Brain and serum cholesterol metabolism during perimenopausal transition: a risk factor for Alzheimer’s disease?

Perimenopause is an endocrine transition state unique to women and is characterized by reproductive and neurological senescence. Further, we posit herein that the perimenopause is also a transition in lipid metabolism that has long term consequences for risk of neurodegenerative diseases in later life, in particular Alzheimer's disease (AD). Aim: The present study was focused on the investigation of brain and serum cholesterol (Chol) metabolism during perimenopause transition in order to better understand how it potentially relates with neurodegeneration. Results: Gene expression analysis, evaluated in rat models with main characteristics of human perimenopause, indicated twodistinct aging programs: chronological and endocrine. Chronological aging showed an activation of genes involved in Chol synthesis, transport and efflux mainly before perimenopause. Conversely, endocrine aging presented a down regulation of the same pathway. Similarly, serum lipid profile analysis showed an age-dependent increase of total Chol and triglycerides levels, but endocrine effects were not correlated to modification of the same markers. Serum Chol profile data in the animal model were comparable to that observed in 139 women in different menopausal stages humans. In conclusion, the perimenopausal transition is composed of both endocrine and chronological aging. Both programs of aging are associated with changes in cholesterol homeostasis mechanisms. Endocrine aging is characterized by a decline in cholesterol homeostatic processes which are sustained during chronological aging. The decline in cholesterol homeostatic, transport and efflux mechanisms early in the female aging brain is consistent with and early prodromal state and risk of Alzheimer's in later life.