Brain and serum cholesterol dyshomeostasis during the perimenopausal transition: A possible risk factor for Alzheimer’s disease

Background and Purpose: The aim of this study was to investigate alterations in cholesterol metabolism during the perimenopausal transition that could increase the long-term risk of neurodegenerative disease in women, particularly Alzheimer’s disease. Methods: Brain and serum cholesterol metabolism during chronological and endocrine aging were evaluated in rat models recapitulating the main characteristics of human perimenopause. Serum cholesterol profile were obtained from 224 women across perimenopausal stages. Results: In rodent brain, chronological aging, particularly before perimenopause, was associated with an up-regulation of genes involved in cholesterol synthesis, efflux, and export. Conversely, endocrine aging in rats was associated with downregulation of these pathways. Analysis of brain proteins involved in cholesterol metabolism showed export and clearance defects during endocrine aging and a decline in mobilization during post-menopausal chronological aging. Peripherally, serum lipid profile analysis in rats and women indicated an chronological age-dependent increase in total cholesterol and triglycerides which did not change with endocrine aging. Conclusions: In brain chronological and endocrinological aging during the perimenopausal transition were associated with changes in cholesterol homeostasis in brain. Endocrine aging was characterized by a decline in cholesterol homeostatic processes which were sustained during post-menopausal chronological aging. The decline in cholesterol homeostatic transport, efflux and clearance mechanisms in brain during midlife aging is consistent with an early prodromal state that potentially contributes to risk of Alzheimer's later in life.