Abstract
Abstract Background Potentially modifiable risk factors have been associated with Alzheimer’s disease (AD). However, the causality of these risk factors on AD is unclear. Using Mendelian randomization we evaluated the causal effect of potentially modifiable risk factors on AD and its associated endophenotypes to inform the development of lifestyle interventions that could reduce risk of developing AD. Methods and Findings Genetic instruments for the exposures were selected from genome wide association studies (GWAS) for traits previously linked to AD in observational studies including alcohol intake, physical activity, lipid traits, blood pressure traits, type 2 diabetes, body-mass index (BMI), depression, sleep, social isolation, smoking, oily fish intake, and educational attainment. The outcomes included AD status, AD age of onset survival (AAOS), hippocampal volume, CSF levels of Aβ 42 , tau, and ptau 181 , and neuropathological burden of neuritic plaques, neurofibrillary tangles, and vascular brain injury (VBI). MR estimates were calculated using an inverse variance weighted approach. Genetically predicted educational attainment (OR [CI]: 0.7 [0.63, 0.78]), diastolic blood pressure (DBP) (OR [CI]: 0.99 [0.98, 0.99]), systolic blood pressure (SBP) (OR [CI]: 0.99 [0.99, 1]) and physical activity (OR [CI]: 2.5 [1.47, 4.23]) were causally associated with AD risk. Genetically predicted BMI (HR [CI]: 1.13 [1.07, 1.2]) and educational attainment (HR [CI]: 0.74 [0.68, 0.82]) were causally associated with AAOS. Genetically predicted alcohol consumption (β [CI]: −0.15 [−0.25, −0.05]), broad depressive symptoms (β [CI]: 0.5 [0.2, 0.8]), major depressive disorder (β [CI]: 0.12 [0.05, 0.18]) and physical activity were causally associated with CSF Aβ 42 (β [CI]: 0.25 [0.1, 0.39]). Genetically predicted DBP was causally associated with CSF total Tau (β [CI]: −0.005 [−0.007, −0.002]). Increased risk of VBI were observed for genetically predicted DBP (OR [CI]: 1.05 [1.02, 1.08]), SBP (OR [CI]: 1.06 [1.03, 1.1]), and pulse pressure (OR [CI]: 1.03 [1.01, 1.05]). Increased risk of neuritic plaque burden were observed for genetically predicted LDL-cholesterol (OR [CI]: 1.87 [1.3, 2.69]) and total cholesterol (OR [CI]: 2.03 [1.44, 2.85]). Genetically predicted insomnia symptoms (β [CI]: −0.2 [−0.34, −0.06]) and total cholesterol were associated (β [CI]: −0.06 [−0.1, −0.03]) with hippocampal volume. Potential limitations include weak instrument bias, non-homogenous samples and other implicit limitations of MR analysis. Conclusions Demonstration of a causal relationship between blood pressure, cholesterol levels, BMI, depression, insomnia symptoms, physical activity and educational attainment on the AD phenome strongly support public health programs to educate the public about these preventable causes of AD.