Many cases of Alzheimer´s disease (AD) and dementia can be caused by unhealthy lifestyle and poor control of vascular and metabolic disorders and can thus be prevented. So far, the only intervention model that demonstrated significant cognitive benefits in at-risk individuals is the multimodal lifestyle-based Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). FINGER combined nutrition, exercise, cognitive training and social activities, and vascular/metabolic risk management in a large (N=1260), longer-term (2 years) randomized controlled trial (RCT).

The FINGER model is currently being tested within the first global network of multimodal dementia prevention trials, World-Wide FINGERS (WW-FINGERS, currently 25 member countries). A key aim of WW-FINGERS is to evolve the FINGER model by combining lifestyle improvement and disease-modifying drugs. This pioneering proposal takes the first step towards this goal by testing a multimodal lifestyle+metformin intervention.

Type-II diabetes (T2D) and insulin resistance are well-known AD risk factors. Drugs treating insulin resistance/diabetes may also prevent dementia. Metformin is a safe, inexpensive medication with proven efficacy in preventing and treating T2D.

The metformin-lifestyle combination has never been tested for dementia prevention. We will test the cognitive benefits of such combination in a RCT enrolling 600 people, including subjects with genetic risk for AD (APOE4 gene). The trial will include individuals from UK, Sweden, Finland, aged 60-80 years, at increased dementia risk based on a validated dementia risk score and no substantial cognitive impairment. Participants will be assigned to either a control group (healthy-lifestyle advice) or an active group (multimodal lifestyle program, alone or in combination with metformin, 2000mg/day or 1000mg/day).

Primary outcome will be change in cognition. Secondary outcomes include intervention effects on brain structure (MRI) and metabolism (FDG-PET).

This project, led by a team of worldwide experts in AD and T2D, will provide crucial knowledge to AD/dementia prevention.