Integration of blood-based biomarkers and genomic variants identifies individuals with mild cognitive impairment who benefit from multidomain intervention

IF 7.4 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2026-10-16 DOI:10.1002/trc2.70329

Tetsuaki Kimura, Akinori Nakamura, Taiki Sugimoto, Tomomi Satou, Naoyuki Sato, Shumpei Niida, Kouichi Ozaki, Takashi Sakurai, Hidenori Arai, Daichi Shigemizu, J-MINT study group

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引用次数: 0

Abstract

INTRODUCTION

Our recent Japan-Multimodal Intervention Trial for the Prevention of Dementia (J-MINT) trial suggested that multidomain lifestyle interventions may delay cognitive decline. However, substantial interindividual variability in response persists, and identifying individuals more likely to benefit from the intervention remains challenging. Blood-based biomarkers (BBMs), which provide a minimally invasive means of assessing Alzheimer's disease (AD)-related pathological processes, may help identify biologically distinct subgroups of individuals with mild cognitive impairment (MCI).

METHODS

Blood-based biomarkers—including amyloid-β42/40 ratio, phosphorylated tau-217, neurofilament light chain, and glial fibrillary acidic protein (GFAP)—were measured in J-MINT participants. Hierarchical clustering based on BBM profiles was used to identify biologically defined subgroups. Whole-genome sequencing data were analyzed using genome-wide association analysis (GWAS) to identify genetic variants associated with the BBM-based subgroup. A prediction model for the subgroup assignment was constructed using the associated incorporating the genetic variants, age, sex, and apolipoprotein E4 (APOE4) allele count. Model performance was evaluated using five-fold cross-validation repeated 1000 times.

RESULTS

BBM-based clustering identified a subgroup characterized by elevated GFAP and multiple biomarker abnormalities. Within this subgroup, the change in cognitive performance from baseline to 18 months differed significantly between intervention and control groups, with greater decline observed in the control group. GWAS identified four variants showing suggestive association with the subgroup, two of which were located in intronic regions of genes associated with hearing loss (PCDH15 and ATP11A).

DISCUSSION

BBM-based clustering identified biologically distinct subgroups among individuals with MCI. The subgroup characterized by multiple biomarker abnormalities and elevated GFAP showed differential cognitive trajectories between the intervention and control groups. These findings suggest that BBMs, potentially in combination with genetic information, may help identify individuals with a more progressive AD-related biological profile who may derive greater benefit from multidomain intervention.

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基于血液的生物标志物和基因组变异的整合识别轻度认知障碍的个体，他们从多领域干预中受益

我们最近的日本-多模式干预试验预防痴呆（J-MINT）试验表明，多领域生活方式干预可以延缓认知能力下降。然而，个体间的反应差异仍然存在，确定个体更有可能从干预中受益仍然具有挑战性。基于血液的生物标志物（BBMs）提供了一种评估阿尔茨海默病（AD）相关病理过程的微创手段，可能有助于识别轻度认知障碍（MCI）个体的生物学不同亚群。方法在J-MINT参与者中测量血液生物标志物，包括淀粉样蛋白-β42/40比值、磷酸化tau-217、神经丝轻链和胶质纤维酸性蛋白（GFAP）。基于BBM特征的分层聚类用于识别生物学定义的亚群。使用全基因组关联分析（GWAS）分析全基因组测序数据，以确定与bbm亚群相关的遗传变异。利用遗传变异、年龄、性别和载脂蛋白E4 （APOE4）等位基因计数等因素建立亚群分配预测模型。通过重复1000次的五重交叉验证来评估模型的性能。结果：基于bbm的聚类确定了一个以GFAP升高和多种生物标志物异常为特征的亚组。在这个亚组中，从基线到18个月的认知表现变化在干预组和对照组之间有显著差异，对照组观察到更大的下降。GWAS鉴定出4个与该亚群有关联的变异，其中两个位于与听力损失相关基因的内含子区域（PCDH15和ATP11A）。基于bbm的聚类鉴定了MCI个体中生物学上不同的亚群。以多种生物标志物异常和GFAP升高为特征的亚组在干预组和对照组之间表现出不同的认知轨迹。这些研究结果表明，脑卒中模型可能与遗传信息相结合，可能有助于识别具有更进步性ad相关生物学特征的个体，这些个体可能从多域干预中获得更大的益处。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.