APOE4 allele modifies the effect of lifestyle interventions on cognition

Abstract

Background: The apolipoprotein E ε4 allele (APOE4) is the main genetic risk factor for incidence and earlier onset of dementia, and APOE4 carriers are thus considered a key target group for dementia risk reduction. APOE4 carriership also impacts the association between lifestyle and cognitive decline. Our meta-analysis investigated whether APOE4 modifies the effect of lifestyle intervention on cognition among people with elevated dementia risk in Finland (FINGER study), France (MAPT) and Japan (J-MINT).

Methods: We collected harmonised estimates from three completed randomised clinical trials investigating the effect of multidomain lifestyle interventions on cognitive decline. Age ranged from 60 to 85 years and risk for dementia was defined with dementia risk score (FINGER), subjective cognitive complaints or signs of frailty (MAPT), or mild cognitive impairment (J-MINT). The meta-analysis was based on random-effects model with maximum likelihood estimation.

Results: Here we show that the benefit of intervention is greater among APOE4 carriers than non-carriers after 12 months of intervention (interaction p = 0.039) and borderline significantly after 24 months ( p = 0.058) for global cognition. Among the cognitive domains, the APOE4 effect modification appears to be more related to executive function than memory or processing speed. Stratified analysis show that the intervention effect on global cognition and executive function is significant among APOE4 carriers at both 12 and 24 months.

Conclusions: Our results indicate that APOE4 carriers are a key target group for lifestyle-based prevention in people with mild cognitive impairment or earlier at-risk stages.

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Cite

BibTeX RIS

BibTeX

@article{lehtisalo2026apoe4,
  title = {{APOE4 allele modifies the effect of lifestyle interventions on cognition}},
  author = {Jenni Lehtisalo and Ari Solomon and Esko Levälahti and Nicola Coley and Christelle Cantet and Francesca Mangialasche and Takashi Sakurai and Taiki Sugimoto and Kazuaki Uchida and Tiia Ngandu and Sandrine Andrieu and Hidenori Arai and Miia Kivipelto},
  journal = {Communications Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s43856-026-01948-1},
  url = {https://www.nature.com/articles/s43856-026-01948-1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - APOE4 allele modifies the effect of lifestyle interventions on cognition
AU  - Jenni Lehtisalo
AU  - Ari Solomon
AU  - Esko Levälahti
AU  - Nicola Coley
AU  - Christelle Cantet
AU  - Francesca Mangialasche
AU  - Takashi Sakurai
AU  - Taiki Sugimoto
AU  - Kazuaki Uchida
AU  - Tiia Ngandu
AU  - Sandrine Andrieu
AU  - Hidenori Arai
AU  - Miia Kivipelto
PY  - 2026
DA  - 2026/10/06
JO  - Communications Medicine
DO  - 10.1038/s43856-026-01948-1
UR  - https://www.nature.com/articles/s43856-026-01948-1
AB  - Background: The apolipoprotein E ε4 allele (APOE4) is the main genetic risk factor for incidence and earlier onset of dementia, and APOE4 carriers are thus considered a key target group for dementia risk reduction. APOE4 carriership also impacts the association between lifestyle and cognitive decline. Our meta-analysis investigated whether APOE4 modifies the effect of lifestyle intervention on cognition among people with elevated dementia risk in Finland (FINGER study), France (MAPT) and Japan (J-MINT).  Methods: We collected harmonised estimates from three completed randomised clinical trials investigating the effect of multidomain lifestyle interventions on cognitive decline. Age ranged from 60 to 85 years and risk for dementia was defined with dementia risk score (FINGER), subjective cognitive complaints or signs of frailty (MAPT), or mild cognitive impairment (J-MINT). The meta-analysis was based on random-effects model with maximum likelihood estimation.  Results: Here we show that the benefit of intervention is greater among APOE4 carriers than non-carriers after 12 months of intervention (interaction p = 0.039) and borderline significantly after 24 months ( p = 0.058) for global cognition. Among the cognitive domains, the APOE4 effect modification appears to be more related to executive function than memory or processing speed. Stratified analysis show that the intervention effect on global cognition and executive function is significant among APOE4 carriers at both 12 and 24 months.  Conclusions: Our results indicate that APOE4 carriers are a key target group for lifestyle-based prevention in people with mild cognitive impairment or earlier at-risk stages.
SN  - 2730-664X
ER  -

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