Fujita Kosuke, Kimura Tetsuaki, Yamakawa Akiko, Niida Shumpei, Ozaki Kouichi, Sakurai Takashi, Arai Hidenori, Shigemizu Daichi
Department of Prevention and Care Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
Alzheimers Res Ther. 2025 Jun 10;17(1):130. doi: 10.1186/s13195-025-01764-0.
The growing prevalence of dementia emphasizes the need for effective prevention strategies. Although the partial efficacy of multidomain interventions for dementia prevention has been demonstrated, understanding the characteristics of individuals who benefit most from these interventions is crucial for optimizing resource allocation. This study investigated the association between participants' genetic backgrounds and the effectiveness of multidomain interventions for preventing dementia.
This study utilized data from the Japan-Multimodal Intervention Trial for the Prevention of Dementia (J-MINT), where older adults with mild cognitive impairment underwent 18 months of multidomain intervention. The intervention included exercise, nutrition, cognitive stimulation, social participation, and vascular risk management. Participants who completed the J-MINT intervention and had genetic data, including whole-genome sequencing (WGS), were analyzed. Using Japanese polygenic risk scores (PRSs) for Alzheimer's disease, participants were stratified into high- and low-genetic-risk groups. Cognitive composite score (CPS) improvement rates at 6-, 12-, and 18-months were compared between intervention and control groups, with subgroup analyses performed by age (< 75 and 75 years). Additionally, a comprehensive variant analysis using WGS was conducted to identify genetic signals potentially associated with the intervention's effectiveness.
Among 289 participants analyzed (168 aged < 75 years; 121 aged ≥ 75 years), 99 were classified into the high-risk PRS group (56 intervention, 43 control) and 190 into the low-risk PRS group (92 intervention, 98 control). For participants aged ≥ 75 years, no statistically significant differences in CPS improvement rates were observed between the intervention and control groups, regardless of PRS classification. However, in participants aged < 75, those in the high-risk PRS group showed significant CPS improvement at the 6-month follow-up. Additionally, analysis of 9,978,605 genetic variants identified two loci, ID3 and LMO1 (rs2067053 and rs201082658), with suggestive associations (P < 1 × 10⁻) to reduced intervention effectiveness.
This study highlighted the utility of PRS in predicting cognitive improvement following multidomain interventions and identified genetic variants that may influence the intervention's effectiveness. The findings provide a valuable foundation for personalized dementia prevention strategies.
痴呆症患病率不断上升，凸显了有效预防策略的必要性。尽管多领域干预对预防痴呆症的部分疗效已得到证实，但了解从这些干预中获益最大的个体特征对于优化资源分配至关重要。本研究调查了参与者的基因背景与多领域干预预防痴呆症效果之间的关联。
本研究利用了日本预防痴呆症多模式干预试验（J-MINT）的数据，轻度认知障碍的老年人接受了18个月的多领域干预。干预包括运动、营养、认知刺激、社会参与和血管风险管理。对完成J-MINT干预并拥有包括全基因组测序（WGS）在内的基因数据的参与者进行分析。使用日本阿尔茨海默病多基因风险评分（PRS），将参与者分为高基因风险组和低基因风险组。比较干预组和对照组在6个月、12个月和18个月时的认知综合评分（CPS）改善率，并按年龄（<75岁和≥75岁）进行亚组分析。此外，进行了一项使用WGS的全面变异分析，以识别可能与干预效果相关的基因信号。
在分析的289名参与者中（168名年龄<75岁；121名年龄≥75岁），99名被归类为高风险PRS组（56名干预组，43名对照组），190名被归类为低风险PRS组（92名干预组，98名对照组）。对于年龄≥75岁的参与者，无论PRS分类如何，干预组和对照组之间的CPS改善率均未观察到统计学上的显著差异。然而，在年龄<75岁的参与者中，高风险PRS组在6个月随访时CPS有显著改善。此外，对9978605个基因变异的分析确定了两个位点，即ID3和LMO1（rs2067053和rs201082658），与干预效果降低存在提示性关联（P<1×10⁻）。
本研究强调了PRS在预测多领域干预后认知改善方面的效用，并确定了可能影响干预效果的基因变异。这些发现为个性化痴呆症预防策略提供了宝贵的基础。
