Grill Joshua D, Tam Steven, Thai Gaby, Vides Beatriz, Pierce Aimee L, Green Kim, Gillen Daniel L, Teng Edmond, Kremen Sarah, Beigi Maryam, Rissman Robert A, Léger Gabriel C, Balasubramanian Archana, Revta Carolyn, Morrison Rosemary, Jennings Robin, Pa Judy, Zhang Jing, Jin Shelia, Messer Karen, Feldman Howard H
From the Institute for Memory Impairments and Neurological Disorders (J.D.G., S.T., G.T., B.V., K.G., D.L.G.), University of California, Irvine; Department of Psychiatry and Human Behavior (J.D.G.), University of California, Irvine; Department of Neurobiology and Behavior (J.D.G., K.G.), University of California, Irvine; Division of Geriatric Medicine (S.T.), Department of Medicine, University of California, Irvine; Department of Neurology (G.T.), University of California, Irvine; Department of Neurology (A.L.P.), Oregon Health and Science University; Department of Statistics (D.L.G.), University of California, Irvine; Department of Neurology and Neurological Sciences (E.T.), Stanford University; Department of Neurology (S.K.), Cedars Sinai Medical Center; Department of Neurology (M.B.), University of California, Los Angeles; Alzheimer's Disease Cooperative Study (R.A.R., G.C.L., A.B., C.R., R.M., R.J., J.P., J.Z., S.J., K.M., H.H.F.), University of California, San Diego; and Department of Neurosciences (G.C.L., J.P., H.H.F.), University of California, San Diego.
Neurology. 2025 Jan 14;104(1):e210152. doi: 10.1212/WNL.0000000000210152. Epub 2024 Dec 13.
Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).
We performed a randomized, placebo-controlled, phase 2a proof-of-concept trial to evaluate the safety and tolerability of 48 weeks of treatment with 1,500 mg of nicotinamide twice a day. The primary outcome was level of tau phosphorylated at threonine 231 (p-tau) in CSF. Prespecified secondary outcomes were levels of p-tau, total tau, amyloid β40 (Aβ), and Aβ in CSF and the clinical measures Alzheimer's Disease Assessment Scale (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). Participants were recruited at 2 academic clinical centers. Enrollment criteria included diagnosis of mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD. The Holm-Bonferroni procedure was used to control type I error within biomarker and clinical domains.
Of 47 participants enrolled (mean age = 73.8 years; 43% female), 1 dropped out before treatment initiation and 6 before completion, including 2 in the nicotinamide and 4 in the placebo arm. Adverse events (AEs) were balanced by arm, with few attributed to treatment. Common AEs included infections and nervous system disorders. There was no statistically significant benefit of nicotinamide on the primary outcome of week 48 change from baseline in CSF p-tau (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; = 0.61), with observed mean decline in CSF p-tau greater in the nicotinamide arm (-4.7 ± 14.5) than in the placebo arm (-2.3 ± 10.6). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p-tau, Aβ, Aβ, and total tau) in similar models (all values >0.05), with observed mean changes in CSF p-tau (0.4 ± 29.8 vs 10.4 ± 41.8) and total tau (8.4 ± 228.6 vs 60.5 ± 237.5) favoring nicotinamide compared with placebo. At week 48, nicotinamide-treated participants experienced less decline on CDR-SB (mixed-effect model with repeated measures; estimate = -1.42, SE = 0.65; = 0.03 unadjusted for multiple comparisons), without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; = 0.32) or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; = 0.10) outcomes.
Nicotinamide was safe but did not alter AD biomarkers.
This study provides Class I evidence that in patients with MCI or mild dementia with positive CSF AD biomarkers, 48 weeks of nicotinamide, 3,000 mg daily, is no better than placebo in reducing CSF p-tau.
ClinicalTrials.gov: NCT03061474.
烟酰胺是一种参与细胞氧化还原反应的辅酶，可抑制Ⅲ类组蛋白去乙酰化酶（HDACs）或沉默调节蛋白。HDAC抑制可影响众多治疗途径，包括tau蛋白磷酸化。我们检验了烟酰胺治疗可降低早期阿尔茨海默病（AD）患者tau蛋白磷酸化的假设。
我们进行了一项随机、安慰剂对照的2a期概念验证试验，以评估每日两次服用1500mg烟酰胺治疗48周的安全性和耐受性。主要结局是脑脊液中苏氨酸231位点磷酸化tau蛋白（p-tau）水平。预先设定的次要结局是脑脊液中p-tau、总tau、淀粉样β40（Aβ40）和Aβ42水平，以及临床指标阿尔茨海默病评估量表（ADAS-cog13）、阿尔茨海默病协作研究-日常生活活动量表-轻度认知障碍（ADCS-ADL-MCI）和临床痴呆评定量表框总和（CDR-SB）。在2个学术临床中心招募参与者。纳入标准包括经脑脊液生物标志物确诊为轻度认知障碍或轻度痴呆的AD患者。采用霍尔姆-邦费罗尼方法控制生物标志物和临床领域内的Ⅰ型错误。
47名纳入研究的参与者（平均年龄=73.8岁；43%为女性）中，1名在治疗开始前退出，6名在治疗结束前退出，其中烟酰胺组2名，安慰剂组4名。各治疗组不良事件（AE）均衡，很少与治疗相关。常见AE包括感染和神经系统疾病。烟酰胺对脑脊液p-tau第48周相对于基线变化的主要结局无统计学显著益处（协方差分析；两组间变化的估计平均差异=-2.06，标准误=4.03；P=0.61），观察到烟酰胺组脑脊液p-tau的平均下降幅度（-4.7±14.5）大于安慰剂组（-2.3±10.6）。在类似模型中，未观察到治疗对次要生物标志物结局（脑脊液p-tau、Aβ40、Aβ42和总tau）有显著影响（所有P值>0.05），与安慰剂相比，观察到烟酰胺组脑脊液p-tau（0.4±29.8 vs 10.4±41.8）和总tau（8.4±228.6 vs 60.5±237.5）的平均变化更有利。在第48周，烟酰胺治疗的参与者在CDR-SB上的下降较少（重复测量混合效应模型；估计值=-1.42，标准误=0.65；未进行多重比较调整的P=0.03），在认知（ADAS-cog；估计值=-1.93，标准误=1.93；P=0.32）或功能（ADCS-ADL-MCI；估计值=-3.10，标准误=1.86；P=0.10）结局方面无显著差异。
烟酰胺安全，但未改变AD生物标志物。
本研究提供Ⅰ级证据，表明在脑脊液AD生物标志物阳性的MCI或轻度痴呆患者中，每日3000mg烟酰胺治疗48周在降低脑脊液p-tau方面并不优于安慰剂。
ClinicalTrials.gov：NCT03061474。
