Latest WAM Grant Recipients Take on Alzheimer’s Disease in Women Across Multiple Fronts

It’s increasingly well recognized that many aspects of Alzheimer’s disease (AD) differ between men and women. Some of those differences call for approaches to AD research specific to women, and that’s the impetus behind the research grant program of the Women’s Alzheimer’s Movement (WAM) at Cleveland Clinic, a pioneering organization devoted to advancing gender-based research, treatment, disease prevention and education for brain health.

WAM at Cleveland Clinic just announced the recipients of its 2024 research grants. The four newly funded projects and their recipients are profiled below.

Female-specific oxidative targets in AD

Category: Award to Established Investigator

Project title: Female-specific oxidative targets and their protection in Alzheimer’s disease

Principal investigators: Tatiana Byzova, PhD, Department of Neurosciences, and Eugene Podrez, MD, PhD, Department of Inflammation and Immunity, both in Cleveland Clinic Lerner Research Institute

Inflammation and its resulting oxidative stress are linked to AD and might explain why the disease affects men and women differently. It has been unclear which molecules are affected by oxidative stress and how to protect them. The researchers receiving this award have previously demonstrated in animal studies and human samples that a specific inflammation-related oxidation process is common in AD. They have pinpointed the exact molecules damaged by this process and have found that the damage differs between females and males.

With this award, the researchers aim to further study how this oxidation affects men and women differently in AD and look for ways to block its harmful effects. They will use models of AD in mice and human samples to find new molecules affected by oxidation, focusing on those unique to females. They are using a new method they developed that combines lipid and protein analysis to identify these molecules more effectively. Additionally, they plan to use a chemical they created to interrupt this damaging oxidation process in live models, aiming to protect molecules that are specifically damaged in females. They expect this work to show how this approach can affect brain plaque buildup, immune cell activation and, eventually, cognitive function in females.

“By identifying new female-specific damage, we expect to open new research directions on sex dimorphism in Alzheimer’s disease and on female-tailored therapeutic approaches to prevent this oxidative damage, thereby supporting the development of novel intervention therapies,” says co-principal investigator Tatiana Byzova, PhD.

The investigators expect that the findings from this work will form the basis for a larger multi-investigator research proposal to the National Institutes of Health on sex-specific oxidation in AD.

Immunometabolism endophenotypes underlying AD sex differences

Category: Young Investigator Award

Project title: Immunometabolism endophenotypes underlying sex differences of Alzheimer’s disease

Principal investigator: Yuan Hou, PhD, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute

Mentor: Feixiong Cheng, PhD, Staff and Director, Cleveland Clinic Genome Center

The research funded by this award is based on the hypothesis that sex-specific variations and treatment responses in AD are associated with immunometabolism-related cellular and genetic changes not adequately captured by traditional assessment methods such as amyloid imaging and cerebrospinal fluid (CSF) analysis. The hypothesis stems from preliminary studies demonstrating sex-specific gene signatures and differences in inflammatory proteins and metabolites among patients with AD. In response, the investigators propose that the so-called immunometabolism endophenotype (i.e, the interplay between cellular metabolism and immune responses) manifests in a sex-dependent fashion in AD.

The researchers will explore these ideas by analyzing large-scale metabolomics and proteomics data derived from blood and CSF samples from human subjects at various stages of AD. The samples will be from the Cleveland Clinic BioRepository and Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. The investigators’ analysis will aim to address the hypothesis that brain cell type-specific immunometabolism endophenotypes exist in AD and operate in a sex-specific fashion. Their work will additionally examine differences in immune-metabolic alterations between central and peripheral systems (i.e., CSF and blood) in male and female patients with AD.

The research will leverage the multi-omics and systems biology expertise and resources of the Feixiong Cheng laboratory established at the Cleveland Clinic Genome Center and Lerner Research Institute, which has a track record of combining tools from genetics and genomics, clinical databases, artificial intelligence, network medicine and experimental systems biology to enhance understanding of AD and other diseases and to identify novel biomarkers and treatment targets.

“We believe the insights from this research will enable a deep, molecular understanding of the immune-metabolic pathways that underlie sex differences in AD,” says principal investigator Yuan Hou, PhD. “These pathways can then potentially be targeted for rapid development of sex-specific precision medicine approaches to the disease.”

Spatial navigation as a screening tool for preclinical cognitive change

Category: Young Investigator Award

Project title: Navigating Alzheimer’s disease: Utility of spatial navigation as a screening tool for preclinical cognitive change in women

Principal investigator: Taylor Fama Levine, PhD, Department of Neuropsychology, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas

Mentor: Jessica Caldwell, PhD, Director, WAM Prevention Center at Cleveland Clinic

On average, women are diagnosed with AD two years later than men are. Some of this diagnostic delay in women has been attributed to current cognitive screening practices, which rely heavily on assessing verbal memory, a realm in which women show an advantage over men in early-stage AD. In contrast, spatial navigation abilities — an area where women tend to perform less well than men — are rarely evaluated in clinical cognitive screening.

This award will fund a pilot study to generate preliminary data to evaluate sex differences in an existing validated spatial navigation task that has been associated with AD biomarker burden and clinical progression. The pilot study will enroll cognitively normal men and women who will complete the computerized spatial navigation task and undergo verbal memory testing, traditional global cognitive screening and assessment of plasma markers of AD pathology.

The primary outcome of interest will be the effect of sex on spatial navigation task performance, which will then be evaluated in the context of the interaction between sex and plasma AD biomarkers. These findings will also be compared with sex-specific performance on verbal memory assessment and global cognitive screening. Additional aspects of the study will explore the impact of depressive symptoms on spatial navigation (and any sex-related differences) and adapt the spatial navigation task to be compatible with MRI scanning.

“Assessing spatial navigation ability is a potential way to improve detection of preclinical AD in women, in view of its association with AD biomarker burden and clinical progression as well as women’s established relative weakness in this domain,” says principal investigator Taylor Levine, PhD. “Integrating a standardized procedure for assessing spatial navigation into clinical screening could enable earlier detection of preclinical AD in women and facilitate earlier intervention, when treatments are more likely to be effective.”

Brain impact of quitting ultra-processed foods

Category: Award co-funded by the brain wellness brand MOSH

Project title: How does quitting ultra-processed foods impact the brain?

Principal investigators: Jessica Caldwell, PhD, Director, WAM Prevention Center at Cleveland Clinic, and Sandra Darling, DO, Department of Wellness and Preventative Medicine, Cleveland Clinic

This award will fund a study testing what happens to the brain when individuals abstain from ultra-processed food for nine months. “While we know that eating fewer processed foods is good for the brain as we age, we do not know how quickly brain effects might be observed when we are younger, so this is a new approach to evaluating diet and Alzheimer’s disease,” explains co-principal investigator Jessica Caldwell, PhD.

The study will enroll 50 participants aged 30 years or older — some with mild cognitive impairment (MCI) and some with normal memory but family history of AD, and all of whom report typically eating more than 50% of daily calories from ultra-processed foods. Participants will undergo baseline brain MRI studies and then receive education about the degree of food processing in various food types based on the NOVA classification. Participants will be instructed to abstain from ultra-processed foods (those in NOVA level 4) and reduce consumption of foods with the next-highest level of processing (NOVA level 3), aiming to consume less than 5% of daily calories from these types of foods.

After nine months of this dietary intervention, participants will undergo repeat brain MRI to assess any changes in brain volume, brain function and other measures and to evaluate any effects in specific brain regions, such as the hippocampus. Pre- and post-intervention levels of blood-based amyloid and tau will also be assessed, as will scores on a cognitive screening assessment. Effects will be analyzed to identify any differences in individuals with and without MCI.

The researchers hope their findings will support larger investigations of nutrition intervention in people who are healthy as well as those who have MCI or even dementia.