Mendelian randomization reveals that Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and vascular dementia affect human lifespan and mediate the impact of modifiable risk factors on lifespan

As the global population continues to age and dementia prevalence rises, elucidating the potential connection between dementia and longevity has become an increasingly critical area of research. While prior observational studies have suggested an association between dementia and a shortened lifespan, the causal relationship remains poorly understood. Mendelian randomization (MR) employs genetic variation to infer causality between exposures and outcomes. We conducted a MR study to investigate the causal effects of Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and vascular dementia (VD) on longevity. Besides, we performed network MR analysis to examine the mediating roles of dementia in the causal chain linking modifiable risk factors to lifespan. Our study indicates that AD, LBD, and VD are associated with a reduction in human lifespan. Network MR revealed that elevated low-density lipoprotein cholesterol (LDL-C) and lower educational attainment (EA) had detrimental effects on lifespan through increasing AD risk, whereas hypertension and T2DM had detrimental effects on lifespan through increasing VD risk. It may be beneficial to adopt a more proactive approach to managing cognitive function in individuals with hypertension, diabetes, elevated LDL-C levels, and low EA, as this could contribute to improved longevity outcomes.