Project 2: Depression and chronic pain: Modifiable targets for prevention of AD/ADRD

Revised Summary/Abstract Depression is a highly prevalent and modifiable risk factor for Alzheimer’s Disease and Alzheimer’s Disease Related Disorders (AD/ADRD). Severe and untreated depression is associated with substantially higher risk of AD/ADRD. Older individuals with comorbidities are more likely to be undertreated for depression, possibly increasing AD/ADRD risk in these groups. Yet the long-term effects of pharmacological and non-pharmacological treatments of depression on AD/ADRD risk are currently unknown. Chronic pain is extremely prevalent and commonly co-occurs and exacerbates depression. Evidence suggests chronic pain is a risk factor for AD/ADRD highlighting the need for a rigorous assessment of independent and joint effects of depression and chronic pain on AD/ADRD risk. We propose a systematic approach to interrogating potential biases by comparing patterns across populations, study designs, and analytic approaches to derive the best possible estimates of the effects of depression, treatment of depression, and chronic pain on AD/ADRD risk. We will leverage complementary sources of data including large cohorts with electronic health record (EHR) databases enriched with survey and genetic information, as well as national cohorts with repeated measures of cognition and depressive symptoms. We propose three aims: Aim 1. Evaluate the effect of depression on AD/ADRD and cognitive decline accounting for cerebrovascular and other comorbidities, as well as severity, recurrence, and duration of depression and the effects of treatment. Aim 2. Examine the direct effect and modifying role of chronic pain on AD/ADRD and cognitive decline in the context of depression. Aim 3: Examine heterogeneity in the distribution and effects of depression and depression treatment as possible drivers of elevated risk of AD/ADRD among subpopulations and evaluate the extent to which these increases in risk could be reduced through improvements in treatment. Working closely with the TIME-AD Cores to field novel and rigorous science in large, heterogeneous data sets, we will provide more compelling and actionable evidence than previously achievable on the independent and joint effects of depression and chronic pain on AD/ADRD and on whether treatment of depression can reduce AD/ADRD risk for all.