Midlife Biomarkers of Alzheimer’s Disease Risk and Impact of Sex Differences

Jill M. Goldstein, PhD
Massachusetts General Hospital and Harvard Medical School (Boston, MA)
Year Awarded:
Grant Duration:
March 30, 2018 to March 29, 2020
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Jill M. Goldstein, Ph.D. is Professor of Psychiatry and Medicine, Harvard Medical School, Founder, Executive Director of the Women, Heart and Brain Global Initiative at Massachusetts General Hospital (MGH), and the Helen T. Moerschner Endowed MGH Research

Development of Clinical Algorithm to Identify Risk for Alzheimer’s disease in Early Midlife


This project will support the launching of a comprehensive effort (integrating clinical, physiological and brain biology traits) to identify in early midlife biomarkers for Alzheimer’s disease risk informed by sex differences in brain aging and memory decline. This is one of the first projects to comprehensively assess multiple predicted biomarkers for Alzheimer’s risk in middle age and relate them to brain scans, physiology, genetics, and clinical data with a specific focus on incorporating differences between men and women in Alzheimer’s development.


Eighteen percent of the U.S. is more than 60 years of age, with projections of rising to 25-30% by 2050. Thus, healthy aging is one of the most important public health challenges of our time. Maintaining intact cognitive function is critical to that end. Most work on cognitive aging and Alzheimer’s begins with people more than 65 years old. However, we now know that successful treatment likely should begin in early midlife. We have an unprecedented opportunity to create a “living laboratory” for the identification of biomarkers and targets for therapeutics to enhance one’s resilience to aging and prevent memory loss beginning in early midlife. We are leveraging the Partners HealthCare Biobank by creating the Healthy Aging Translational Cohort (HATCH). As part of this effort, with BrightFocus Foundation funds, we are launching the development and validation of a quantitative tool, a clinical risk algorithm, that integrates polygenic-clinical-physiological and brain phenotyping to identify in early midlife (ages 45-70 years), people who may already have accumulated amyloid pathology and are at highest risk for cognitive decline and Alzheimer’s later in life. Given this is a critical period of the menopausal transition in women, we have a specific focus on identifying the impact of ovarian decline on aging of memory circuitry and Alzheimer’s risk. Identification of sex-selective predictors of early cognitive decline may have substantial implications for development of sex-selective preventions and therapeutics.

About the Researcher

Jill M. Goldstein, Ph.D. is Professor of Psychiatry and Medicine, Harvard Medical School, Founder, Executive Director of the Women, Heart and Brain Global Initiative at Massachusetts General Hospital (MGH), and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women’s Health. She is a clinical neuroscientist and expert in sex differences in health and diseases associated with the central nervous system, in particular, depression, its comorbidity with heart disease, and risk for Alzheimer’s disease. She leads the interdisciplinary research program (NIH-funded for more than 30 years) Clinical Neuroscience Laboratory of Sex Differences in the Brain (http://cnl-sd.mgh.harvard.edu). She has received numerous awards, served on scientific review boards, and participated in strategic planning for the National Institute of Health Office for Research on Women’s Health (ORWH), National Institute for Mental Health, and the Institute of Medicine. She has spent her career at Harvard training the next generation of women and men in women’s health and sex differences in medicine, including leading an ORWH Harvard junior faculty training program on building interdisciplinary careers in women’s health. In 2018, she launched the Women, Heart and Brain Global Initiative, a collaboration between MGH and the Harvard-T.H. Chan School of Public Health, partnering with WomenAgainstAlzheimer’s, to tackle sex differences in the shared causes of the co-occurrence of depression, heart disease, and Alzheimer’s, and to develop personalized sex-selective therapeutics and healthcare systems globally.

Personal Story

Although men and women share much of their biology, there are important differences between the brain and body that have critical implications for understanding the substantial sex differences in frequency, expression, course and therapeutic responses across most chronic diseases, including Alzheimer’s disease (AD). Largely these sex and gender differences in AD and other diseases have been ignored, and men and male animals are used as the standard. After 30 years of discoveries in my lab regarding sex differences in the development and aging of the brain, I am excited about the opportunity to translate these discoveries into therapeutics. BrightFocus Foundation has launched our ability to begin to develop an innovative tool to identify who, in early midlife, may be at highest risk for AD later in life, in order to identify who to treat early. Early midlife includes the menopausal transition in women, and we will incorporate the impact of menopause on memory function into the development of this novel tool.  BrightFocus has had a long-term interest in sex differences in AD. Therefore, I am thrilled to partner with them to raise awareness of the importance of one’s sex in the science and treatment of this devastating disease. This study will also launch our Healthy Aging Translational Cohort, which we hope to increase to 10,000 members, to provide opportunities for others to study many different disorders of aging across the lifespan. 

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