of the Alzheimer's Disease Genetics Consortium

AU - Andrews, Shea J.

AU - Fulton-Howard, Brian

AU - O'Reilly, Paul

AU - Marcora, Edoardo

AU - Goate, Alison M.

AU - Farrer, Lindsay A.

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Naj, Adam C.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard D.

AU - Wang, Li San

PY - 2020

Y1 - 2020

N2 - 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 (Aβ42), tau, and ptau181, 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 2020.

AB - 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 (Aβ42), tau, and ptau181, 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 2020.

UR - http://www.scopus.com/inward/record.url?scp=85095691159&partnerID=8YFLogxK

U2 - 10.1002/ana.25918

DO - 10.1002/ana.25918

M3 - Article

C2 - 32996171

AN - SCOPUS:85095691159

SN - 0364-5134

JO - Annals of Neurology

JF - Annals of Neurology

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this