Longitudinal Change in Blood-Based Biomarkers and the Association With MRI-Measured Neurodegeneration in Cognitively Unimpaired Individuals

BACKGROUND AND OBJECTIVES: Blood-based biomarkers are reliable indicators of Alzheimer disease (AD)-related pathology in cognitively normal individuals. However, it remains unclear how changes in these biomarkers relate to emerging brain atrophy. We aimed to investigate longitudinal associations between blood-based biomarkers and brain atrophy, and the temporal sequence of these processes. METHODS: ], phosphorylated tau pTau217, glial fibrillary acidic protein GFAP, and neurofilament light NfL) using the SIMOA platform. AD-signature brain volumes (5 temporal, 4 parietal, and 2 frontal regions) were determined using the FreeSurfer pipeline. We used linear mixed models to examine associations between baseline or slope of biomarker and brain volume changes. In an exploratory analysis, extrapolated pTau217 trajectories were compared with hippocampal volume trajectories to estimate the temporal gap between these changes. RESULTS: showed only associations with hippocampal atrophy (0.01 0.00-0.03), but not after FDR correction. Using baseline and (extrapolated) trajectories over time, we estimated that changes in pTau217 preceded hippocampal atrophy by 19.8 (10.7-43.7) years. DISCUSSION: Blood-based biomarkers capture distinct aspects of brain atrophy, with pTau217 primarily indicating atrophy in medial temporal regions and GFAP more widespread neurodegeneration. This supports the complementary use of both markers for early identification and monitoring in preventive trials and clinical care.