With a $45 million grant from the National Institutes of Health and National Institute on Aging, the Alzheimer’s Disease Cooperative Study (ADCS) at University of California San Diego, in collaboration with Burke Neurological Institute (BNI) and Columbia University Irving Medical Center, will launch a nationwide clinical trial to further investigate the therapeutic potential of benfotiamine, a synthetic version of thiamine (B1), as a metabolic treatment approach to Alzheimer’s disease.

The trial advances the ADCS mission to develop and test therapies to benefit those at risk or experiencing the symptoms of Alzheimer’s disease (AD). ADCS will coordinate the multi-center trial to evaluate whether high doses of benfotiamine benefit people with mild AD or mild cognitive impairment due to AD (MCI).

The trial addresses tissue deficiency of thiamine-regulated metabolic pathways linked to AD. Previous work by co-principal investigator Gary E. Gibson, PhD, professor of neuroscience at Brain and Mind Research Institute, part of Weill Cornell Medicine, has found that a reduction in glucose metabolism is linked to this deficiency in thiamine-dependent processes.

Using multiple experimental models, Gibson and others have shown that increasing thiamine to very high levels using benfotiamine supplementation appeared to be protective against Alzheimer’s-like symptoms. For the study, ADCS will enroll approximately 400 patients at up to 50 U.S.-based clinical trial sites, beginning in early 2023.

“We are excited to receive this funding, which will enable expanded testing of benfotiamine through to its clinical proof of concept, including adaptively testing for the optimal dose and treatment response across clinical and biomarker measures,” said Howard Feldman, MD, dean of Alzheimer’s Disease Research and professor of neurosciences at UC San Diego School of Medicine.

The benfotiamine study will monitor participants over 18 months, using several measures, including cognitive tests and blood markers that signal AD and MCI status and progression.

"At the Burke Neurological Institute, we have been studying the effects of thiamine on neurodegenerative diseases for more than 40 years,” said Gibson. “This important grant will allow us to test the treatment with hundreds of Alzheimer's disease patients across the U.S. We are eager to begin this critical new stage of the research.

“I am particularly excited about this trial because it will determine how relevant these decades of research are to the treatment of Alzheimer’s disease.”

The trial highlights ADCS’ efforts to develop new interventional approaches. In collaboration with the University of Southern California, ADCS was the recent recipient of a $50 million gift from the Epstein Family Foundation to support two programs: one investigating the use of gene therapy to treat AD and the other a “powder for pennies” (P4P) program designed to expedite the testing of existing or repurposed drugs and natural products for its treatment.

Benfotiamine is a good example of the P4P approach. If found to be beneficial, the treatment would be widely available and affordable.

Educational and lifestyle interventions are other approaches being developed at ADCS. A study called HALT-AD, a pilot for the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia, is a bilingual, bicultural program that recruits community members to join education programs and discussion groups, enabling them to learn more about dementia and to practice preventive measures.

The recently completed EXERT study, coordinated nationwide by ADCS, was a Phase III clinical trial to test whether physical exercise can slow the progression of mild memory loss and/or MCI in adults between the ages of 65 and 89. Results of the study will be presented at the Alzheimer’s Association International Conference in San Diego in late-July.

“It’s crucial that ADCS help lead the way in looking at new possibilities for preventing and treating dementia,” Feldman said. “All indicators suggest we can make progress by implementing a wide range of study methods.”

The benfotiamine study continues work funded by the Alzheimer’s Drug Discovery Foundation (ADDF).

“It is gratifying to see research which the ADDF initially identified as promising and supported in a pilot study continue funding from the NIH’s National Institute on Aging,” said Howard Fillit, ADDF co-founder and chief science officer. “With the improved biomarkers that have been developed since the pilot, this next phase will provide a deeper understanding of how benfotiamine works in the brain.”

Joining Feldman and Gibson as a co-principal investigator in the new trial is José Luchsinger, MD, professor of medicine and epidemiology at Columbia University Irving Medical Center.

Additional academic laboratory collaborators include the University of Gothenberg, Sweden; University of Cambridge, UK; and Georgetown University, Washington, D.C. Another study partner is C2N Diagnostics, a St. Louis company focused on advanced brain health diagnostics.

More than 6 million Americans currently live with AD, a figure forecast to rise to nearly 13 million by 2050. Globally, the prevalence of AD is projected to grow from a current 57 million to 153 million in 2050. Currently, there is no cure for AD.