Review of cross-sectional EEG study on 32-Hz stimulation in Alzheimer's disease and mild cognitive impairment

Background and Objectives Gamma entrainment responses in Alzheimer's disease are heterogeneous, but factors underlying this variability remain unclear. Cognitive reserve may influence how large-scale brain networks reconfigure during stimulation, particularly in prodromal Alzheimer's disease. We examined whether cognitive reserve was associated with stimulation-related functional network changes across the Alzheimer's disease spectrum and hypothesized a condition-by-diagnosis-by-cognitive reserve interaction. Methods In this cross-sectional EEG study, adults aged 55 years or older were recruited from a memory clinic and community. Participants underwent amyloid PET and standardized neuropsychiatric and neuropsychological assessments and were classified as amyloid-negative cognitively normal, amyloid-positive mild cognitive impairment, or amyloid-positive Alzheimer's disease dementia. Amyloid-negative mild cognitive impairment and amyloid-positive cognitively normal participants were excluded from the primary analyses. Cognitive reserve was indexed using an education- and occupation-based composite and dichotomized at the median. Functional networks during rest and 32-Hz visual stimulation were derived from spectral Granger causality EEG and summarized using mean strength, weighted clustering coefficient, average shortest path length, and outreach. Mixed-design repeated-measures ANCOVA adjusted for age, sex, and APOE genotype was used for the primary analysis. Results Significant condition-by-diagnosis-by-cognitive reserve interactions were observed for mean strength, weighted clustering coefficient, and outreach, but not for average shortest path length. These effects were driven primarily by prodromal Alzheimer's disease, in which the low cognitive reserve subgroup showed larger rest-to-stimulation increases than the high cognitive reserve subgroup for mean strength, weighted clustering coefficient, and outreach. In secondary analyses, the low cognitive reserve prodromal subgroup also showed higher 32-Hz entrainment, and entrainment strength correlated positively with stimulation-related network change across the full sample. Discussion Cognitive reserve may be associated with heterogeneity in stimulation-related network reconfiguration, with the clearest signal observed in prodromal Alzheimer's disease. Because the low-reserve prodromal subgroup was small and findings were sensitive to alternative modeling choices, these results should be considered preliminary. Reserve-related factors may warrant explicit consideration in future studies of sensory gamma stimulation in Alzheimer's disease.