The current research framework recommends using biomarkers to further understand Alzheimer’s disease (AD) pathogenesis, including other contributing factors like cerebrovascular disease. In longitudinal studies of people with neuropathological examination after death, baseline loneliness was associated with lower cognition, faster cognitive decline, and future AD risk, independent of AD pathology. Examination of memory impairment along with AD and cerebrovascular biomarkers, could aid risk reduction efforts earlier in the lifecourse and among populations with more exposure to loneliness. We hypothesized that loneliness is associated with amyloid, vascular, and neurodegeneration biomarkers; with worse memory; and that loneliness increases the susceptibility to biomarker-related memory impairment.

A subset of cognitively unimpaired older adults with available amyloid PET, vascular MRI (white matter hyperintensity volume, WMH), structural MRI (cortical thickness in AD signature regions), neuropsychological testing (memory factor score), dichotomized loneliness data (one item from CES-D), and relevant medical data were drawn from the community-based Washington Heights-Inwood Columbia Aging Project (WHICAP; n=169; covariates included age=81±6 years; 63% women; 49/31/20% Non-Hispanic Black/Non-Hispanic White/Hispanic; education=13±4 years; 32% APOE-e4 carriers). General linear models in the overall sample and stratified by race and ethnicity tested the association between loneliness and AD and cerebrovascular biomarkers, loneliness and memory, and the interaction of loneliness and biomarkers on memory, adjusting for covariates.

Loneliness was endorsed in 18% of participants, marginally associated with older age (2.1 [-0.2, 4.4], p=0.08), was more likely in those with untreated diabetes (13/0.1% lonely/not lonely, p=0.001), associated with lower cortical thickness (-0.05 [-0.09, -0.02], p=0.01), and associated with lower memory (0.3 [-0.6, -0.001], p=0.05). In Non-Hispanic White participants, loneliness was associated with greater WMH volume (0.5 [0.07, 0.82], p=0.03), while in Hispanic participants, loneliness was associated with lower cortical thickness (-0.16 [-0.24, -0.08], p=0.0006). In Non-Hispanic Black participants, loneliness was associated with lower memory (-13 [-26, -0.5], p=0.05), and the association between lower cortical thickness and lower memory was stronger in those that endorse loneliness (5 [0.2, 10], p=0.05). In Hispanic participants, loneliness was associated with higher memory (13 [4, 22], p=0.009), but the association between higher amyloid burden and lower memory was stronger in those that endorse loneliness (-12 [-20, -4], p=0.006); further, loneliness was marginally associated with lower memory (-0.7 [-1.4, 0.1], p=0.09), independently of WMH.

Associations between loneliness and biomarkers may relate to health seeking behavior, reported as treatment status for diabetes, for cerebrovascular burden and general neurodegeneration, but might be more complex for amyloid. The degree to which loneliness increased the susceptibility to amyloid and neurodegeneration-related, but not cerebrovascular-related, memory impairment, specifically, may suggest that domains beyond memory should be considered. Future work should be longitudinal to disentangle the effects of loneliness from related constructs like depression and anxiety, incorporate other AD biomarkers such as hyperphosphorylated tau, and incorporate biological mechanisms (e.g., stress, inflammation) into models of loneliness and AD pathogenesis. Older adults from all backgrounds may be more susceptible to loneliness, which was associated with lower memory; culturally-humble, social support-based interventions may reduce the risk of cognitive impairment.