Loneliness, cerebrovascular and Alzheimer's disease pathology, and cognition

INTRODUCTION Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts ( N = 680; 89 ± 9 years old; 25% dementia) to the US‐representative Health and Retirement Study ( N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross‐sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. Highlights Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition–neuropathology associations. Transportability methods can provide insight into selection bias.