Association of loneliness, social isolation, and neuroticism in Alzheimer’s disease risk:  a two-step Mendelian randomization study

Alzheimer's disease (AD) is a significant global health concern, yet psychosocial factors and human behaviours with the potential to influence genetic factors and dementia risk remain largely underexplored. We employed a two-sample Mendelian randomization (MR) approach to investigate the causality of genetically determined loneliness and social isolation in neuropsychiatric symptoms and AD. We uncovered a potentially causal link between loneliness and social isolation with AD, facilitated by a two-step progression involving neuroticism. Our findings also highlight the effects of a healthy and physically engaged lifestyle which may ameliorate the risk of depressive symptoms, but not neuroticism on AD risk. The enduring influence of personality traits, particularly neuroticism, suggests personalized and pharmacological approaches for managing disease outcomes. Finally, we identified two significant gene networks and six genes (PAFAH1B1, GRM5, GNAO1, NFIA, CNTN5, and PROX2) warranting further functional studies in developing therapeutics for AD risk. This paper provides the first genetically informed evidence that reducing loneliness and social isolation may play a causal role in decreasing the risk of AD, and these findings support efforts to reduce loneliness and social isolation to prevent or ameliorate AD, particularly relevant given the long-term effects of the COVID-19 pandemic on mental health.