By Harshit
BOSTON, DECEMBER 13, 2025 —
Two of the largest Alzheimer’s clinical trials ever conducted have delivered deeply disappointing results for one of America’s most celebrated drug classes. Oral semaglutide — a daily GLP-1 medication widely used for diabetes and weight loss — failed to slow cognitive decline in nearly 4,000 patients with early-stage Alzheimer’s disease, according to data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in San Diego.
The findings sharply contrast with years of hope, early animal studies, real-world observations, and anecdotal patient reports suggesting GLP-1 drugs might offer neuroprotective benefits. Instead, the results mark the clearest evidence yet that semaglutide, despite its broad therapeutic impact across metabolism and cardiovascular health, does not improve clinical outcomes for Alzheimer’s disease progression.
A Major Blow to a Widely Hyped Therapeutic Class
“These results are very disappointing,” said Daniel Drucker, the pioneering endocrinologist whose foundational research enabled the creation of GLP-1 drugs including Ozempic, Rybelsus, Mounjaro, and others.
For years, GLP-1 medications have been hailed as “wonder drugs,” credited with improving not just diabetes and obesity but also cardiovascular disease, liver disease, migraines, sleep apnea, and even reducing substance-use craving. This wide-ranging potential led researchers to ask whether GLP-1 drugs could also protect the brain.
“People questioned if there was anything GLP-1s couldn’t do,” Drucker said. “The answer, clearly, is yes.”
Paul Edison of Imperial College London called the results an “undeniable setback,” especially following similar failures in recent GLP-1 trials for Parkinson’s disease.
What the New Trials Showed — and Didn’t Show
The paired Alzheimer’s trials — named evoke and evoke+ — followed nearly 4,000 people, average age 70, over two years. Participants were randomized to either daily oral semaglutide or placebo.
Researchers measured:
• Cognitive decline
• Clinical dementia scores
• Alzheimer’s biomarkers
• Inflammatory markers
They found:
• No slowing of cognitive decline
• No improvement in clinical dementia scores
• Slight reductions in an inflammatory biomarker
• Small changes in Alzheimer’s biomarkers that did not translate into real-world benefit
“It became immediately clear there was no clinical benefit whatsoever,” said Reisa Sperling of Brigham and Women’s Hospital. “This was a very well-run set of trials. The answer was clear.”
Jeffrey Cummings, trial co-leader, confirmed:
“We did not see the corresponding benefit on cognition that we had hoped for.”
Why Did Semaglutide Fail?
Experts believe several factors could explain the drug’s lack of effect:
1. Too little drug enters the brain
GLP-1 drugs primarily act in the gut, pancreas, liver, and cardiovascular system. Only tiny amounts cross the blood–brain barrier.
2. Treatment may need to begin earlier
GLP-1s may help prevent neurological disease, not reverse existing damage.
3. Disease may have been too advanced
Even “early-stage” Alzheimer’s represents substantial neurodegeneration.
4. Dose may have been insufficient
Higher doses could have stronger central effects but raise tolerability issues.
5. Alzheimer’s is extraordinarily complex
Inflammation, metabolism, and glucose control are just one part of a larger biological cascade.
“These are all possibilities the field now needs to investigate,” Drucker said.
Why Scientists Believed GLP-1 Drugs Might Work
Prior evidence had fueled optimism:
• Observational data showed patients on GLP-1 drugs had lower dementia rates.
• Animal studies showed reduced brain inflammation and improved neural signaling.
• A small liraglutide trial suggested slower cognitive decline.
• Patients often reported “mental clarity” on the drugs.
But experts emphasize that anecdotes are not substitutes for randomized trials.
“These Alzheimer’s trials give us a definitive answer,” Edison said. “Semaglutide doesn’t slow disease progression.”
What Happens Next?
Scientists stress that this is not the end of GLP-1 drugs in neurology — but a reset.
Future research directions include:
• Testing higher-dose or injectable semaglutide formulations
• Exploring GLP-1 combinations (e.g., dual GLP-1/GIP drugs like tirzepatide)
• Identifying patient subgroups that may benefit
• Evaluating earlier preventive use in at-risk populations
• Developing new GLP-1 drugs that cross into the brain more efficiently
“We need to rethink our strategy,” Drucker said. “The field is not stopped — but we need to take a step back.”
A Reality Check for a Miracle Drug Era
For a decade, GLP-1 drugs have reshaped metabolic medicine, weight loss, and cardiovascular risk — an unmatched impact in modern pharmaceuticals. But the Alzheimer’s results reinforce a scientific reality:
These medications, however powerful, cannot solve every disease.
“I think we need to ask ourselves, ‘How do these GLP-1s work anyway — and where do they not work?’” said Standaert.
The trials provide that clarity:
Semaglutide is transformational for metabolism.
It is not, at current dosing and formulation, a treatment for Alzheimer’s.