Subthreshold early white-matter hyperintensity increase predicts accelerated hippocampal and whole-brain atrophy in anti-amyloid-β immunotherapy

Abstract

Background Anti-amyloid-β (anti-Aβ) therapy slows cognitive decline but paradoxically accelerates whole-brain gray matter atrophy, complicating outcome prediction. Objective To identify early imaging markers that predict long-term prognoses. Methods This longitudinal cohort study prospectively enrolled participants with early Alzheimer's disease, initiating anti-Aβ therapy. We performed automated T1-weighted MRI volumetric analysis of the whole-brain gray matter, hippocampus, and white matter hyperintensities (WMH). Temporal dynamics were characterized using piecewise linear regression, and predictive utility was assessed using multivariate linear regression analyses. Results Twenty-two participants (74 ± 11 years; 14 women) were followed for 376 ± 146 days. Significant volume changes occurred in all regions (p < 0.01). No overt amyloid-related edema was detected, and hemorrhagic events were mild to moderate. Piecewise regression revealed an initial WMH surge that decelerated after 60 days (β=-0.19 [95%CI: −0.33, −0.042], p = 0.01), whereas gray matter regions showed linear volume decline. Early subthreshold WMH expansion predicted long-term atrophy independent of baseline covariates (age, sex, amyloid burden, mini–mental state examination score, drug, and hemorrhagic events) in the hippocampus (β=-0.058 [95%CI: −0.092, −0.025], p = 0.003), and whole-brain gray matter (β=-0.033 [95%CI: −0.065, −0.002], p = 0.04). Early whole-brain gray matter atrophy correlated with the WMH surge (β=-0.53 [95%CI: −0.69, −0.38], p < 0.001) and predicted long-term hippocampal atrophy (β=0.098 [95%CI: 0.038, 0.16], p = 0.004). Conclusions A transient WMH surge within the first 60 days of therapy mirrors the known time course of amyloid-related imaging abnormalities. Along with concurrent early whole-brain volume loss, this surge independently predicts accelerated long-term hippocampal and whole-brain atrophy, highlighting its potential as an early prognostic imaging marker.