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NEW STUDY SHOWS ALZHEIMER’S DISEASE CAN BE REVERSED  
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Bill Lubinger
December 23, 2025
Case Western University Newsroom
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_ A new study by researchers from Case Western Reserve University,
University Hospitals and the Cleveland VA shows Alzheimer’s disease
can be reversed to achieve full neurological recovery—not just
prevented or slowed—in animal models. _

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For more than a century, people have considered Alzheimer's disease
(AD) an irreversible illness. Consequently, research has focused on
preventing or slowing it, rather than recovery. Despite billions of
dollars spent on decades of research, there has never been a clinical
trial of any drug to reverse and recover from AD.

A research team from Case Western Reserve University, University
Hospitals (UH) and the Louis Stokes Cleveland VA Medical Center has
now challenged this long-held dogma in the field, testing whether
brains already badly afflicted with advanced AD could recover. 

The study, led by Kalyani Chaubey, from the PIEPER LABORATORY
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was published online Dec. 22 in _CELL REPORTS MEDICINE_
[[link removed](25)00608-1].
Using diverse preclinical mouse models and analysis of human AD
brains, the team showed that the brain’s failure to maintain normal
levels of a central cellular energy molecule, NAD+, is a major driver
of AD, and that maintaining proper NAD+ balance can prevent and even
reverse the disease. 

_Restoring the brain’s energy balance led to both pathological and
functional recovery_

NAD+ levels decline naturally across the body, including the brain, as
people age. Without proper NAD+ balance, cells eventually become
unable to execute many of the critical processes required for proper
functioning and survival. In this study, the team showed that the
decline in NAD+ is even more severe in the brains of people with AD,
and that this same phenomenon also occurs in mouse models of the
disease. 

While AD is a uniquely human condition, it can be studied in the
laboratory with mice that have been genetically engineered to express
genetic mutations known to cause AD in people. 

The researchers used two of these mouse models: One carried multiple
human mutations in amyloid processing; the other carried a human
mutation in the tau protein. 

Amyloid and tau pathology are two of the major early events in AD.
Both lines of mice develop brain pathology resembling AD, including
blood-brain barrier deterioration, axonal degeneration,
neuroinflammation, impaired hippocampal neurogenesis, reduced synaptic
transmission and widespread accumulation of oxidative damage. These
mice also develop the characteristics of severe cognitive impairments
seen in people with AD. 

After finding that NAD+ levels in the brain declined precipitously in
both human and mouse AD, the research team tested whether preventing
loss of brain NAD+ balance before disease onset or restoring brain
NAD+ balance after significant disease progression could prevent or
reverse AD, respectively. 

The study was based on their previous work, published in Proceeding of
the National Academy of Sciences USA, showing that restoring the
brain's NAD+ balance achieved pathological and functional recovery
after severe, long-lasting traumatic brain injury. They restored NAD+
balance by administering a now well-characterized pharmacologic agent
known as P7C3-A20, developed in the Pieper lab.

Remarkably, not only did preserving NAD+ balance protect mice from
developing AD, but delayed treatment in mice with advanced disease
also enabled the brain to fix the major pathological events driven by
the disease-causing genetic mutations. 

Moreover, both lines of mice fully recovered cognitive function. This
was accompanied by normalized blood levels of phosphorylated tau 217,
a recently approved clinical biomarker of AD in people, providing
confirmation of disease reversal and highlighting an objective
biomarker that could be used in future clinical trials for AD
recovery.

“We were very excited and encouraged by our results,” said Andrew
A. Pieper, the study’s senior author, a professor at the Case
Western Reserve School of Medicine and director of the Brain Health
Medicines Center, Harrington Discovery Institute at UH. “Restoring
the brain's energy balance achieved pathological and functional
recovery in both lines of mice with advanced Alzheimer's. Seeing this
effect in two very different animal models, each driven by different
genetic causes, strengthens the new idea that recovery from advanced
disease might be possible in people with AD when the brain's NAD+
balance is restored.” 

Pieper also holds the Morley-Mather Chair in Neuropsychiatry at UH and
the CWRU Rebecca E. Barchas, MD, DLFAPA, University Professorship in
Translational Psychiatry. He serves as psychiatrist and investigator
in the Louis Stokes VA Geriatric Research Education and Clinical
Center. 

The results prompt a paradigm shift in how researchers, clinicians and
patients can think about treating AD in the future. 

“The key takeaway is a message of hope—the effects of Alzheimer's
disease may not be inevitably permanent,” Pieper said. “The
damaged brain can, under some conditions, repair itself and regain
function.” 

“Through our study, we demonstrated one drug-based way to accomplish
this in animal models, and also identified candidate proteins in the
human AD brain that may relate to the ability to reverse AD,”
Chaubey said.

Pieper emphasized that current over-the-counter NAD+-precursors have
been shown in animal models to raise cellular NAD+ to dangerously high
levels that promote cancer. The pharmacological approach in this
study, however, uses a pharmacologic agent (P7C3-A20) that enables
cells to maintain their proper balance of NAD+ under conditions of
otherwise overwhelming stress, without elevating NAD+ to
supraphysiologic levels. 

“This is an important factor when considering patient care, and
clinicians should consider the possibility that therapeutic strategies
aimed at restoring brain energy balance might offer a path to disease
recovery,” Pieper said. 

This work also encourages new research into complementary approaches
and eventual testing in patients, and the technology is being
commercialized by Cleveland-based company Glengary Brain Health, which
Pieper co-founded.

“This new therapeutic approach to recovery needs to be moved into
carefully designed human clinical trials to determine whether the
efficacy seen in animal models translates to human patients,” Pieper
said. “Additional next steps for the laboratory research include
pinpointing which aspects of brain energy balance are most important
for recovery, identifying and evaluating complementary approaches to
Alzheimer's reversal, and investigating whether this recovery approach
is also effective in other forms of chronic, age-related
neurodegenerative disease.” 

_With over 30 years of experience as a newspaper journalist, Bill
Lubinger leads the media relations team at Case Western Reserve
University._

 

 

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