Interventions focused on disease prevention are a promising strategy for combating the rising incidence of dementia, but more evidence from clinical trials is needed to establish their feasibility and effectiveness.

New research reveals that the risk of developing dementia is much higher than previously estimated, with the burden in the US population projected to grow substantially in the coming decades1. Globally, dementia cases are expected to triple by 2050, with low- and middle-income countries (LMICs) accounting for about two thirds of all cases. A growing body of evidence links dementia risk to several modifiable factors, including lifestyle choices. With limited curative options available, addressing these modifiable risk factors remains the most viable strategy for curbing the rising incidence of dementia. However, data from randomized controlled trials (RCTs) on the effectiveness of these interventions are limited and often yield mixed results, posing a considerable challenge to the development of evidence-based prevention strategies.

There is compelling evidence to support efforts to address various risk factors for dementia. Longitudinal observational studies show that several potentially modifiable risk and protective factors — such as vascular, lifestyle-related and psychosocial factors — are associated with the development of late-life dementia and Alzheimer’s disease. The 2024 update of the Lancet Commission on dementia underscores the high potential for prevention, suggesting that nearly half of all dementia cases could theoretically be prevented by mitigating 14 risk factors2. Even targeting a subset of these factors could bring substantial benefits. For instance, a modeling study in the UK showed that treating hypertension, smoking cessation and providing hearing aids could reduce the dementia prevalence by 8.5% and save England £1.86 billion annually3. Moreover, the existence of these risk factors creates opportunities for public health approaches and individually tailored interventions, which can be globally accessible and scalable.

Although observational studies clearly highlight the promise of lifestyle or modifiable risk factor interventions to prevent dementia, these have not consistently translated into successful outcomes in clinical trials. Dietary interventions such as the Mediterranean–DASH Intervention for Neurodegenerative Delay diet and omega-3 supplements have shown limited benefits in RCTs4. Similarly, results from the SPRINT Trial showed that treatment to lower systolic blood pressure did not result in a clinically relevant difference in memory or processing speed compared with standard treatment5. Physical-activity interventions have produced mixed results, with large trials such as the LIFE trial reporting no significant differences between groups, in contrast to smaller studies or studies of shorter duration that have shown some positive outcomes6. Multi-domain lifestyle interventions, which target several risk factors and mechanisms simultaneously, have also produced varied results. The FINGER trial demonstrated cognitive benefits from a 2-year multi-domain intervention, but similar efforts in France and Japan failed to replicate these results6.

Robust evidence is needed to determine which interventions are effective and under what circumstances. RCTs are considered the gold standard in medical research because they provide the most reliable evidence on the effectiveness and safety of interventions. They also provide important insights into the feasibility, acceptability and cost-effectiveness of interventions, including how best to implement these approaches in a target population. Modeling, observational and epidemiological studies, while important, cannot replace or eliminate the need to evaluate these interventions in trials. However, RCTs of modifiable or lifestyle dementia risk interventions are extremely difficult to perform. Dementia typically has a long prodromal phase, with neuropathological changes occurring decades before cognitive symptoms emerge. Trials might require decades of intervention and follow-up before clinical dementia occurs, which leads to prohibitive costs and bias because of selective drop-out. Additionally, it might be unethical or impossible to randomly assign people to a treatment group.

The field of dementia prevention is still developing, and results from RCTs have provided considerable steps forward toward the identification and optimization of effective preventive interventions. For example, analysis of the large Age Well RCT of a multi-domain dementia risk intervention that showed no improvements in cognition after 24 months suggested that the intervention was not targeted enough or intense enough7. Investigators in the SMARRT trial used a similar, but in this case personalized, multi-domain intervention and saw an improvement on a composite cognitive score after 2 years8. These findings suggest that the diversity of risk profiles among older adults is important, and tailored interventions may yield better outcomes. New blood and neuroimaging biomarkers are also affecting trials in this area, improving participant selection and providing better surrogate endpoints for efficacy. Early and reliable measures of an intervention’s impact can substantially reduce the clinical follow-up times needed for traditional approaches. Furthermore, the increasing use of digital tools to deliver interventions has boosted adherence to interventions and improved trials that target under-represented populations.

Dementia is a major public health issue and will continue to grow unless effective interventions are identified. Funders must prioritize resources to support more RCTs that evaluate interventions aimed at reducing dementia risk. The limited evidence from clinical trials risks investments in ineffectual interventions, and more data are needed on how physical, social and cultural environments alter the effectiveness of available interventions. Ensuring equity in prevention strategies is not only ethically imperative but also essential for optimizing accessibility and maximizing global impact.