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.
