Coley Nicola, Zetterberg Henrik, Cantet Christelle, Guyonnet Sophie, Ashton Nicholas J, Vellas Bruno, Blennow Kaj, Andrieu Sandrine
Centre for Epidemiology and Research in Population Health, INSERM-University of Toulouse, UPS, Toulouse, France; Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, Hong Kong Special Administrative Region, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Lancet Healthy Longev. 2024 Feb;5(2):e120-e130. doi: 10.1016/S2666-7568(23)00255-6.
It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects.
This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts.
Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]).
Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required.
Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.
多领域干预可能有助于维持晚年认知功能，但尚不清楚其是否会影响阿尔茨海默病的病理变化。此前的研究在多领域试验参与者的小样本中测量了脑脊液和影像学阿尔茨海默病生物标志物。新开发的检测方法能够在更大样本中测量基于血液的阿尔茨海默病生物标志物。我们旨在评估苏氨酸181位点磷酸化的血浆tau蛋白（p-tau181）能否检测或预测为期3年的多领域干预效果。
这是一项对随机对照的多领域阿尔茨海默病预防试验（MAPT）的二次分析，该试验在法国和摩纳哥的13个记忆中心对70岁及以上个体进行了为期3年的多领域干预、补充ω-3脂肪酸或两者与安慰剂的对比研究。在527名参与者的子样本中，基于意向性分析对储存的血样进行p-tau181检测。认知得分变化通过以下测试的Z评分平均值的综合指标计算：简易精神状态检查表定向项目、自由和线索选择性回忆测试（自由回忆和总回忆得分之和）、类别流畅性和数字符号替换测试。使用具有中心特异性随机截距的线性混合模型估计干预对p-tau181浓度3年变化的影响。
招募工作于2008年5月30日至2011年2月24日进行。总样本中p-tau181的基线中位数为8.8 pg/mL（四分位间距6.7-11.9），在老年人、男性、APOE ε4携带者以及肾功能不全或PET淀粉样蛋白扫描呈阳性的参与者中显著更高。在3年随访期间，基线p-tau181升高的个体认知功能下降更明显（例如，在使用12.4 pg/mL作为异常基线p-tau181的临界值的完全调整模型中，基线p-tau正常和异常的对照组参与者在综合认知得分3年变化上的平均差异为-0.34[效应量-0.52；95%置信区间-0.61至0.07]），但在该亚组或总体人群中，干预对p-tau181的变化均无影响，对基线p-tau181升高的个体的认知变化也无影响（例如，在使用12.4 pg/mL作为p-tau181异常临界值的完全调整模型中，该亚组对照组与多领域+ω-3组、ω-3组和多领域干预组在综合认知得分3年下降上的平均差异[95%置信区间]分别为：0.13[-0.21至0.47]、0.03[-0.30至0.36]和0.10[-0.26至0.46]）。令人惊讶的是，基线p-tau181升高的个体在随访期间p-tau181出现下降（例如，在基线p-tau181异常的对照组受试者中[使用12.4 pg/mL异常p-tau临界值]，未调整的平均[95%置信区间]3年变化为-3.01 pg/mL（-4.45至-1.56））。
我们的结果支持p-tau181作为一种预后生物标志物的效用，但在本研究中它并未预测或检测到干预效果。需要进一步研究其作为预防试验结果指标的有用性。
图卢兹老年医学中心、法国卫生部和皮埃尔·法布尔研究所。
