Loneliness relates to smaller hippocampal subfield volumes in individuals with elevated plasma pTau217: results from IGNITE

Loneliness is associated with cognitive decline and dementia risk, but the role of Alzheimer's disease (AD) pathology in its associations with medial temporal lobe (MTL) morphology remains unclear. We examined whether loneliness was related to total hippocampal volume, hippocampal subfields, and entorhinal cortex (ERC) volumes, and whether plasma phosphorylated tau 217 (pTau217) moderated these relationships. We analyzed baseline data from cognitively unimpaired older adults aged 65-80 years enrolled in IGNITE. Loneliness was assessed using the revised UCLA Loneliness Scale. Structural 3 T MRI included a high-resolution T2-weighted hippocampal sequence. Hippocampal subfields and ERC volumes were extracted using ASHS, and FreeSurfer estimated total hippocampal volume and intracranial volume. Participants were classified as pTau217-positive or negative using an Aβ-PET-calibrated threshold (> 0.46 pg/mL). Covariate-adjusted linear regression models tested loneliness associations and loneliness×pTau217 interactions. We included 601 participants (69.8 ± 3.7 years; 72.2% female; 76.4% White); 582 had usable pTau217 data, of whom 28.9% were pTau217-positive. pTau217 moderated associations with CA3 (β = - 0.215, 95% CI - 0.381 to - 0.048) and ERC (β = - 0.167, 95% CI - 0.318 to - 0.016), with negative associations observed among pTau217-positive but not pTau217-negative participants. Greater loneliness was associated with smaller total hippocampal volume (β = - 0.077, 95% CI, - 0.147 to - 0.007, p = 0.031), but not with individual subfields. Loneliness showed biomarker-dependent associations with MTL subfields, suggesting that pTau217-defined biological risk may modify links between psychosocial factors and neuroanatomical vulnerability. This biomarker-informed framework may help explain heterogeneity in prior loneliness-neuroimaging findings.Trial registrationClinicalTrials.gov Identifier: NCT02875301.