What if one of the most promising approaches to Alzheimer’s disease doesn’t involve removing amyloid plaques from the brain, but instead focuses on protecting neurons, reducing inflammation, and restoring the brain’s ability to function?
That’s the intriguing possibility raised by research published in Alzheimer’s Research & Therapy, examining an experimental treatment called NeuroEPO plus, a specially modified form of the hormone erythropoietin (EPO), administered as a nasal spray.
The findings are remarkable. And while I want to emphasize that this research remains preliminary and requires independent confirmation, I believe it represents an exciting direction in our efforts to confront Alzheimer’s disease.
More importantly, it aligns closely with the central message of my new book, Brain Defenders: To meaningfully address neurodegenerative disease, we must look beyond the damage we see in the brain and begin addressing the biological processes that create that damage in the first place.
Most people associate erythropoietin with its well-established role in stimulating red blood cell production. Produced primarily by the kidneys, EPO helps ensure that our bodies have sufficient oxygen-carrying capacity.
But EPO has another fascinating identity.
It also functions as a signaling molecule in the nervous system, where it can help protect neurons against injury, reduce oxidative stress, influence inflammatory responses, and support cellular survival. These properties have attracted considerable attention from researchers investigating neurological disorders.
The challenge has been delivering EPO to the brain without producing unwanted effects elsewhere in the body. Conventional EPO can increase red blood cell production and potentially raise the risk of hypertension and dangerous blood clots.
Researchers in Cuba developed NeuroEPO plus, a modified version designed to preserve its neuroprotective properties while minimizing its effects on red blood cell production. And here’s another innovation: It is administered intranasally, offering a potential route for delivering this molecule to the central nervous system without relying on high systemic doses.
The ATHENEA trial was a randomized, double-blind, placebo-controlled study involving 174 individuals with mild-to-moderate Alzheimer’s clinical syndrome. Of these, 170 received treatment.
Participants received either NeuroEPO plus or placebo three times weekly for 48 weeks. Researchers assessed cognition using the Alzheimer’s Disease Assessment Scale, or ADAS-Cog11, a widely used measure of cognitive performance.
At the end of the study, participants receiving NeuroEPO demonstrated median improvements of three to four points on this scale. Meanwhile, participants receiving placebo worsened by four points. That translates into a seven- to eight-point difference between the treatment and placebo groups. These are substantial findings, especially in a disease generally characterized by progressive cognitive deterioration. To be fair, I have never seen results like this. The researchers also reported improvements in other measures, including the Montreal Cognitive Assessment, neuropsychiatric symptoms, and clinician assessments incorporating caregiver observations.
A smaller imaging substudy suggested improvements in blood flow to certain brain regions.
And although the treatment was generally well tolerated, the study was not large enough to establish long-term safety. One treated participant experienced serious complications, including thrombosis and pulmonary embolism, although investigators did not attribute the events to treatment.
What particularly interests me about NeuroEPO is not simply the reported improvement in cognitive performance. It’s the biology. In my latest book, Brain Defenders, I explore how the brain’s resident immune cells, called microglia, play a central role in determining whether our brains remain resilient or become vulnerable to neurodegeneration.
Microglia are constantly surveying the brain, responding to injury, clearing cellular debris, and helping maintain healthy neural connections. But when these cells become chronically activated by metabolic dysfunction, environmental toxins, infections, or other challenges, their protective activities can give way to persistent inflammation.
This inflammatory environment can compromise neuronal function, damage mitochondria, and ultimately contribute to brain degeneration. The critical question neuroscientists should be asking is not simply how we remove the debris associated with Alzheimer’s disease, but how we restore the biological environment that allows neurons to thrive.
That’s where EPO becomes particularly interesting.
Experimental research suggests that EPO signaling can reduce inflammatory activity, protect neurons from oxidative injury, and activate cellular survival pathways.
In animal models of Alzheimer’s disease, NeuroEPO has been associated with reduced inflammatory signaling, decreased glial activation, protection of hippocampal neurons, and improved memory.
These findings suggest that NeuroEPO may influence several interconnected processes rather than targeting a single molecular feature of Alzheimer’s disease. This is consistent with the broader concept of immunometabolism that I emphasize in Brain Defenders: The functional behavior of immune cells is intimately connected to their metabolic state.
To be clear, the ATHENEA trial did not directly measure microglial metabolism or establish that NeuroEPO reprogrammed microglial activity in its participants. That remains an important hypothesis for future investigation.
For decades, Alzheimer’s research has been dominated by efforts to reduce amyloid accumulation.
But even today, amyloid-targeting medications have demonstrated only minimal slowing of cognitive decline in selected patients, while they have not restored normal cognitive function, and their potential adverse effects are very real and require careful consideration.
I believe we must broaden our approach.
Alzheimer’s disease involves far more than amyloid. Mitochondrial dysfunction, impaired insulin signaling, oxidative stress, vascular abnormalities, and chronic neuroinflammation all contribute to the complex biology of brain degeneration.
NeuroEPO is interesting precisely because its proposed actions intersect with several of these pathways.
Rather than focusing exclusively on a downstream hallmark of disease, it may help strengthen the brain’s intrinsic mechanisms of protection and repair.
That represents an important conceptual shift.
We should be encouraged by these findings, but we must also recognize their limitations. This was a relatively small study conducted at two centers in Cuba. The study also involved investigators associated with the organization developing the treatment. And we cannot yet determine whether the cognitive improvements represent sustained modification of the disease process.
Larger, independently conducted trials should incorporate biomarkers such as phosphorylated tau, neurofilament light chain, and measures of neuroinflammation and mitochondrial function.
NeuroEPO plus has received accelerated approval in Cuba, but it is not FDA-approved for Alzheimer’s disease in the United States. Still, I find these results genuinely hopeful and plan to follow these developments closely. In addition, I’ll do my best to get these researchers on The Empowering Neurologist podcast
The larger lesson is one I’ve emphasized throughout Brain Defenders: Our brains are not simply passive victims of aging or accumulating pathology. They possess powerful systems of protection, adaptation, and repair.
We are beginning to understand how those systems might be supported through lifestyle interventions and, potentially, innovative therapeutics.
NeuroEPO may or may not ultimately fulfill its early promise. Only rigorous additional research can answer that question. But the direction of this research is encouraging.
Because the future of Alzheimer’s treatment may depend not only on removing what harms the brain, but on restoring what protects it. And that is a future worth all of our effort.