Perimenopause in Brain Aging and Alzheimer's Disease

PROJECT SUMMARY – OVERALL
Each year ~1.5 million American women enter into the perimenopause, a midlife neuroendocrine transition state
unique to the female. As of 2020, there are 45 million US women over the age of 55. Globally, there are currently
over 850 million women aged 40-60 years of age. Worldwide women have a 2-fold greater risk for developing
Alzheimer’s.
The mission of the Perimenopause in Brain Aging and Alzheimer’s Disease Program Project is to discover
biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes
predictive of risk for Alzheimer’s disease (AD). Research goals are to identify the mechanisms by which these
transformations occur and to translate these discoveries into strategies to prevent or delay conversion to AD.
Our research has shown that the greater risk for AD is not because women live longer than men but because
the disease can start earlier in women, at midlife during the perimenopausal transition. In the Perimenopause in
Brain Aging and Alzheimer’s Disease program of research, we advance mechanistic, clinical and population
discovery science and translate these discoveries into a platform for precision medicine to prevent, delay and
treat Alzheimer’s disease. Herein we specifically focus on the complex interaction between APOE genotype and
the metabolic and immune systems that initiate and drive pathologies of Alzheimer’s.
To achieve our mission, we have developed a focused research center model with an integrated set of four
Projects and three Cores. Projects 1, 2 and 3 are basic, mechanistic and preclinical translational science
investigations of the perimenopausal brain utilizing humanized APOE mouse models relevant to Alzheimer’s risk
and to human perimenopause. These projects investigate the molecular, cellular and systems biology of immune
signaling in brain and periphery that initiate and drive development of Alzheimer’s disease in brain and
autoimmunity in peripheral organs. Project 4 investigates development of the endophenotype of early stage
Alzheimer’s disease in perimenopausal to postmenopausal women using multi-modal brain imaging and
analyses of peripheral biomarkers. All Projects and Cores are highly integrated and supported by a suite of
enabling strategies and technologies.
Outcomes of proposed aims will generate a mechanistic foundation on which to conduct hypothesis driven
medical informatics, develop neuro-immune biomarkers specific to stages of brain aging and a platform for
precision neuro-immune therapeutics.
The Perimenopause in Brain Aging and Alzheimer’s Disease program of research addresses key strategic goals
of the National Institutes on Aging’s 2016: Aging Well in the 21st Century: Strategic Directions for Research on
Aging, specifically Goals A (1,2,3,7,8,11) & D (1,2,4).

Grant Number: 5P01AG026572-20
NIH Institute/Center: NIH
Principal Investigator: ROBERTA BRINTON