Genetic background and multidomain interventions in mild cognitive impairment.

Kosuke Fujita, Shumpei Niida, Daichi Shigemizu, Kouichi Ozaki, Hidenori Arai, Takashi Sakurai, Tetsuaki Kimura, Akiko Yamakawa

Journal: Alzheimer's research & therapy 2025;17(1):130

PMID: 40490801

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Plain Language Summary

Mild cognitive impairment (MCI) is a condition where older adults experience noticeable memory and thinking problems that are greater than expected for normal ageing, but not severe enough to be diagnosed as dementia. Some people with MCI go on to develop Alzheimer’s disease. Research has shown that lifestyle interventions such as improving diet, increasing exercise, stimulating the brain, staying socially active, and managing blood pressure may help slow cognitive decline. However, it is unclear whether a person’s genetic risk for Alzheimer’s disease affects how well these interventions work.This study analysed data from the Japan-Multimodal Intervention Trial for the Prevention of Dementia (J-MINT), an 18-month randomised controlled trial.

The results showed that the multidomain intervention improved cognitive function. Importantly, individuals with higher genetic risk for Alzheimer’s disease also benefited from the intervention, and genetic risk did not prevent participants from responding positively. In some analyses, certain genetic profiles appeared to influence the magnitude of cognitive improvement, suggesting that genetic background may modify response to lifestyle interventions.

In conclusion, multidomain lifestyle interventions can be beneficial for older adults with MCI regardless of their genetic risk for Alzheimer’s disease. These findings support the idea that lifestyle changes remain important even for individuals who may be genetically predisposed to dementia. Healthcare professionals can use this information to inform patients about the benefits of preventive lifestyle strategies, even when genetic risk is present, and may consider genetic background when tailoring long-term prevention plans.

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Address: 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.; 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.; Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan.; RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.; 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. [email protected].; Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, 734-8551, Japan. [email protected].

DOI: 10.1186/s13195-025-01764-0