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

Abstract (English)

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: In the prospective observational Subjective Cognitive Impairment Cohort based in Amsterdam, individuals with subjective cognitive decline recruited from a memory clinic underwent repeated blood sampling (484 samples, follow-up 5 &#xb1; 3 years) and MRI scans (457 scans, follow-up 5 &#xb1; 3 years). We measured blood-based biomarkers (A&#x3b2;42/40 ratio [A&#x3b2;_42/40], 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: A total of 167 individuals were included (49 amyloid-positive and 118 amyloid-negative), with amyloid-positive individuals being older (age: 66 &#xb1; 8 years, 57.1% female) than amyloid-negative individuals (61 &#xb1; 8 years, 33.9% female). Baseline levels and longitudinal increases in GFAP showed associations with higher rates of atrophy across nearly all AD-signature regions (&#x3b2; range -0.02 to -0.00, 95% CI range -0.04 to -0.00, <i>p</i>_FDR < 0.05). Baseline pTau217 was associated with atrophy across several medial temporal regions (&#x3b2; range -0.03 to -0.01, 95% CI range -0.04 to -0.00, <i>p</i>_FDR < 0.05), whereas increases in pTau217 were only associated with atrophy primarily in temporal regions (&#x3b2; range -0.02 to -0.01, 95% CI range -0.02 to -0.00), although the latter associations were only trend-level after FDR correction (<i>p</i>_FDR = 0.077). Baseline concentrations, but not increases in NfL, showed associations with temporal regions (&#x3b2; range -0.02 to -0.01, 95% CI range -0.04 to -0.00, <i>p</i>_FDR < 0.05). By contrast, baseline A&#x3b2;_42/40 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.