Alzheimer's disease (AD), the most common form of dementia, affects over 50 million people globally and is projected to increase dramatically by 2050. The substantial economic burden and public health implications necessitate effective prevention strategies. While AD has no cure, numerous modifiable risk factors (MRFs) exist, including poor diet, lack of exercise, and cognitive inactivity. Meta-analyses suggest that targeting these MRFs could significantly reduce AD incidence. Previous research has shown mixed results for interventions targeting single MRFs; therefore, a multidomain approach that tackles multiple risk factors simultaneously is increasingly being investigated as a more promising strategy for AD prevention. This review aims to assess the current evidence from randomized controlled trials (RCTs) of multidomain lifestyle interventions on cognitive decline and AD prevention in adults aged 45 and older, published up to May 31, 2021, filling a gap in the literature by including studies published after the previous comprehensive review in 2019.

Three previous literature reviews have examined multidomain lifestyle interventions, concluding that these interventions hold significant potential for enhancing cognitive reserve and reducing AD risk. However, these reviews lacked comprehensive data on studies completed after August 2019. The current review builds on this existing evidence base to provide a more updated and comprehensive analysis of the efficacy and impact of these interventions on AD outcomes.

The researchers conducted a literature search in PubMed and Scopus databases for studies published in English up to May 31, 2021, using keywords related to multidomain interventions, AD, cognitive decline, and prevention. After removing duplicates and screening titles and abstracts, nine studies were included. Inclusion criteria included the presence of a control group, randomization, at least three combined interventions, a study interval of six months or longer, and clear cognitive outcome measures (neuropsychological tests, AD incidence, or risk scores). Participants were aged 45 and older. The quality of the included studies was assessed using the revised Cochrane risk-of-bias tool for randomized trials. Data extraction focused on outcomes related to global cognition (MMSE, MoCA, or composite Z-score), specific cognitive domains (as defined by DSM-5), AD incidence, and AD risk scores. Two reviewers independently assessed study eligibility and quality, achieving 100% agreement.

The review included nine multidomain lifestyle intervention studies—three of which were pilot studies—all of which were RCTs. The studies differed in intervention components, with all including physical activity, eight including diet, and six including cognitive training. Eight studies targeted metabolic or cardiovascular risk factors. Two studies included social activities, two included medication, and one included omega-3 PUFAs supplementation. Eight studies assessed global cognition, with four showing significant improvements in the intervention group. Two out of the three studies that assessed specific cognitive domains showed significant improvements. Two studies assessed AD incidence, showing no significant effect, while one study, which measured AD risk scores, showed significant results. Specifically, the FINGER study demonstrated significant improvement in global cognition and specific cognitive domains (processing speed and executive functioning) after two years. The MAPT study showed less cognitive decline in the intervention groups compared to controls, although not always statistically significant. The Taiwan Multidomain Intervention Efficacy Study found significant improvement in concentration and overall cognition in participants aged 75 and older. Conversely, some studies failed to find significant effects, likely due to methodological differences (short duration, small sample sizes, different intervention components and frequencies). The review concludes that the studies reporting on AD outcomes had limitations, including early study termination or loss to follow up.

The findings suggest that multidomain lifestyle interventions may be effective in improving cognition and potentially reducing the risk of cognitive decline, although more robust evidence is needed to definitively confirm their impact on AD incidence. The heterogeneity of the included studies—in terms of population, duration, components, and outcome measures—challenges the drawing of firm conclusions. Methodological limitations, such as short study duration, small sample size, and lack of standardized outcome measures, may explain the inconsistencies in findings. The lack of significant results in studies examining AD incidence could be attributed to several factors, including the high quality of standard cardiovascular care in some studies. Future research needs to address these limitations.

Multidomain lifestyle interventions may offer a promising avenue for mitigating cognitive decline, but further research is essential to conclusively demonstrate their effectiveness in preventing AD. Future studies should employ longer follow-up periods, consistent methodology, well-defined intervention components, and standardized outcome measures. The inclusion of sleep as an intervention component and studies conducted in low- and middle-income countries are also recommended.

This literature review has limitations. It is not a systematic review, potentially overlooking relevant studies. Furthermore, some included studies did not prioritize cognition or AD as primary outcomes, which could influence the study's power. The heterogeneity of the included studies makes direct comparisons challenging. The cognitive status of participants varied across studies, and most were conducted in high-income countries, limiting the generalizability of results to other populations.