59: Stage-Specific BIN1 Effects Link Tau to Preclinical Functional Connectivity in Alzheimer's Disease

Music City Center 

We model mediation of BIN1 genetic risk (rs6733839) on functional connectivity (FC) through tau pathology in Alzheimer's disease, comparing cognitively normal (CN, n=104) and mild cognitive impairment (MCI, n=101) groups. Using baseline data from ADNI with temporally ordered biomarkers (preceding imaging), we identified FC components (IC1–IC10) via ICA and found IC5 (Dorsal Attention-Default Mode/Visual networks) associated with Aβ (p = 0.00027) and group-dependent tau effects (IC5×Group interaction: p = 0.002). We then tested SNP→tau→IC5 paths using multi-group mediation, allowing group-specific slopes. In CN, the BIN1 risk allele (T) linked to reduced tau (β=−0.12, p=0.03) and marginal indirect preservation of IC5 (β=0.16, p=0.08). In MCI, direct SNP effects dominated (β=−0.39, p=0.005), with no tau mediation. Paradoxically, the T allele associated with lower tau (β=−0.11, p=0.04) despite being an AD risk variant, suggesting stage-dependent BIN1 isoform effects (early clearance vs late aggregation). Temporal precedence (biomarkers pre-imaging) strengthens causal plausibility. Results suggest IC5 as a preclinical resilience marker and highlight shifting pathways.

multi-group SEM

mediation analysis

Alzheimer’s disease

functional connectivity

BIN1

tau pathology 

Section on Statistics in Genomics and Genetics