New WAM Grants Support Research on Gut-Brain Interactions, Menopause and Sarcopenia

Women account for two-thirds of cases of Alzheimer’s disease (AD) and little is known about sex-based differences in risk and disease progression.

To fill those knowledge gaps, the Women’s Alzheimer’s Movement (WAM) at Cleveland Clinic awarded grants for three of the most promising research projects in the field. The two-year projects focus on the connection between the gut and brain health, the impact of menopause-related hormonal changes on cognitive decline and the neuroprotective benefits of resistance training.

WAM at Cleveland Clinic is a collaboration between WAM, founded by Maria Shriver, and Cleveland Clinic. It is focused on raising awareness about women’s increased risk of AD and supporting education, prevention and treatment for this highly elusive and prevalent disease.

The recipients of the 2026 awards and their projects are described below.

Early warning

Biological “early warning signs” of impending cognitive decline among women with and without memory and language decline

Category: Internal Funding

Project title: Gut-Brain Interactions as Modifiable Targets for Preclinical Cognitive Health

Principal investigator: Darlene Floden, PhD, staff neuropsychologist in the Neurological Institute and associate professor of Neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

Alzheimer's disease is an escalating public health crisis and there are limited tools to detect or prevent it during the preclinical “silent” phase, when irreversible brain damage has not yet occurred. Identification of reliable molecular biomarkers and risk factors predictive of early cognitive decline is crucial.

To that end, Dr. Floden and her group will leverage stool and peripheral blood samples from the Cleveland Clinic Brain Study – a longitudinal, prospective study designed to intricately profile the “silent” phase of AD through biospecimen collection and comprehensive cognitive testing – to define biological “fingerprints” associated with early brain changes. The researchers will use systems biology and machine learning models to integrate gut microbiome and blood transcriptomic data to identify early signatures that predict future cognitive decline.

Biologically coherent, modifiable pathways elucidated through the project will serve as targets in a planned interventional trial. Ultimately, this research may guide personalized strategies, such as dietary or microbiome-based interventions, to help preserve brain health and delay or prevent AD.

“This is a unique opportunity to look at what is happening in the gut-brain axis just before cognitive change starts,” Dr. Floden says. “The hope is to intervene in the disease process before symptoms appear.”

Menopause and memory

Genetic influences on menopause-related memory change and the medial temporal lobe

Category: Internal Funding

Project title: Co-Occurrence of Menopause and Memory Decline: Hormone-Genetic Effects on Pattern Separation and Hippocampal Endophenotype

Principal investigator: Xiaowei Zhuang, PhD, research associate, Lou Ruvo Center for Brain Health, Cleveland Clinic.

The apolipoprotein E4 (APOE4) gene variant is significantly linked to development of AD late in life. APOE4-associated pathological amyloid accumulation and cognitive impairment are known to be greater in women than in men. The mechanism underlying the elevated risk, however, is poorly understood. Also unknown is how menopause-related hormonal changes interact with the APOE genotype to shape vulnerability in the early medial temporal lobe (MTL), the key memory region.

Dr. Zhuang’s group will use memory tasks to examine the interactions among the APOE genotype, MTL activation and connectivity in women across all menopausal stages. The participants will perform object and spatial pattern separation tasks sensitive to early dysfunctions in the hippocampus and surrounding memory regions, and during the latter battery, a subset will undergo functional brain magnetic resonance imaging. The researchers hypothesize that menopausal transition and related hormonal changes will be associated with worse pattern separation performance, particularly in APOE4 carriers, and that estrogen depletion will interact with APOE4 to exacerbate MTL dysfunctions.

The project will provide preliminary information about genetic influences on menopause-related memory changes and MTL-centered neural dysfunctions, establish sensitive behavioral and neural markers of preclinical AD risk, and inform sex- and genotype-specific strategies for early risk stratification and prevention during the menopausal transition.

“Understanding how hormonal changes and genetic risk interact during midlife may be the first step toward earlier, more precise prevention strategies for women during this critical window of brain health,” says Dr. Zhuang.

Resistance training

Feasibility and acceptability of resistance training as an adjunct to existing AD therapy in women at risk for AD and with early symptoms

Category: Internal Funding

Project title: Addressing Sarcopenia in Alzheimer’s Disease Care: A Patient-Centered Pilot Study of a Resistance Training Model for Women at Increased Risk and Early-Stage Alzheimer’s Disease

Principal investigators: Ruth Farrell, MD, MA, Interim Research Director of the Cleveland Clinic Women’s Comprehensive Health and Research Center, and Lauren Wichman, MD, staff physician with Cleveland Clinic Sports Medicine.

Sarcopenia – age-related loss of muscle mass – is prevalent in individuals with AD and contributes to cognitive decline and functional impairment. Resistance training is a low-cost, accessible strategy for mitigating sarcopenia, which has neuroprotective benefits. Research is lacking, however, on integration of it into care of women at increased risk for AD or who are living with early-stage AD.

Drs. Farrell and Wichman will collaborate with Pelin Batur, MD, Jagan Pillai, MD, PhD, and Sandra Darling, DO, MPH, from Cleveland Clinic, and Stacy Sims, PhD, to develop a novel intervention that can be integrated into patients' care management plans. They will conduct a study to assess the usability, acceptability and feasibility of a tailored resistance training intervention for women 45 and older who have increased risk or early stage AD.

Based on current evidence, a series of total body resistance training exercises, with tailored recommendations for exercise intensity, repetitions and sets, will be developed. MedBridge, a program designed for patients to access, follow and track individually assigned exercise programs at Cleveland Clinic, will be used to deliver the intervention. They will also collect a series of other measures, including patients' overall function and wellbeing.

The research will produce a body of scientific evidence about the specific needs, preferences and barriers faced by women who are at increased risk for Alzheimer's disease or have early stage disease when considering resistance training as part of their care regimen. It will also result in development of a tailored intervention that addresses the unique physical, cognitive and logistical challenges of this population that can work in synergy with other therapeutic approaches.

The results will break new ground in guiding future strategies that combine exercise, established therapeutics and healthy lifestyle changes to improve the health and well-being of women who are IR-AD and ES-AD and serve as a foundation for a larger trial to examine the impact of this novel intervention among different patient populations.