Cerebral amyloid-β burden and white matter injury: associations, clues for underlying mechanisms, and implication on cognitive trajectory after lecanemab therapy

White matter hyperintensities (WMH) are linked to cognitive decline and risk of Alzheimer's disease (AD).

To test whether amyloid-β (Aβ) deposition contributes to white matter injury and whether WMH dynamics can modulate the clinical efficacy of the anti-Aβ therapy.

Twenty patients with early AD who are receiving lecanemab and a matched cohort of 110 untreated AD patients were followed. Linear mixed-effects models were used to examine the interplay between WMH trajectories and lecanemab on cognitive decline. The roles of Aβ burden in predicting baseline severity and progression rates of WMH were evaluated in a larger cohort of 1,031 adults. Finally, cerebrospinal fluid (CSF) proteomic and bioinformatic analyses were performed to identify potential candidate mediators and pathways linking Aβ to WMH progression.

Following lecanemab treatment (median = 13 times), 80 % of patients showed WMH reductions, predominantly in periventricular and frontoparietal regions. Compared to the reference cohort, WMH progression is significantly slower among those with anti-Aβ therapy. WMH trajectory significantly modified the relationship between anti-Aβ therapy and cognitive decline, with greater cognitive improvement observed among those with smaller WMH reductions. The levels of Aβ burden were correlated with higher burden and accelerated rates of WMH. Eight proteins in CSF were identified as candidate mediators linking WMH to Aβ. They were enriched in vascular-endothelial, neuro-cytoskeletal, and neuroinflammation pathways.

The interplay of Aβ with white matter integrity contributes to cognitive decline in the context of Alzheimer's disease.