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The following is a summary of “Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease,” published in the December 2024 issue of Neurology by Grill et al.
Nicotinamide is a coenzyme involved in oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins, affecting therapeutic pathways such as tau phosphorylation.
Researchers conducted a prospective study to evaluate whether nicotinamide treatment could reduce tau phosphorylation in individuals with early Alzheimer’s disease (AD).
They performed a randomized, placebo-controlled, phase 2a trial to assess the safety and tolerability of 1,500 mg of nicotinamide twice daily for 48 weeks. The primary outcome was cerebrospinal fluid (CSF) phosphorylated tau at threonine 231 (p-tau231) levels. Secondary outcomes included CSF p-tau181, total tau, amyloid beta 40 (Aβ40), amyloid beta 42 (Aβ42), and clinical measures: Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale-Mild Cognitive Impairment (ADCS-ADL-MCI), and Clinical Dementia Rating Summary of Boxes (CDR-SB). The Holm-Bonferroni procedure was used to control type I errors.
The results showed 47 individuals (mean age = 73.8 years, 43% female), 6 individuals dropped out, including 2 in the nicotinamide arm, and AEs were balanced between groups. No significant benefit was observed for nicotinamide on CSF p-tau231 (mean difference = −2.06, SE = 4.03, P=0.61), with slight mean declines in p-tau231 in the nicotinamide arm (−4.7 ± 14.5) vs. placebo (−2.3 ± 10.6). No significant effects were observed for secondary biomarker outcomes (CSF p-tau181, Aβ40, Aβ42, total tau, all P>0.05). Nicotinamide-treated individuals had less decline on CDR-SB (estimate = −1.42, SE = 0.65, P=0.03), but no significant differences in cognitive (ADAS-cog; estimate = −1.93, SE = 1.93, P=0.32) or functional (ADCS-ADL-MCI; estimate = −3.10, SE = 1.86, P=0.10) outcomes.
They concluded that nicotinamide was safe but did not alter AD biomarkers after 48 weeks of treatment.
Source: neurology.org/doi/10.1212/WNL.0000000000210152
