Project Summary/ Abstract Millions of middle-aged and older adults are using statins, and despite the attention that has been given to the possibility that statin treatment may reduce risk of Alzheimer’s Disease and Related Dementias (ADRD), there is substantial uncertainty about such a benefit, as well as concern regarding possible adverse effects of statins on cognitive function. Even a small benefit or harm for ADRD risk could be of substantial public health importance, but prior research has not had access to sufficiently large cohorts with detailed covariate data to provide precise estimates with full control for confounding by indication or other threats to internal validity. This project uses the comprehensive electronic health records (EHRs) of Kaiser Permanente Northern California on a diverse, multi-ethnic cohort of over 1 million individuals age 65 and over (34% statin users), with longitudinal data on laboratory measures (including LDL cholesterol) and related clinical conditions, and a survey of 254,000 providing additional socioeconomic and behavioral risk factor data. These data resources combine the advantages of both a large administrative longitudinal data set with the advantages of detailed lab, pharmacy, and covariate control. With these data we will be able to evaluate (AIM 1) the net effect of initiating statins on the risk of ADRD and whether the effects of statins depend on type, timing, duration, or dose. These are all easily modified factors and precise estimates of their potential benefit or harm would have immediate clinical relevance. We will also evaluate (AIM 2) whether effects differ based on social, demographic, clinical, or genetic background. The KPNC membership is exceptionally racially/ethnically diverse, so we will be able to provide rigorous tests of whether effects differ for African Americans, Latinos, Asian Americans, or non-Latino Whites. Genetic information is available for over 67,000 participants, permitting evaluation of whether major ADRD genetic risk factors or genetic variants related to lipid response and cardiovascular disease modify the effects of statins on ADRD. Finally, we will evaluate (AIM 3) whether statins influence ADRD risk via changes in LDL levels, diagnosed cerebrovascular or cardiovascular disease, or via other mechanisms. If so, this opens the path for future research on how to leverage these different mechanisms, either with statins or potentially via other pharmacotherapies or interventions. These aims are independently essential to help explain inconsistent results from prior research on statins and dementia. The research team assembled to accomplish these aims includes expertise on all the data sources, statins, pharmacoepidemiology, statistical genetics, and epidemiologic methods for study of ADRD. The possibility that statins might be judiciously applied to reduce lifetime risk of ADRD would impact current guidelines for use of statins and would be a powerful advance towards a population prevention strategy for ADRD. The main KPNC cohort and linked survey and genetic data provide an unparalleled resource. In the absence of extremely large RCTs, the proposed research will provide the most conclusive evidence for the effects of statins on ADRD.

Project Narrative Millions of middle-aged and older adults are being treated with statins, and despite the attention that has been given to the possibility that statin treatment may reduce risk of Alzheimer’s Disease and Related Dementias (ADRD), there is substantial uncertainty about such a benefit. The global prevalence of dementia is expected to increase to ~75 million by 2030, making it among the most important public health problems in the world today. This study will thoroughly investigate the effects of statin treatment on risk of developing ADRD, using the comprehensive electronic health records (EHRs) of Kaiser Permanente Northern California on a diverse, multi-ethnic cohort of over 1 million individuals age 65 and over (34% statin users), with linked data on genetic, plus socioeconomic and behavioral risk factors, to address the question of potential harms and benefits of statin treatment in relation to dementia.