Stanford neurologist outlines diagnostics, lifestyle prevention and a local drug moving toward a pivotal trial

Dr. Frank Longo, a neurologist and researcher at Stanford, framed Alzheimer’s as a disease of synaptic loss and reviewed current diagnostic and research advances.

Longo described three pathological contributors to Alzheimer’s—amyloid plaques, tau pathology and neuroinflammation—and emphasized that synaptic connections are the mechanistic target for preserving cognition. He walked the audience through clinical evaluation steps used at a memory clinic: careful history and neurologic exam, cognitive screening with tools such as the Montreal Cognitive Assessment (MoCA) and, when indicated, a more detailed neuropsychological battery. He said MRI is used to exclude treatable causes (hydrocephalus, tumor) while amyloid PET shows brain amyloid but is expensive. Longo highlighted an emerging class of blood biomarkers (pTau217), which he said the FDA cleared for use in symptomatic patients; he reported that in symptomatic populations some assays show high accuracy (the speaker cited roughly 92% accuracy) for indicating Alzheimer’s pathology.

On prevention Longo summarized evidence that physical exercise (moderate activity, and potentially brief vigorous intervals) is associated with substantially lower dementia risk in observational studies — he cited meta‑analytic ranges and step‑count studies — and recommended regular physical activity, cognitive engagement and sleep hygiene while noting most evidence is associative. He cautioned that many widely marketed supplements lack robust proof and walked through trial data that have not shown consistent benefits for vitamin B, lithium or certain off‑label drugs.

Longo described current disease‑modifying therapies that target amyloid: they lower brain amyloid on scans but provide only modest clinical slowing of decline and require monitoring for brain swelling and microhemorrhages. He said more powerful therapeutics that address synaptic resilience against multiple pathologies are needed.

Longo then described a Stanford‑origin small molecule, LM11A31 ("C31"), that modulates the p75 neurotrophin receptor to shift intracellular signaling away from degenerative pruning and toward synaptic survival. He said preclinical mouse studies showed restoration of synaptic spines and that a randomized phase 2a safety and exploratory biomarker trial (241 participants across 18 sites) showed favorable safety and changes in multiple biomarkers (MRI, FDG‑PET, CSF and plasma measures). He said the company met with the FDA and plans a pivotal trial that it aims to launch by the end of 2026 pending fundraising; he described typical trial side effects observed in phase 2a (transient diarrhea, sore throat, headache, small eosinophil increases) and noted the drug is orally administered and metabolized in blood.

Longo addressed genetics and risk: late‑onset Alzheimer’s is largely sporadic but parental history and APOE genotype change risk (single APOE‑ε4 copy confers roughly a two‑ to threefold increased risk). He characterized memantine as a symptomatic drug that may temporarily improve cognition but does not change disease trajectory. In audience questions he reiterated that blood biomarkers and trial enrollment are becoming more accessible and encouraged informed conversations with clinicians about testing and trial participation.

Longo and the company’s CEO (Ann) said the next pivotal trial will be a large, multisite effort and that interested people should watch for trial site announcements and enrollment opportunities. They said slides and the event recording will be distributed to attendees.