Project 2: Metabolic and Immune Systems of Biology Interactions as Initiators and Drivers of Alzheimer's Pathology in Brain: Therapeutic Targets and Windows

PROJECT SUMMARY – PROJECT 2
The mission of the Perimenopause in Brain Aging and Alzheimer’s disease (P3) 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). Each year ~1.5 million American women enter into the perimenopause, a
neuroendocrine transition state unique to the female. Herein, we focus on the neuro-immune system as a key
driver of chronological and endocrinological aging that occurs in the midlife female brain. Our goals are to identify
the mechanisms by which these transformations occur and to translate these discoveries into strategies to
prevent conversion to an at-Alzheimer's-risk phenotype. Project 2 contributes to achieving P3 goals by
determining the systems of immune biology activated across midlife chronological and endocrinological aging,
the dynamic conversions in immune transcriptome and phenotype, the contributing cells, the map of neural
immune responses and therapeutics that specifically target each stage of immune conversion. The overall
hypothesis guiding Project 2 program of research is that the immune system is the initiator and driver of the
metabolic crisis in brain. Based on our preliminary evidence, we anticipate that the neuro-immune profile in brain
will be dynamic and endocrine aging stage dependent. Further, we hypothesize that APOE genotype will be a
key regulator of the neuro-immune system of biology in brain. Aim 1 addresses fundamental systems biology of
the interface between the bioenergetic and immune systems in brain. Aim 1 analyses will determine the dynamic
neuro-immune genotypic/phenotypic signatures that emerge over the course of the pre, peri, and
postmenopausal transition. The goal of Aim 2 is to establish a foundation for precision immune modulating
therapies for reduction of Alzheimer’s disease risk in women based on endocrine aging status and APOE
genotype which will be achieved through computational medical bioinformatics strategies. The translational goal
of Aim 3 is to create a platform for precision neuro-immune therapy based on APOE4 genetic burden and
endocrine aging status. Aim 3 objectives will be achieved by: 1) integrating neuro-immune signatures derived
from Aim 1 with therapeutic candidates from Aim 2; 2) treating hAPOE mice with neuro-immune therapy specific
to endocrine aging transition; 3) determining efficacy of precision neuro-immune therapy to prevent, delay and
treat hallmark pathologies of Alzheimer’s disease. Collectively, outcomes of these analyses will provide a
platform on which to achieve precision neuro-immune medicine to intervene with the right therapy at the right
time in the right APOE genotype.
Research proposed herein addresses strategic goals of the National Institutes on Aging’s 2016: Aging Well in
the 21st Century: Strategic Directions for Research on Aging, specifically Goals A1, 2, 3, 7, 8 & 11 and Goals
D1, 2, & 4.

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