Insulin resistance is a common phenomenon, closely associated with obesity, and defined as the inability of target tissues to respond normally to insulin. Insulin resistance typically precedes the onset of type 2 diabetes by several years. Type 2 diabetes is a risk factor for dementia and for Alzheimer´s disease (AD), the most common type of dementia. Some epidemiological studies suggest that insulin resistance increases the risk for dementia and AD, even in non-diabetic populations. In vitro and animal studies indicate that insulin resistance can contribute to the pathogenesis of AD through multiple different pathways. 

This thesis was set out to explore the cross-sectional and longitudinal associations between insulin resistance and cognitive functioning in the Finnish large, nationwide Health 2000 survey, and its follow-up, Health 2011. The possible modulating effects of sex and apolipoprotein E ε4 genotype (APOEε4), the most significant genetic risk factor for sporadic AD, were of specific interest. The aim of this thesis was also to investigate whether midlife insulin resistance increases the risk for brain amyloid accumulation, which is considered an early sign of AD. 

Insulin resistance was associated with poorer verbal fluency in women and in non-carriers of APOEε4 cross-sectionally (n=5935). Insulin resistance was an independent predictor of poorer verbal fluency performance after 11 years, and of a steeper decline in verbal fluency during the follow-up in both men and women, and in carriers and non-carriers of APOEε4 (n=3695). Midlife insulin resistance increased the risk for brain amyloid accumulation, measured with positron emission tomography (PET), after a 15-year follow-up (n=60). The risk was similar in both carriers and non-carriers of APOEε4. 

These results indicate that midlife insulin resistance is an independent risk factor for cognitive decline, and for late-onset AD.