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Background: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration: ClinicalTrials.gov (NCT05109169). [ABSTRACT FROM AUTHOR]

Background and purpose: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at‐risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU‐ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. Methods: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU‐ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU‐ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU‐ADRI, and the potential impact of baseline ANU‐ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. Results: A higher ANU‐ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was −0.028 [−0.032 to −0.025]) and over the 2‐year study (e.g., estimate for 2‐year changes in ANU‐ADRI and per‐year changes in global cognition [95% confidence interval] was −0.068 [−0.026 to −0.108]). No significant beneficial intervention effect was reported for ANU‐ADRI, and baseline ANU‐ADRI did not significantly affect the response to the intervention on changes in cognition. Conclusions: The ANU‐ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context. [ABSTRACT FROM AUTHOR]

Introduction: Mechanisms underlying the positive association between occupational mental demands and late-life cognition are poorly understood. The objective of this study was to assess whether the association between occupational complexity and cognition is related to and moderated by brain integrity in individuals at risk for dementia. Brain integrity was appraised throughout structural measures (magnetic resonance imaging, MRI) and amyloid accumulation (Pittsburgh compound B (PiB)-positron emission tomography, PiB-PET). Methods: Participants from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) neuroimaging sample – MRI (N = 126), PiB-PET (N = 41) – were included in a post hoc cross-sectional analysis. Neuroimaging parameters comprised the Alzheimer's disease signature (ADS) cortical thickness (FreeSurfer 5.3), medial temporal atrophy (MTA), and amyloid accumulation (PiB-PET). Cognition was assessed using the neuropsychological test battery. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Linear regression models included cognition as dependent variable, and occupational complexity, measures of brain integrity, and their interaction terms as predictors. Results: Occupational complexity with data and substantive complexity were associated with better cognition (overall cognition, executive function) when adjusting for ADS and MTA (independent association). Significant interaction effects between occupational complexity and brain integrity were also found, indicating that, for some indicators of brain integrity and cognition (e.g., overall cognition, processing speed), the positive association between occupational complexity and cognition occurred only among persons with higher brain integrity (moderated association). Conclusions: Among individuals at risk for dementia, occupational complexity does not seem to contribute toward resilience against neuropathology. These exploratory findings require validation in larger populations. [ABSTRACT FROM AUTHOR]