REV-ERBα Inhibition Boosts Brain NAD+ for Alzheimer’s Therapy

I’m Sara Morgan. I study psychology and neuroscience with a focus on real-world applicability. Here’s the blunt take: a Nature Aging paper from Oct 2025 shows that inhibiting the circadian protein REV-ERBα raises brain NAD+ in mouse models of Alzheimer’s and reduces tau pathology. That’s a nontraditional path for a disease often framed around amyloid and tau therapies. Now the hard work begins: translate this into human relevance, safety, and practical targets.

Core findings and brain-specific NAD+ modulation

Let’s get to the core findings. In two mouse setups, global REV-ERBα deletion and astrocyte-specific deletion, NAD+ levels in the brain rose significantly. These are neurons and glia responding to a clock protein, not peripheral changes. In the astrocyte model, removing REV-ERBα directly boosted NAD+ and prevented tauopathy in the P301S mice.

Importantly, this pathway operates via the NFIL3-CD38 axis (Brain-specific signaling module driving NAD+ increase in astrocytes) in astrocytes, not NAMPT, which differs from patterns seen in cardiac tissue. So the brain uses a distinct lever to raise NAD+, and CD38 becomes a central gatekeeper here.

From a therapeutic angle, an experimental REV-ERBα-targeting drug protected mice from tau-related pathology. That suggests a potential to slow neurodegeneration by re-timing or reprogramming metabolism in the aging brain. And this isn’t a minor detour: more than 50% of Alzheimer’s risk genes are under circadian rhythm control, underscoring a deep clock-disease connection. The study, led by Erik Musiek, MD, PhD, and Jiyeon Lee, PhD, from Washington University School of Medicine, shifts the focus away from solely amyloid/tau downstream effects toward how brain energy and immune signaling adapt to the 24-hour cycle.

Tissue-specific mechanisms and therapeutic implications

On the tissue specifics, the brain’s response differs from the heart’s. REV-ERBα’s control of NAD+ hinges on different gene networks across organs. In the brain, NAMPT levels stay unchanged with REV-ERBα inhibition, which means the NAD+ rise isn’t coming from a NAMPT shift. Instead, the NFIL3-CD38 axis in astrocytes drives the change.

That has concrete implications for drug design: you’d want compounds that modulate this axis in brain cells without triggering NAMPT-related pathways elsewhere. In other words, a brain-targeted approach could minimize off-target metabolic effects.

Connecting data to patient paths and broader context

Let me connect the data to the patient path. If REV-ERBα suppression protects against tau buildup in the medial temporal lobe, the region that first shows Alzheimer’s changes, that could delay symptom onset or slow progression. The paper also notes a broader context: 82 genes linked to Alzheimer’s risk intersect with circadian regulation. That’s not a neat line; it’s a complex, overlapping network. Still, it provides a rationale for exploring chronopharmacology or astrocyte-focused NAD+ strategies as adjuncts to imaging-guided interventions.

By the way, they also note that NAD+ supplementation trends in anti-aging circles are widespread, but this study points to a more precise mechanism for brain NAD+ modulation. It’s not about popping NAD+ pills; it’s about steering endogenous production and consumption within astrocytes to support neuronal resilience. This matters for trial design: you’d look for biomarkers tied to NFIL3-CD38 activity and astrocyte NAD+ pools, not just peripheral NAD+ levels.

Practical roadmap and next steps

From a practical standpoint, here’s how I’d think about moving forward. First, validate in human-derived systems. If astrocytes from aged human tissue or iPSC-derived models show the same NFIL3-CD38-NAD+ dynamics, that strengthens the case for a human trial.

Second, define a safety profile for chronically modulated REV-ERBα activity, given its role in circadian regulation. Third, pair this approach with existing strategies that address tau and amyloid, not as a replacement, but as a complementary route that may enhance neuronal energy balance and resilience.

What do we know for sure now? REV-ERBα inhibition can boost brain NAD+ via the NFIL3-CD38 axis in astrocytes, lowers tau pathology in Alzheimer’s models, and is tied to a broad clock-related gene network linked to disease risk. NAMPT isn’t the lever in the brain, so expect brain-specific mechanisms to guide any human therapies. The apoptosis and inflammatory milieu in aging brains add complexity (but this pathway gives a tangible target).

Key takeaways for researchers and clinicians

Here’s what I take away. One, circadian biology is a básico layer in brain aging and neurodegeneration. Two, astrocytes play a central role in energy balance and neuroprotection through NAD+ control. Three, nontraditional approaches that modulate brain metabolism could complement anti-amyloid strategies and potentially extend the window for intervention. Four, any clinical work must measure CNS-specific NAD+ dynamics, tau markers, and circuit-level outcomes, not just peripheral indicators.

Key points to keep in mind as you read more and talk with teams:

• REV-ERBα inhibition raises brain NAD+ in mouse models and reduces tau pathology.
• The effect is mediated by the NFIL3-CD38 axis in astrocytes; NAMPT in the brain stays unchanged.
• Astrocyte-specific REV-ERBα deletion prevents tauopathy in P301S mice.
• Over 50% of Alzheimer’s risk genes are circadian-regulated, underscoring the clock-disease link.
• Findings appear in Nature Aging (Oct 2025), from WashU Medicine under Erik Musiek and Jiyeon Lee.
• An experimental REV-ERBα-targeting drug shows neuroprotective potential beyond tau, including earlier models with amyloid and Parkinson’s pathology.

If you’re building a project plan or a grant proposal, structure it around validating the axis in human cells, developing brain-penetrant selective inhibitors, and designing CNS biomarkers that track NFIL3-CD38 activity and NAD+ levels. And keep a sharp eye on circadian timing of dosing to align with natural NAD+ rhythms and astrocyte activity.

I’d like to hear what you think. Do you see this axis fitting with other metabolic interventions in neurodegenerative disease? What outocmes would you require to move into a human trial? Share your views in the comments. Also, if you want to dive deeper, read the WashU/Nature Aging paper and follow-up coverage in SciTechDaily, ScienceDaily, and Popular Mechanics. Do you think this line could reshape how we approach Alzheimer’s care in the next decade? I’m curious about your take.

Sara Morgan

Dr. Sara Morgan takes a close, critical look at recent developments in psychology and mental health, using her background as a psychologist. She used to work in academia, and now she digs into official data, calling out inconsistencies, missing info, and flawed methods—especially when they seem designed to prop up the mainstream psychological narrative. She is noted for her facility with words and her ability to “translate” complex psychological concepts and data into ideas we can all understand. It is common to see her pull evidence to systematically dismantle weak arguments and expose the reality behind the misconceptions.