Predicting longitudinal basal forebrain volume in the Alzheimer's disease spectrum: the role of sex and ApoE epsilon 4 genotype.

INTRODUCTION: Imaging studies showed early atrophy of the cholinergic basal forebrain (BF) already at prodromal stages of sporadic Alzheimer's disease (AD). Women and carriers of the ApoE epsilon 4 (ApoE ε4) allele are more likely to develop the disease; however, the underlying mechanisms are still unclear. Here we aimed at exploring the impact of sex and ApoE ε4 genotype in the AD spectrum on longitudinal measures of the basal forebrain and hippocampus, as a comparison region.

METHODS: We leveraged the German multi-centered study DELCODE and analyzed 712 individuals (median age: 71.25 years, interquartile range [IQR] = 9.22) with follow-up MRI scans (median time: 2.8 years, [IQR] = 1.75). Diagnostic groups comprised cognitively normal ( = 184), subjective cognitive decline ( = 331), mild cognitive impairment ( = 128) and AD ( = 69). Regarding ApoE genotype, 5% of participants were ε4 homozygotes, while 27% were heterozygotes. Volume segmentation and linear mixed-effect models were used to calculate the effects of ApoE ε4 genotype, sex, diagnosis, age, time and their interactions in TIV-adjusted basal forebrain and hippocampal volumes.

RESULTS: The hippocampus, but not the basal forebrain, showed significant atrophy over time (Hipp:  = -0.014,  < 0.001; BF:  = 0.040,  = 0.044). Post-TIV correction, female participants had significantly larger baseline basal forebrain ( = 0.300,  < 0.001) and hippocampal volumes ( = 0.273,  < 0.001). ApoE ε4 predicted smaller baseline volumes in both regions. After adjusting for multiple comparisons, faster longitudinal atrophy was observed only for ApoE ε4 homozygotes in the hippocampus ( = -0.037,  < 0.001), with no corresponding effect in the basal forebrain ( = 0.000,  = 0.841).

DISCUSSION: Our findings did not show the anticipated longitudinal effects of sex and ApoE ε4 on longitudinal basal forebrain volume. Only hippocampal atrophy progressed significantly faster in ApoE ε4 homozygote carriers. This dissociation may reflect stage-dependent neurodegenerative processes, with early basal forebrain vulnerability followed by more rapid hippocampal decline, as well as methodological and sample-related constraints. If replicated, these findings suggest that hippocampal measures may be more sensitive longitudinal biomarkers in ApoE ε4 homozygotes, while sex- and ApoE ε4-related effects on the cholinergic system may be more prominent at earlier disease stages.

Copyright © 2026 Grazia, Levin, Jessen, Wagner, Peters, Priller, Schneider, Wiltfang, Düzel, Buerger, Perneczky, Laske, Spottke, Ramirez and Teipel.

PMID: 41716658