Sex-specific gene expression and biological pathways in Alzheimer disease
According to the Alzheimer’s Association, approximately 7.2 million Americans age 65 or older are living with Alzheimer disease, the most common form of dementia. The earliest symptom is memory loss. With progression of the disease, symptoms can include disorientation, mood swings or behavioral issues, difficulty with language, loss of motivation, and self-neglect. The etiology of the disease remains poorly understood. However, it has been found that pathogenesis involves accumulation of misfolded protein deposits—that is, beta-amyloid (Aβ) plaques and tau neurofibrillary tangles—in the brain. Alzheimer disease disproportionately affects women, who account for two-thirds of cases in the United States. Women also exhibit increased neuropathology and more rapid cognitive decline. The molecular factors that account for sex-based disparities in the disease have been explored but remain unclear. The authors conducted a study in which they investigated sex-specific genetic expression and biological pathways in Alzheimer disease. Autopsy samples of three different brain sites—dorsolateral prefrontal cortex, posterior cingulate cortex, and head of the caudate nucleus—were collected from 767 decedents for the Religious Orders Study/Memory and Aging Project. RNA expression analysis was performed on 17,091 autosomal, 645 X-linked, and 83 Y-linked genes from the decedents, which formed an analytical data set of 1,490 samples. The authors examined brain gene-expression associations with measures of Aβ and tau burden at autopsy and with a longitudinal global cognition composite score. Transcriptome-wide analyses yielded more than 23,118 gene-expression associations with Aβ, tau tangles, and longitudinal cognition. The majority of associations were identified in the dorsolateral prefrontal cortex and associated with tau tangles—10,882 were autosomal and 332 were X linked. Ten percent of associations were sex specific, with 1,697 female stratified (1,622 autosomal and 75 X linked) and 623 male stratified (609 autosomal and 14 X linked). In particular, expression of MCF2, HDAC8, SLC10A3, and FTX was found to differ significantly between the sexes in terms of tau tangle burden and cognitive decline. MCF2 and FTX expression was associated with fewer tau tangles in females and slower cognitive decline in males, with the protective effect of FDX expression appearing to be driven by male APOE-ε4 (the most common genetic risk factor for sporadic Alzheimer disease) carriers. In contrast, enhanced expression of HDAC8 and SLC10A3 correlated with greater tau tangle burden and faster cognitive decline in females only. Interestingly, FTX and HDAC8 showed higher expression in males than females despite being X linked. Investigation of sex-stratified biological pathways revealed that females demonstrated upregulation of neuronal development and immune-regulated pathways and downregulation in neurotransmission-related pathways. These results further understanding of the molecular process of Alzheimer disease progression and support the need for precision medicine approaches that take into account sex-specific biological pathways when selecting targets for Alzheimer disease therapeutic interventions.
Seto M, Clifton M, Gomez ML, et al. Sex-specific associations of gene expression with Alzheimer’s disease neuropathology and ante-mortem cognitive performance. Nat Commun. 2025. doi.org/10.1038/s41467-025-64525-5
Correspondence: Dr. Logan Dumitrescu at logan.c.dumitrescu@vumc.org