A better Alzheimer’s drug?

Frank Longo spent a lot of time during his childhood in California thinking about brain science. “I had a sister, a year younger than me, who was confined to a wheelchair and cognitively impaired,” said Longo, MD, PhD, the George E. and Lucy Becker Professor in Medicine.

“I asked my mother, who was a nurse, ‘Why can’t Patti walk?’ She explained to me that my sister, born prematurely, had cerebral palsy due to her brain being deprived of oxygen pre-birth, and that there were no treatments for this and other brain conditions. That really stuck in my head somehow.”

Driven by the desire to help people like his sister, Longo studied the brain and nervous system and, after attaining professorships at the University of California, San Francisco, and the University of North Carolina at Chapel Hill, joined the Stanford School of Medicine’s faculty in 2006 as a professor of neurology and neurological sciences and, until 2023, as department chair.

For much of that time, Longo and his lab team have been exploring mechanisms that seem to slow or even reverse a correlate of brain aging and dementia: damage to and loss of synapses, the electrochemical junctions through which nerve cells in the brain transfer signals among one another. He sees this approach as a way to counter Alzheimer’s and other neurodegenerative diseases.

The upshot: Longo has developed a compound that, unlike existing Alzheimer’s drugs, could simultaneously tackle several mechanisms leading to neurodegeneration. This compound is now being tested in patients.

The journey begins

The human brain is said to contain about 86 billion neurons and at least hundreds of trillions of synapses, enabling cognitive feats from playing piano concertos or solving math problems to recalling events of your childhood or what you ate for dinner the previous night.

In fetal and early childhood development, our brains acquire a surfeit of synapses. The resulting redundancy actually impedes cognition but, fortunately, is rectified by a brainwide pruning process that’s regulated locally by a receptor on synapses’ surfaces. A cell surface receptor that contributes to the trimming is called p75NTR.

But this receptor, which quiets down after its childhood hyperactivity, becomes gradually more active in most of us as we age, or in the presence of Alzheimer’s and other brain diseases — sometimes pronouncedly so, precipitating inappropriate synaptic pruning and loss of cognitive function. An unexpected finding within a large extended Alzheimer’s disease-stricken family in Colombia has inspired Longo and his team to gain further insights into the capabilities of p75NTR.

Members of this family have inherited a mutation causing their brains to massively overproduce a substance called amyloid-beta (or A-beta) which is considered to be a primary contributor to Alzheimer’s disease.

Remarkably, one individual within this family who had large amounts of amyloid seemed to have inherited a gene that renders synapses resilient to A-beta and who remained dementia-free for decades. This gene controls many of the same nerve cell signaling mechanisms regulated by p75NTR. Longo and his team found that targeting p75NTR can create resilience to amyloid.

While still at UCSF, Longo and his colleague Stephen Massa, MD, PhD, identified a molecule that selectively interfered with p75NTR’s activity to confer synaptic resilience, much like that promoted by the beneficial mutation. To develop the compound, dubbed LM11A-31, as a drug to combat Alzheimer’s, he co-founded PharmatrophiX Inc. with his wife, CEO Anne Chun Longo, where he serves as chairman of the board. The company exclusively licensed LM11A-31 from UCSF and UNC. 

Longo said he sees LM11A-31 as an alternative, or adjunct, to the current batch of pricey drugs recently approved for targeting amyloid plaque and the A-beta that precipitates to form those gummy deposits. Although small soluble clusters of A-beta are probably involved in the early stages of Alzheimer’s disease, Longo said, the insoluble plaques those clusters eventually coagulate into may be more a fossil remnant than an active cause of the disease.

Other substances and processes become the primary causes of nerve cell and synapse degeneration.

Amyloid plaques may show up in brain-imaging scans two decades or more before outward symptoms develop, if they ever do. Many people with manifold plaques nevertheless have perfectly normal cognition, pointing to the phenomenon of resilience.

A Phase 2a clinical trial of LM11A-31 conducted among patients diagnosed with mild to moderate Alzheimer’s disease (whose results were published in 2024 in Nature Medicine) confirmed its safety for use in humans.

LM11A-31 also inhibited accumulation of another Alzheimer’s-associated protein called tau, protected synapses from ravages wrought by A-beta, and dialed down inflammation in the brain’s in-house immune cells.

“The plaque-attack drugs are narrowly focused on removing amyloid,” Longo said. “That’s only one of several parallel mechanisms causing the neurodegeneration. LM11A-31 slows down a broad range of the degenerative cascade.”

Key answers lie ahead

Longo’s Stanford Medicine lab does no commercial-development work but continues to explore the degenerative mechanisms occurring in neurodegenerative diseases and ways various therapeutic target candidates might slow them down.

PharmatrophiX is working on funding a definitive Phase 3 clinical trial of LM11A-31 in Alzheimer’s patients.

“That’s the big mountain that needs to be climbed,” said Howard Fillit, MD, a co-founder and the chief scientific officer of the Alzheimer’s Drug Discovery Foundation, the largest nonprofit, nongovernment funder of dementia-focused drug development in the world — and an early investor in PharmatrophiX.

“LM11A-31 could really be a breakthrough if it gets through Phase 3. If it’s successful, it will be the first neuroprotective drug to prove itself for Alzheimer’s disease.”

LM11A-31’s multiple mechanisms of action confer unusual flexibility on its potential use. Preclinical studies indicate it could prove relevant to many indications, including Huntington’s disease, HIV-associated dementia, stroke and traumatic brain injury.

A recent study Longo co-authored, published in early 2025 in Brain, found, in mice, that LM11A-31 prevented cognitive deficits that otherwise occurred due to perinatal oxygen deprivation. “That’s exactly what caused my sister’s cerebral palsy,” Longo said.