Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Article type: Research Article

Authors: Gibson, Gary E.^{a; b; *} | Luchsinger, José A.^c | Cirio, Rosanna^b | Chen, Huanlian^b | Franchino-Elder, Jessica^b | Hirsch, Joseph A.^{b; d; e} | Bettendorff, Lucien^f | Chen, Zhengming^g | Flowers, Sarah A.^h | Gerber, Linda M.^g | Grandville, Thomas^d | Schupf, Nicoleⁱ | Xu, Hui^b | Stern, Yaakov^j | Habeck, Christian^k | Jordan, Barry^{l; m} | Fonzetti, Pasqualeⁿ

Affiliations: [a] Brain and Mind Research Institute, Weil Cornell Medicine, New York, NY, USA | [b] Burke Neurological Institute, White Plains, NY, USA | [c] Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY, USA | [d] Burke Rehabilitation Hospital, White Plains, NY, USA | [e] Lenox Hill Hospital, New York, NY, USA | [f] Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liege, Belgium | [g] Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA | [h] Department of Neuroscience, Georgetown University, Washington, DC, USA | [i] Mailman School of Public Health, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA | [j] Departments of Neurology, Psychiatry, GH Sergievsky Center, the Taub Institute for the Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA | [k] Department of Neurology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA | [l] Rancho Los Amigos National Rehabilitation Center, Downey, CA, USA | [m] Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA | [n] Einstein College of Medicine, Bronx NY; Westmed Medical Group White Plains, NY, USA

Correspondence: [*] Correspondence to: Gary E. Gibson, PhD, Brain and Mind Research Institute, Weill Cornell Medicine, Burke Neurological Institute, White Plains, NY, USA. Tel.: +1 914 597 2291; E-mail: [email protected].

Abstract: Background:In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective:To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods:A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results:Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion:Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

Keywords: Advanced glycation endproducts, Alzheimer’s disease, benfotiamine, glucose, inflammation, oxidative stress

DOI: 10.3233/JAD-200896

Journal: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 989-1010, 2020