Besides age, inheritance of the ApoE4-encoding form of the apolipoprotein E (APOE) gene is the most important risk factor for developing Alzheimer’s disease. We have discovered a mechanism by which ApoE works to promote Alzheimer’s disease: it binds to the amyloid-beta peptide and converts it into toxic species that kill neurons and cause neurodegeneration, with the ApoE4 form being the most detrimental. We are using complementary approaches to identify drugs that prevent ApoE from promoting this neurodegenerative pathway in Alzheimer’s disease. Our recent high-throughput drug screening efforts have identified two drugs that are FDA-approved for other conditions that block the effects of ApoE4 on amyloid-beta in test tubes and in cells. Our subsequent analyses of clinical data revealed that taking either of the two medications, imipramine or olanzapine, may be associated with improved cognition over time and a better clinical diagnosis in Alzheimer’s disease patients, and our findings have been published .

Dr. Potter’s laboratory has developed a cerebral organoid model system to study key aspects of Alzheimer’s disease and Down syndrome neuropathology. Cerebral organoids are miniature brains grown from human induced pluripotent stem cells (iPSCs) in the lab, and they include neurons, glial cells, and neural progenitor cells organized into layers that resemble the human cerebral cortex. We have also established a collaboration with Dr. Natalia Vergara, whose laboratory has developed a retinal organoid model system, to study aspects of Alzheimer’s disease and Down syndrome pathology in the eye. For example, we are using cerebral and retinal organoids derived from APOE4 carriers to assess Alzheimer’s disease and Down syndrome pathologies and to gain an increased understanding of the underlying pathological mechanisms associated with different APOE genotypes. We are also using these organoid systems in preclinical studies to evaluate the potential efficacy of drugs we have identified in our ongoing screens for apoE inhibitors.

Dr. Potter’s laboratory is studying the role of the KIF11/Kinesin-4/Eg5 kinesin motor protein in Alzheimer’s disease. Research from our lab has shown that amyloid-beta peptides inhibit the activity of kinesin motors, such as KIF11, which results in the disruption of intracellular transport and leads to chromosome mis-segregation and aneuploidy. We are studying whether increased expression of KIF11 rescues learning and memory deficits as well as long-term potentiation in the 5xFAD mouse model of Alzheimer’s disease. We are also carrying out pre-clinical studies with a set of small molecules that we discovered in a screen to identify drugs that block amyloid-beta-mediated inhibition of kinesin motor proteins, which may serve as a new therapeutic approach to Alzheimer’s disease.

Mosaic neuronal aneuploidy and consequent apoptosis characterize and may underlie neuronal loss in many neurodegenerative diseases and neurodevelopmental disorders. Our laboratory is studying the underlying mechanisms associated with aneuploidy in Alzheimer’s disease, frontotemporal dementia, and Huntington’s disease. Our findings are likely to provide insights into the diagnosis, prevention, and treatment of these disorders.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a natural human protein that stimulates and modulates the immune system. We identified GM-CSF as a protein that is upregulated in the blood of people with rheumatoid arthritis, and we hypothesized that it may explain why they are partially protected from developing Alzheimer’s disease. We first tested GM-CSF treatment in an Alzheimer’s disease mice model and found that it reversed cognitive deficits and reduced amyloidosis. Our recently published Phase 2 clinical trial in participants with mild-to-moderate Alzheimer’s disease showed that treatment with recombinant human GM-CSF (sargramostim) improved cognition and reduced measures of brain pathology. We recently discovered that GM-CSF treatment also improves cognition and reduces markers of Alzheimer’s disease brain pathology in the Dp16 mouse model of Down syndrome. We are currently expanding our translational research to include studies of GM-CSF as a potential treatment for traumatic brain injury, cognition in Down syndrome, viral diseases, specifically West Nile Virus and COVID-19, and even normal aging. Our recent findings have been published and .

We are carrying out pre-clinical studies to test the efficacy of small molecules that contain fragments of granulocyte-macrophage colony-stimulating factor (GM-CSF) yet still function like GM-CSF (mimetics). If our research program is successful, these molecules will be a more cost-effective therapy for Alzheimer’s disease and possibly for many other disorders.

A key aspect of any translational research program aimed at developing new treatments for neurodegenerative diseases and other disorders is the identification of improved diagnostic measures. Every cell in the body secretes fragments of itself, termed exosomes, which can be isolated from the blood and cerebrospinal fluid (CSF). These include exosomes from cells in the brain. Thus, taking a small sample of blood can be similar to taking a brain biopsy, and it allows a non-invasive window into the brain and its pathologies. Specifically, we are working on ways to isolate exosomes from the blood that are secreted by each of the cell types in the brain, including neurons, in order to detect, for example, AD pathology, before it can be measured in any other manner.

Alzheimer’s disease and other neurodegenerative diseases, including Down syndrome, are often characterized by physiological changes, including inflammation. These changes can be detected by measuring proteins in the blood or cerebral spinal fluid (CSF). We are collecting and studying blood and sometimes CSF samples from our research participants and testing for various biomarkers that may, in the future, not only allow us and patients to know whether they are at risk for AD, but may also allow us to measure the effectiveness of new therapies.