Blood Biomarkers of Alzheimer's Disease and Patterns of Structural Brain Changes in the Community

OBJECTIVE: We aimed to investigate the associations between Alzheimer's disease (AD)-related blood biomarkers and changes in brain volumes and cerebrovascular burden in community-dwelling older adults. METHODS: We included 361 dementia-free participants with a Mini-Mental State Examination (MMSE) score ≥ 27 and without prior cerebrovascular events from a Swedish population-based study. Blood phosphorylated-tau217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured at baseline. Brain magnetic resonance imaging (MRI) was performed at baseline and after 3 and/or 6 years. Linear mixed models were used to examine associations between AD-related blood biomarkers and changes in volumes of total brain tissue (TBTV), lateral ventricles, hippocampus, amygdala, and white matter hyperintensities (WMHs). RESULTS: During the follow-up, higher p-tau217 was associated with faster volume loss in the hippocampus (β*year = -0.047, 95% confidence interval [CI] = -0.077 to -0.018) and in the amygdala (β*year = -0.064, 95% CI = -0.105 to -0.022). Elevated GFAP was linked to faster TBTV decline (β*year = -0.040, 95% CI = -0.059 to -0.021), ventricular enlargement (β*year = 0.028, 95% CI = 0.013 to 0.042), and hippocampal shrinkage (β*year = -0.038, 95% CI = -0.064 to -0.013). Participants with higher NfL showed steeper TBTV decline, ventricular enlargement, hippocampal and amygdala shrinkage, and faster WMH accumulation. Results remained largely consistent after excluding participants with mild cognitive impairment at baseline. INTERPRETATION: In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation. These findings suggest that AD-related blood biomarkers may capture different dementia-related structural brain changes already at early stages. ANN NEUROL 2026.