Connecting disease risk estimation with prediction of response to multimodal lifestyle interventions was done by using several complementary approaches, e.g. observational and interventional randomized controlled trial data, analysis ranging from machine learning to traditional statistics, and multi-dimensional predictors and outcomes (e.g. cognitive, clinical, blood, cerebrospinal fluid, brain imaging markers, genetic and modifiable factors).
Among the main results, multimodal lifestyle interventions for dementia risk reduction were particularly beneficial when targeted specifically to at-risk individuals. Overall, earlier interventions were more likely to show benefit, although there was still room for risk reduction in people with cognitive impairment who did not yet have dementia (prodromal AD). People with higher genetic risk for AD also benefited from early interventions. Metabolomic and other biomarker analyses provided new knowledge on potential intervention mechanisms. These findings provide an important alternative for dementia risk reduction because, as shown in the project, many at-risk people may not be eligible for new AD drugs.
Project results were also used for the development of World-Wide FINGERS (WW-FINGERS), the first global network of multimodal dementia prevention trials (currently 68 member countries). This has facilitated harmonisation across trial protocols and joint analyses that can continue to provide highly valuable knowledge as more trials will be conducted by network members, including in low/middle income countries.
Some at-risk individuals may need more than lifestyle intervention for optimal benefit. To design the first multimodal prevention trial combining lifestyle-based and pharmacological intervention, a drug repurposing approach was used due to several AD drug trial failures during 2019-2020. Metformin, commonly used for diabetes treatment, was identified as a suitable putative disease-modifying drug. A novel updated FINGER 2.0 precision prevention model was developed, combining multidomain lifestyle intervention with metformin. Although routinely used for diabetes, this combination therapy has not been previously tested for dementia risk reduction. MET-FINGER is the first WW-FINGERS trial testing a FINGER 2.0 combination therapy model and may provide a much-needed therapeutic approach for a large group of people at-risk for dementia who are asymptomatic and/or not eligible for new AD drugs.
