Methods to Test Biomarkers of Aging as Shared Determinants of Alzheimers Disease and Related Dementias and Physical Disability - Dementia affects over 44 million adults worldwide, and Alzheimer’s disease (AD) and related dementias (ADRD) account for 60%-80% of all cases among older adults. Physical disability is often the final consequence of ADRD before death. One-third of dementia cases may be attributable to modifiable factors, and due to unclear benefit of AD treatments, there is a need to identify intervention targets to prevent ADRD and physical disability. Since both conditions may be preceded by poor cognitive and physical performance by over a decade, shared biological determinants of dual cognitive-physical decline that impact neurological and musculoskeletal systems may predict and inform therapeutic targets to prevent ADRD and physical disability. The geroscience hypothesis posits that targeting the biology of aging may better impact human health, such as prevention of ADRD and physical disability, than targeting specific diseases. Indeed, parallel lines of research indicate that biomarkers reflecting the underlying biology of aging are related to cognitive and physical decline as separate endpoints. This work includes biomarkers of inflammation and biomarkers of hallmarks of aging such as cell senescence, altered cell communication, epigenetic changes, telomere attrition, nutrient signaling, and loss of proteostasis. However, rigorous epidemiologic studies have not fully investigated whether biological mechanisms of aging affect relations and dynamics between cognitive and physical decline, or ADRD and physical disability onset, over time. Thus, identifying early biomarkers of biological aging mechanisms that are related to dual cognitive-physical decline and joint ADRD-disability onset in initially healthy older adults is a key step toward geroscience-guided prevention trials. A major barrier to this goal is that studies of longitudinal cognitive and physical endpoints are vulnerable to survival bias and unmeasured confounding. Extant statistical methods are limited in their ability to overcome this barrier; therefore, shared biological mechanisms of cognitive and physical endpoints are not fully known, and new statistical methods are needed. To overcome the barriers to filling these knowledge gaps, specific aims of this proposal are to: 1) test relations of biomarkers of aging with longitudinal dual cognitive-physical decline; 2) test relations of biomarkers of aging with time to incident joint dementia (i.e., ADRD)-disability onset; and 3) develop/validate a biomarker of aging risk score to predict joint dementia (i.e., ADRD)-disability. To this end, we propose to extend statistical methods for multi- iate longitudinal and time-to-event outcomes and apply them to harmonized data from 8 cohort studies of >11,000 community-dwelling adults aged at least 65 years. We hypothesize that biomarkers of aging predict and explain, in part, relations between cognitive and physical endpoints beyond known risk factors. New statistical methods developed as essential tools to jointly study cognitive and physical endpoints will be shared with the scientific community. This project’s ultimate public health impact is the potential for novel biomarkers of aging to inform geroscience strategies to prevent and predict ADRD and physical disability in older adults.
