Despite advances in medicine, the etiology of dementia remains elusive, and no cure has been discovered yet. Implementing timely preventive strategies for dementia is challenging due to the lack of reliable biomarkers for prediction and early diagnosis. Important pre-clinical measures of dementia include subjective cognitive complaints, impaired performance on cognitive tests of processing speed, reduced physical function, and disability in activities of daily living. Physical inactivity is a known risk factor for dementia. However, the pathways through which these are linked are still unclear. Identifying biomarkers associated with pre-clinical measures of dementia, and determining whether these biomarkers mediate associations between physical activity and pre-clinical dementia will improve etiological understanding and will facilitate earlier diagnosis of dementia. Using the unique data available in SIMPER, we aim to improve understanding of the biological mechanisms behind cognitive and physical impairment in dementia-free general and clinical populations (i.e., cancer survivors/diabetes patients) by focusing on novel molecular pathways and the role of physical activity Every year more than 60,000 individuals in Sweden are diagnosed with cancer. Physical inactivity, obesity, and type 2 diabetes (T2D) have been robustly associated with a higher risk of some types of cancer. However, the extent to which these important risk factors are causally linked and the mechanisms linking them are incompletely understood. A better understanding of the biological pathways underlying important risk factors and their interactions is necessary to highlight previously unknown opportunities for cancer prevention. Over the last three years, my team has filled gaps in knowledge relating to the patterns, determinants, and consequences of (change in) physical activity after a cancer diagnosis among individuals with type 2 diabetes. One key finding was that higher levels of physical activity before a cancer diagnosis seemed to represent a health ‘buffer’ with regards to mortality. However, the mechanisms behind this observation have not yet been explored. Enhanced mechanistic understanding of (change in) physical activity in relation to cancer survival is therefore vital. Using data in SIMPLER we also aim to examine the aetiology, mechanisms, and pathways linking (change in) physical inactivity, obesity, and T2D with incidence of and survival after breast, colorectal and endometrial cancer.