Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in huma [View all]

[LiberalArkie]

December 22, 2025

Introduction

Alzheimer’s disease (AD), commonly considered irreversible since its discovery over a century ago, is the leading cause of dementia and is projected to afflict >150 million people by 2050.1,2,3 Current therapies targeting amyloid beta (Aβ or clinical symptoms offer limited benefit to patients,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 highlighting the need for complementary and alternative treatments. Notably, people who carry autosomal dominant AD mutations can remain symptom-free for decades before clinical onset, and some individuals known as nondemented with Alzheimer’s neuropathology (NDAN) accumulate abundant amyloid plaques yet remain cognitively intact.21,22,23,24,25,26,27 These findings imply the existence of intrinsic brain resilience mechanisms that delay or counteract disease progression, suggesting the possibility of preserving or enhancing such processes to modify disease trajectory or foster recovery from AD.
Nicotinamide adenine dinucleotide (NAD+) homeostasis is central to cellular resilience against oxidative stress, DNA damage, neuroinflammation, blood-brain barrier (BBB) deterioration, impaired hippocampal neurogenesis, synaptic plasticity deficits, and neurodegeneration. Prior studies report NAD+ depletion in AD models and partial attenuation of pathology with NAD+ precursor supplementation.28,29,30,31,32,33,34,35,36,37,38,39 However, NAD+ precursors may also produce supraphysiologic NAD+ levels that promote cancer.40,41,42,43,44,45,46,47,48,49,50 Thus, maintaining physiologic NAD+ homeostasis is critical. Notably, the relationship between NAD+ homeostasis, disease severity, and therapeutic reversibility of AD has not been previously explored.
Here, we show that pharmacologic restoration of NAD+ homeostasis via P7C3-A20, a neuroprotective compound that restores NAD+ homeostasis without producing supraphysiologic NAD+ levels,51,52,53,54,55,56 reverses cognitive deficits and neuropathology in advanced Aβ- and tau-driven AD models. We identify conserved molecular signatures between human and mouse AD and show that the magnitude of NAD+ homeostasis disruption correlates with pathology and symptom severity in mouse and human AD. We also demonstrate that NDAN brains display transcriptional profiles compatible with preserved NAD+ homeostasis and that P7C3-A230 restores NAD+ homeostasis and prevents oxidative damage and mitochondrial dysfunction in oxidatively stressed human brain microvascular endothelial cells (HBMVECs), a key component of the BBB. We additionally identify 46 conserved protein alterations in human and mouse AD brain that are corrected by AD reversal, together with overlapping transcriptomic changes in human AD. This highlights potential mechanisms and therapeutic targets for preserving and restoring brain resilience to AD.
These findings of cognitive recovery and pathological reversal in diverse models of advanced AD support disease progression as modifiable and driven by diminished brain resilience, with early cognitive impairment resulting from processes that promote neurodegeneration rather than solely from fixed neuronal loss. We propose that therapies to restore brain resilience, such as normalization of NAD+ homeostasis, merit clinical evaluation for prevention and reversal of AD and related dementias.

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https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1