The causes and consequences of Alzheimer's disease: phenome-wide evidence from Mendelian randomization

MedRxiv : the Preprint Server for Health Sciences
Roxanna Korologou-LindenNeil M Davies


Importance Alzheimer's disease is the leading cause of disability and healthy life years lost. However, to date, there are no proven causal and modifiable risk factors, or effective interventions. Objective We aimed to identify: a) factors modified by prodromal Alzheimer's disease pathophysiology and b) causal risk factors for Alzheimer's disease. We identified factors modified by Alzheimer's disease using a phenome-wide association study (PheWAS) on the Alzheimer's disease polygenic risk score (PRS) (p[≤]5x10-8), stratified by age tertiles. We used two-sample bidirectional Mendelian randomization (MR) to estimate the causal effects of identified risk factors and correlates on liability for Alzheimer's disease. Design, setting, and participants 334,968 participants of the UK Biobank aged 39 to 72 years old (111,656 in each tertile) met our eligibility criteria. Exposures Standardized weighted PRS for Alzheimer's disease at p[≤]5x10-8. Main outcomes and measures All available phenotypes in UK Biobank, including data on health and lifestyle, as well as samples from urine, blood and saliva, at the time of analysis. Results Genetic liability for Alzheimer's disease was associated with red blood cell indices and cognitive meas...Continue Reading

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