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Causal associations between potentially modifiable risk factors and the Alzheimer's phenome: A Mendelian randomization study

By Shea J. Andrews, Brian Fulton-Howard, Paul F O'Reilly, Lindsay A. Farrer, Jonathan L. Haines, Richard P. Mayeux, Adam C. Naj, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Li-San Wang, Edoardo Marcora, Alison M Goate

Posted 02 Jul 2019
bioRxiv DOI: 10.1101/689752

Objective: To evaluate the causal association of 22 previously reported risk factors for Alzheimer's disease (AD) on the "AD phenom": AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of AB42, tau, and ptau181, and the neuropathological burden of neuritic plaques, neurofibrillary tangles, 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 was used to evaluate 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. PRS for increased total cholesterol and moderate-vigorous physical activity were associated with an increased risk of 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, while 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 and BMI with decreased cortical thickness; and sleep duration with increased cortical thickness. Interpretation: Our comprehensive examination of the genetic evidence for the causal roles of previously reported risk factors in AD using PRS and MR, supports a causal role for education, blood pressure, cholesterol levels, smoking, and BMI with the AD phenome. ### Competing Interest Statement The authors have declared no competing interest.

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