OBJECTIVES: Loneliness is associated with an elevated risk of dementia. There is mixed evidence from imaging studies on whether loneliness is associated with neuropathology in dementia-free adults. This study tests whether loneliness is associated with plasma neurobiomarkers of amyloid (Aβ42/Aβ40), phosphorylated tau 181 (pTau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) and imaging measures of amyloid and tau. METHODS: Participants were cognitively unimpaired older adults from the Baltimore Longitudinal Study on Aging (BLSA
N = 1,028 individuals and up to 2,277 neurobiomarker measurements
Baseline mean age = 66, SD = 15 years) and the UK Biobank (N = 1,263 individuals and up to 2,526 neurobiomarker measurements
Baseline mean age = 60, SD = 7 years). Single-item measures of loneliness and the Quanterix Single Molecule Array assays were used in both samples. In a subset of BLSA participants, positron emission tomography (PET) was used to assess cerebral amyloid burden (n = 220) and tau in the entorhinal cortex (n = 102). RESULTS: In both samples and meta-analyses, loneliness was unrelated to plasma measures of Aβ42/Aβ40, pTau181, NfL, and GFAP. Changes in loneliness were also unrelated to changes in the plasma neurobiomarkers, and no consistent evidence of moderation by age, sex, or APOE ε4 allele was found. Loneliness was also unrelated to PET-based measures of amyloid and tau. DISCUSSION: This study found no associations between loneliness and measures of Alzheimer's disease pathology, axonal damage, or astrogliosis.