Sex-dependent cholinergic effects on amyloid pathology: A translational study

Introduction: About two-thirds of Alzheimer's Disease (AD) patients are women, who exhibit more severe pathology and cognitive decline than men. Whether biological sex causally modulates the relationship between cholinergic signaling and amyloid pathology remains unknown.

Methods: We quantified amyloid beta (Aβ) in male and female App-mutant mice with either decreased or increased cholinergic tone and examined the impact of ovariectomy and estradiol replacement in this relationship. We also investigated longitudinal changes in basal forebrain (cholinergic function) and Aβ in elderly individuals.

Results: We show a causal relationship between cholinergic tone and amyloid pathology in males and ovariectomized female mice, which is decoupled in ovary-intact and ovariectomized females receiving estradiol. In elderly humans, cholinergic loss exacerbates Aβ.

Discussion: Our findings emphasize the importance of reflecting human menopause in mouse models. They also support a role for therapies targeting estradiol and cholinergic signaling to reduce Aβ.

Highlights: Cholinergic tone regulates amyloid beta (Aβ) pathology in males and ovariectomized female mice. Estradiol uncouples the relationship between cholinergic tone and Aβ. In elderly humans, cholinergic loss correlates with increased Aβ in both sexes.