ABSTRACTImportanceAlzheimer’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.ObjectiveWe 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≤5×10−8), 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 participants334,968 participants of the UK Biobank aged 39 to 72 years old (111,656 in each tertile) met our eligibility criteria.ExposuresStandardized weighted PRS for Alzheimer’s disease at p≤5×10−8.Main outcomes and measuresAll 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.ResultsGenetic liability for Alzheimer’s disease was associated with red blood cell indices and cognitive measures at all ages. In the middle and older age tertiles, ages 53 and above, higher genetic liability for Alzheimer’s disease was adversely associated with medical history (e.g. atherosclerosis, use of cholesterol-lowering medications), physical measures (e.g. body fat measures), blood cell indices (e.g. red blood cell distribution width), cognition (e.g. fluid intelligence score) and lifestyle (e.g. self-reported moderate activity). In follow-up analyses using MR, there was only evidence that education, fluid intelligence score, hip circumference, forced vital capacity, and self-reported moderate physical activity were likely to be causal risk factors for Alzheimer’s disease.Conclusion and relevanceGenetic liability for Alzheimer’s disease is associated with over 160 phenotypes, some as early as age 39 years. However, findings from MR analyses imply that most of these associations are likely to be a consequence of prodromal disease or selection, rather than a cause of the disease.QuestionHow does higher genetic liability for Alzheimer’s disease affect the phenome across the life course and do any phenotypes causally affect incidence of disease?FindingIn this population-based cohort study of 334,968 participants, higher genetic risk for Alzheimer’s disease was associated with medical history (e.g. higher odds of diagnosis of atherosclerotic heart disease), cognitive (e.g. lower fluid intelligence score), physical (e.g. lower forced vital capacity) and blood-based measures (e.g. lower haematocrit) as early as 39 years of age.MeaningMost of the identified phenotypes are likely to be symptoms of prodromal Alzheimer’s disease, rather than causal risk factors.
The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
