7. PROJECT SUMMARY The long-term goal of the proposed career development award is to provide the training necessary to develop an independent research program investigating how chronic pain is related to dementia risk. Such research is timely given recent links between chronic pain and a doubled risk of dementia due to Alzheimer's disease (AD). Chronic pain may lead to general, AD-unspecific, neurodegeneration that increases susceptibility to AD dementia, supported by studies linking chronic pain to smaller brain volumes in adults. Alternatively, recent animal studies suggest that the biological processes underneath chronic pain may promote amyloidosis and tau seeding, but there is less focus on the relationship of chronic pain and AD-related neurodegeneration in humans. A training emphasis focused on incorporating biological measures will complement my existing expertise in chronic pain, cognitive aging, and advanced statistical analysis to conduct this research program. The proposed training goals are to: 1) attain proficiency in neuroanatomy and neuroimaging relevant to aging and AD; 2) obtain competence in assessment and biology of pain; and 3) establish a multidisciplinary program studying brain changes and AD risk. Training will involve a combination of formal coursework, and hands-on activities, and discussion with mentors and other field experts. The Department of Psychiatry at the University of California San Diego is an ideal environment for the proposed training activities with access to world-renown researchers and research centers focused on chronic pain, neuroimaging, and Alzheimer's disease as well as an excellent departmental record of career development for junior researchers. The proposed project will examine how chronic pain relates to indicators of general neurodegeneration and AD-related neurodegeneration across independent samples of older adults including the Framingham Heart Study, the Religious Orders Study/Memory Aging Project, and the Vietnam Era Twin Study of Aging. Aim 1 will examine how chronic pain relates to indicators of general neurodegeneration, including brain age, an estimation of age based on thickness/volume across a wide arrange of AD-unspecific brain regions, as well as neurofilament light, a protein released during neurodegeneration. Aim 2 will examine how chronic is associated with indicators of AD-related neurodegeneration. Indicators include AD brain signatures capturing thickness/volume and mean diffusivity in AD-vulnerable brain regions, biomarkers of amyloid and tau, and diagnosis of mild cognitive impairment and AD dementia. Analyses will help clarify how chronic pain contributes to dementia risk, either through general neurodegeneration or AD-related neurodegeneration. Multiple datasets will improve the rigor of analyses by allowing for replication.