Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit

Background Brain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects. Methods We studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores. Results Connectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p