25 Dec Case Western Scientists Reverse Advanced Alzheimer’s Pathology in Mice

MedicalResearch.com Interview with:

Dr. Pieper

Andrew A. Pieper M.D., Ph.D.
Professor, Department of Psychiatry, School of Medicine
Professor, Department of Neurosciences
Professor, Department of Pathology
Investigator, University Hospitals Harrington Discovery Institute, Harrington Discovery Institute
Associate Director, Medical Scientist Training Program, School of Medicine
Case Western Reserve University, University Hospitals Cleveland Medical Center, and
at the Louis Stokes Cleveland VA Medical Center

MedicalResearch.com: What is the background for this study?

Response: NAD+, a central cellular energy and signaling molecule, declines with age throughout the body, including the brain. When NAD+ falls below necessary levels, cells lose their ability to carry out essential maintenance and survival functions. We found that the NAD+ decline is more severe in brains from people with Alzheimer’s disease (AD) and in mouse models of AD, whereas brains of people with AD pathology but preserved cognition show gene-expression patterns consistent with maintained NAD+ homeostasis.

MedicalResearch.com: What are the main findings?

Response:  We then showed that restoring and maintaining NAD+ balance in two distinct AD mouse models (amyloid-driven 5xFAD mice and tau-driven PS19 mice) both prevented disease and, importantly, reversed advanced pathology and fully restored cognition after delayed treatment. Treatment normalized multiple pathological features, including blood–brain barrier integrity, axonal integrity, neuroinflammation, hippocampal neurogenesis, synaptic function, and oxidative damage, and reduced clinically diagnostic blood biomarker of AD (phosphorylated tau217). Proteomic analysis also identified 46 proteins that were altered in diseased mouse brain that were normalized by restoration and maintenance of NAD+ homeostasis and also show similar changes in human AD brain, pointing to potential translational targets.

MedicalResearch.com: Is there a risk or benefit to individuals from taking over the counter NAD+ supplements?

Response:  This is an important point and thanks for asking this question. Caution with these supplements is certainly warranted as they can raise cellular NAD+ to supraphysiologic levels, which has been shown to promote cancer in animals. Our compound, P7C3‑A20, acts differently. Specifically, it helps cells restore and maintain appropriate NAD+ homeostasis under stress without driving NAD+ to abnormally high levels. That balanced restoration produced disease reversal in mice while avoiding the risks associated with excess NAD+. Individuals considering over the counter NAD+ supplements should discuss the risks and benefits with their physician.

MedicalResearch.com: What should readers take away from your report?

Response: Advanced Alzheimer’s-like pathology in mice can be reversed and cognition fully restored by reestablishing healthy NAD+ balance. This provides proof of principle that some forms of dementia may not be inevitably permanent, and that the damaged brain can, under the right conditions, repair itself and recover function.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: Foremost, these findings need to be translated into carefully designed human clinical trials to test safety and efficacy.  In addition, the precise components of NAD+ and energy homeostasis that are essential for recovery need to be determined. Other future directions include exploring complementary or synergistic approaches to enhance reversal, and testing whether the same strategy works in other chronic, age-related neurodegenerative diseases.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: I and some co‑authors hold patents related to this work. I am also a co‑founder of Glengary Brain Health. Substantial funding and support were provided by The Valour Foundation, the Case Western Reserve University Rebecca E. Barchas MD DLFAPA University Professorship in Translational Psychiatry, and the University Hospitals Morley‑Mather Chair in Neuropsychiatry. We thank all collaborators and funders for their essential support.

Citation:

Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain

Chaubey, Kalyani et al.

Cell Reports Medicine, Volume 0, Issue 0, 102535
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1

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Last Updated on December 25, 2025 by Marie Benz MD FAAD