THE ZACHARY AND ELIZABETH M. FISHER ALZHEIMER’S DISEASE EDUCATION AND RESOURCES PROGRAM AT THE NYU GROSSMAN SCHOOL OF MEDICINE
Dr. Martin Sadowski, Co-Director
Martin J. Sadowski, MD, PhD, DSci, is an Associate Professor in the Departments of Neurology, Psychiatry, and Biochemistry and Molecular Pharmacology at the New York University School of Medicine.
Dr. Sunnie Kenowsky, Co-Director
The niece of the late Zachary and Elizabeth Fisher, Dr. Kenowsky conducts research at the Fisher Alzheimer’s Disease and Education program at NYU school of Medicine with a goal to change the standard of care for AD patients.
About The Zachary and Elizabeth M. Fisher Alzheimer’s Disease Education and Resources Program at the NYU Grossman School of Medicine
The primary research projects supported by the Fisher Center for Alzheimer’s Research Foundation address their mission to find the cause of Alzheimer’s disease, improve the care of those living with it, and eventually find a cure.
Project 1 uses mathematical modeling to identify genes affecting the rate of Alzheimer’s disease progression. Project 2 explores the role of an astrocytic protein, Peroxiredoxin 6, and its overexpression for Alzheimer’s disease therapy. Project 3 explores benefits of the Comprehensive, Individualized, Person-Centered Management Program in patients with advanced Alzheimer’s disease. Project 4 explores the role of apolipoprotein E in regulating acquisition by microglia features of neurodegenerative microglia (MGnD) and Project 5 explores effects of 40-Hz light stimulation for Alzheimer’s therapy.
Discovery of genes regulating progression of Alzheimer’s disease.
Accumulation of β-amyloid peptide in the brain is a prerequisite of Alzheimer’s disease, but its mere presence does not produce disease symptoms. Instead, β-amyloid initiates an insidious neurodegenerative cascade involving intraneuronal accumulation of hyperphospho-rylated tau (p-tau), acquisition by microglia features of neurodegenerative microglia (MGnD), loss of synapses, and nerve cell bodies, which all tightly correlate with severity of dementia symptoms. Genes regulating the brain’s susceptibility to β-amyloid and the tempo neurodegeneration progresses are largely unknown.
To identify genes regulating the rate of Alzheimer’s disease progression we use linear mixed modeling of longitudinal cognitive data from Alzheimer’s patients, whose genome has been sequenced. The KL-VShet+ variant of the Klotho’s gene is an example of a gene whose protective effect on Alzheimer’s disease we have recently established. KL-VShet+ promotes physical and mental longevity during normal aging, but its role in Alzheimer’s disease has been unknown. We determined the KL-VShet+ variant significantly retards progression of Alzheimer’s disease in male patients who do not carry the APOE ε4 allele (Figure 1). Both klotho and apoE4 are pleiotropic proteins exerting opposing effects on a number of biological processes involved in Alzheimer’s disease: neuroinflammation, oxidative stress, p-tau accumulation, and synaptic plasticity. A protective effect of KL-VShet+ in respect to all these processes cancels out by negative effects of the ε4 allele encoding the apoE4 protein. KL-VShet+ endowed protective effects also are absent in female patients. Our results were published in Genes (Chen RX et al. Genes 2023 14(4):917 https://doi.org/10.3390/genes14040917).
Role of Peroxiredoxin 6 (PRDX6) in Alzheimer’s disease.
Accumulation of p-tau protein in neurons is a hallmark of Alzheimer’s disease. P-tau-bearing neurons are accompanied by neurodegenerative microglia (MGnD) and neurotoxic astrocytes (A1), which both perpetuate tau accumulation and directly contribute to neuronal demise. P-tau accumulation and neuronal loss directly correlate with severity of dementia. Factors, endowing astrocytes with resistance to acquire the neurotoxic A1 state and thus attenuating the inflammatory cascade associated with p-tau accumulation are unknown. We hypothesize the PRDX6 protein, which restores cells damaged by oxidative stress, can be such a factor. In the brain PRDX6 is expressed by astrocytes and becomes highly upregulated in astrocytes associated with β-amyloid plaques and p-tau-bearing neurons. However, the precise role of PRDX6 in Alzheimer pathogenesis is unknown.
To explore the effect of PRDX6 on p-tau pathology, we genetically modulated its expression level in PS19 transgenic mice with intraneuronal p-tau accumulation and appearance of neurodegenerative microglia (MGnD) and A1 neurotoxic astrocytes. We determined PRDX6 overexpression reduces acquisition of the A1 state by astrocytes, which is associated with reduced p-tau accumulation and expression of A1 and MGnD defying genes, while reduced PRDX6 expression has opposite results. A manuscript detailing this work is currently in preparation. We also are exploring a prospect of conditional overexpression of PRDX6 as a therapeutic approach for Alzheimer’s disease. To this end we have developed transgenic mice with the human PRDX6 gene sequence inserted within the ROSA locus, whose expression is blocked by a loxP flanked STOP codon. They will be crossed to PS19 mice and to Cre recombinase lines to enable cell-lineage specific conditional PRDX6 overexpression in animals with already established p-tau pathology.
Comprehensive, Individualized, Person-Centered Management (CI-PCM) Program for Patients with advanced AD.
Patients with advanced Alzheimer’s disease decline quickly and pose multiple challenges for providing appropriate care. They gradually lose the ability to perform basic activities of daily living and become completely caregiver-dependent. In addition, over the course of disease 90% of patients develop Behavioral and Psychological Symptoms of Dementia, which cause substantial distress for both the person living with Alzheimer’s disease and their caregiver. Thus, we have advocated for the CI-PCM Program to improve care of patients with advanced Alzheimer’s disease. This program was developed by Drs. Sunnie Kenowsky and Barry Reisberg at NYU and relies on teaching the care partners to properly recognize and respond to patients’ needs by appropriately managing their medical problems and also re-educating the patients how to perform basic skills and activities of daily living.
We previously completed a 28-week, single-blinded, randomized, controlled trial testing efficacy of CI-PCM and memantine treatment on functional and behavioral symptoms in advanced Alzheimer’s patients. We showed CI-PCM+memantine is ~7.5 times more beneficial than memantine alone. Recently, we performed a 24-week extension study and showed that benefits of the CI-PCM program are retained at 52 weeks both on FAST and ADCS-ADL-sev-abv functional scales. We also analyzed benefits of CI-PCM on the risk of emergency room visits and hospitalizations, which in CI-PCM subjects decreased by 80% and 75% compared to the control group, respectively.
Role of apoE in regulating characteristics of neurodegenerative microglia.
We are exploring whether apoE expressed by astrocytes and by activated microglia exert oppositional control on the behavior of neurodegenerative microglia (MGnD) in Alzheimer’s disease. We also examine therapeutic merit of apoE-based approaches to attenuate inflammatory character of microglia.
The potential impact of this project has been acknowledged by the National Institute on Aging, who awarded us a new five-year grant totaling $3.45M R01 AG075840 Role of Microglia in Neurodegeneration -Effect of ApoE (6/15/22-2/28/27, PI M Sadowski).
Effects of 40-Hz light stimulation on Alzheimer’s pathology.
There is a growing interest in noninvasive brain stimulation to ameliorate Alzheimer’s disease symptoms. In collaboration with the Buzsáki Laboratory, we validated previously claimed effects of 40-Hz flickering light on reducing β-amyloid deposition in Alzheimer’s transgenic mice. We found that 40-Hz flickering simulation did not engage native gamma oscillations in those brain areas, which are important for Alzheimer’s disease and also, in contrast to previously published reports, we found no reliable changes in β-amyloid plaque count or microglia activation. Though our study presented mainly negative findings, due to strong interest in noninvasive brain stimulation, it gained the attention of Nature Neuroscience, where it was published. (Soula M et al. Nat. Neurosci. 2023 26(4):570-578 https://doi.org/10.1038/s41593-023-01270-2)