Grant recipient: Dr. Laura Cox, postdoctoral fellow at Brigham and Women’s Hospital, and Instructor at Harvard Medical School
Question: Could manipulating the gut microbiome help treat women with Alzheimer’s?
In the past several years, scientists have turned their attention to the gut microbiome. We are learning that the bacteria it contains hold clues to diseases throughout the body—including the brain. A continuation of two years of WAM-funded studies, Dr. Cox will apply her grant to further exploration into how the gut microbiota can affect the development of Alzheimer’s, and to identify new therapeutic approaches to treat women with the disease. Using animal studies, Dr. Cox will colonize the GI tracts of mice with microbiota from Alzheimer’s patients, then track disease progression to identify which members of the microbiota and which immune pathways may contribute to the disease. She will also test whether adding beneficial bacteria to the gut microbiome or giving specific antibiotics can help treat the disease. Looking at this through a gendered lens is important, since previous WAM-funded research has identified female-specific microbiota that may contribute to Alzheimer’s disease development. The hope is that this research will uncover beneficial bacteria or other approaches to target the microbiome that can be developed into new therapies for women with AD.
Grant recipient: Dr. Rudy Tanzi, Co Vice-Chair for Research and Dr. Dmitry Prokopenko, Department of Neurology at Massachusetts General Hospital
Question: Where on a woman’s genetic code do markers for Alzheimer’s show up?
Up until recently, genetic testing for Alzheimer’s disease had a big limitation. Doctors and researchers were looking at certain places on a person’s genome for the presence or absence of certain disease markers—including APOE, which is the gene with the greatest known association with developing late-onset Alzheimer’s. But the map used to locate those markers doesn’t distinguish between genders, and those genetic clues appear in different places on the genome for females and males. A continuation of his WAM-sponsored work, Dr. Tanzi will use whole genome sequencing data from the National Institutes of Mental Health and the National Institute of Aging for sex-specific association using family-based data groups, which tend to be more reliable. Then, he and his team will replicate the research in non-family based groups at the population level. These findings will help create a more accurate map of the locations that genetic markers for Alzheimer’s disease appear on a woman’s genome. And it will help doctors better understand the disease risk for women with—and without—a family history of Alzheimer’s.
Grant Recipient: Dr. Lisa Mosconi, Director of the Women’s Brain Initiative Research Program at Weill Cornell Medicine
Question: Does a sudden loss of estrogen act as a trigger for Alzheimer’s?
There is evidence that changes in estrogen levels during menopause can make women more vulnerable to developing Alzheimer’s disease, but the circumstances under which that happens aren’t totally understood. Figuring this out can help identify effective interventions to reduce risk of developing the disease, as well as maintain cognitive function. Last year, WAM-funded work conducted by Dr. Mosconi led to the finding that middle-aged women tend to develop Alzheimer’s-related brain changes earlier than men of the same age, specifically during perimenopause, and that undergoing a hysterectomy as a pre-menopausal woman increased her Alzheimer’s risk, while hormone therapy actually decreased that same risk. The key now is to understand whether sudden estrogen loss is indeed the driver of Alzheimer’s plaque accumulation in women. Using a cutting edge new PET tracer also developed with funding from WAM, Dr. Mosconi will scan the brains of women before and after they undergo treatment that induces early menopause—either a hysterectomy with ovary removal, or taking so-called “anti-estrogen” cancer drugs—to measure the impact on the brain of a sudden loss of estrogen. These findings could help women anticipate Alzheimer’s risks later in life, and help researchers create new interventions to safely counteract possible side-effects of cancer treatments.
Grant Recipient: Dr. Richard Isaacson, MD, Director of the Alzheimer’s Prevention Clinic at Weill Cornell, and Professor of Neurology and Director of the Neurology Residency Program at Weill Cornell and New York-Presbyterian
Question: How do we build an Alzheimer’s prevention consortium among six sites that harmonize data and research in order to better understand sex differences in Alzheimer’s prevention and health outcomes?
One of the major shortcomings in women-specific Alzheimer’s disease research is the lack of established channels among centers of research and care to share and maximize data. The WAM/Alzheimer’s Prevention Clinical Research Consortium, established by Dr. Isaacson, will encompass sites across two countries that are providing direct care to women at risk of Alzheimer’s disease. Personnel at each site will be trained in how to provide individualized clinical care, while also harmonizing and sharing data and carefully tracking outcomes. Data sharing is crucial, as it allows for an increased number of patients from which to draw stronger conclusions. When smaller numbers of women are pooled together from different sites to have greater numbers, it strengthens the conclusions that scientists are able to make. This consortium represents a crucial missing piece in Alzheimer’s treatment. Dr. Isaacson’s research has shown that individualizing care for people at risk for Alzheimer’s disease is effective, and the necessary next step is to scale this approach at multiple sites. This will also open the door to establishing Alzheimer’s prevention as a subspecialty of medicine, which will expand the number of doctors trained in caring for patients at risk. In addition to the Alzheimer’s Prevention Clinic at Weill Cornell, the consortium will be comprised of The Poplars Centre in Jersey, England, and four leading institutions across the United States.
Grant Recipient: Dr. Mathew Blurton-Jones, Assistant Professor of Neurobiology and Behavior at UC Irvine; and Dr. Sunhil P. Gandhi, Associate Professor of Neurobiology and Behavior at UC Irvine
Question: Is there a sex difference in microglia—the brain’s immune cells?
Women have a significantly increased risk of developing Alzheimer’s Disease during their lifetime, and recent genetic evidence suggests that microglia—a form of neuro-immune cell, or immune cells in the brain—are key to Alzheimer’s risk and may be different in male and female brains. Last year, with funding from the WAM/UCI MIND Women’s Initiative, Drs. Mathew Blurton-Jones and Sunil Gandhi used cutting edge approaches to understand how this plays out in the brain. They engineered human skins to become stem cells and then to become microglia and introduced these human microglia into the brains of both female and male mouse models of Alzheimer’s disease. Using new technology that can visually capture the reaction of the microglia, they were able to show that the microglia placed into female brains reacted more aggressively—overreacted—to the pathology of Alzheimer’s. This suggests that the local brain environment, including the brain’s immune response, may place female brains at higher risk for Alzheimer’s. Since inflammation seems to be involved in the connection between women and Alzheimer’s and other neurological autoimmune diseases, this is an important step in understanding how. With the continuation of this partnership, this year, these investigators will further explore whether and why female microglia show a diminished response to localized brain injuries. The team also hopes to learn how the brain environment—and the presence or absence of estrogen—affects microglia, using animal models. Uncovering functional differences in microglia could help researchers develop more effective drugs to treat Alzheimer’s. UCI and WAM are excited to announce that this research has resulted in an additional $1.9 million multi-year grant from the National Institutes of Health for Drs. Blurton-Jones and Gandhi to continue their important work.
Grant Recipient: Dr. Jessica Z.K. Caldwell, Clinical Neuropsychologist at the Lou Ruvo Center at Cleveland Clinic
WAM funding over the past three years has helped Dr. Jessica Caldwell, a clinician-scientist, leap from small studies of sex differences in Alzheimer’s disease to building a substantial program of sex- and gender-based research on Alzheimer’s disease biomarkers. Dr. Caldwell’s initial WAM funding, on how sex impacts the way amyloid effects memory and hippocampus volumes, led to publications that in turn led to her joining a major grant as project lead, which led to even more data, publications, and collaborations. Dr. Caldwell’s most recent WAM grant has allowed her to hire a postdoctoral fellow to help her expand and enrich our understanding of these critical differences in Alzheimer’s. Altogether, WAM grants have led to a wide-ranging program of sex differences in Alzheimer’s disease that reaches other investigators, studies, trainees, and patients. Aside from papers and grants, WAM has played a critical role in helping her find her career calling to build research programs that can have real-world impact for women at risk for Alzheimer’s, as well as for trainees.
Grant Recipients: Alzheimer’s Association, Women’s Alzheimer’s Research Initiative
Dr. Sarah J. Banks, Associate Professor in the Departments of Neurology and Psychiatry at the University of California, San Diego, with Dr. Erin Sundermann, Assistant Professor in the Department of Psychiatry at UCSD
Dr. Sarah Banks first benefitted from WAM funding when at the Lou Ruvo Center for Brain Health in Las Vegas, where she collaborated closely with Dr. Caldwell. A generous WAM grant obtained then allowed time to focus a series of studies on why women seem to react differently to key Alzheimer’s pathology than men. Since 2018, Dr. Banks has been building her lab at the University of California, San Diego, with a focus on sex differences in Alzheimer’s disease. Building directly on her WAM funded work, she has obtained state and federal funding to continue this work, with a particular focus on how women tend to accumulate more tau pathology (a bad protein that builds up in Alzheimer’s) than men, and how genetics might drive this relationship, as well as how it is reflected on scanning and with memory tests. She is building her collaborative network at UCSD where she works as an Associate Professor, and now works closely with Dr. Erin Sundermann on several projects. She is also a passionate clinician, and is focused on making strides in using sex differences as a window to examine Alzheimer’s, and her latest ideas extend into how modifiable risk factors such as exercise and sleep might explain sex differences in tau.
Grant recipient: Dr. Roberta Diaz Brinton, Director of the Center for Innovation in Brain Science, and Professor in the Departments of Pharmacology and Neurology, at the University of Arizona
For the past four years, WAM has supported Dr. Brinton’s groundbreaking work on the relationship between estrogen and Alzheimer’s disease. Dr. Brinton and her colleagues investigated the impact of breast cancer therapies on the risk of developing Alzheimer’s later in life. Outcomes of their research yielded exciting findings which are currently embargoed but will appear soon in the March 24, 2020 issue of JAMA Open Network. To ensure that the women, clinicians and scientists worldwide are informed, the results of Brinton’s WAM study will be freely available through the JAMA Open Network Neurology.