There is an urgent need to identify novel, potentially modifiable risk factors for Alzheimer’s disease (AD)
and AD related dementias (ADRD). Sarcopenia is defined as aging-related declines in skeletal muscle mass and
strength. Sarcopenia can be modified by behavioral and pharmacologic interventions. Key sarcopenia
components such as hand grip strength and appendicular lean mass are associated with cognitive functioning
and with AD incidence in older adults. But treatment trials of sarcopenia-related interventions such as exercise
and strength training have failed to demonstrate consistent benefit in preventing dementia. Thus, uncertainty
remains as to whether sarcopenia is causally related to AD/ADRD risk. Without resolution of this question,
the scientific community lacks data needed to determine whether additional sarcopenia interventional studies
are justified as part of an ADRD prevention strategy. This proposal will augment the scientific evidence base
on whether the relationship between sarcopenia and ADRD risk is causal, which in turn will provide specific
evidence to help determine the potential value of sarcopenia-targeting interventions to lower risk of AD-related
outcomes. The proposal responds to NOT-AG-21-020 which calls for secondary analyses of existing datasets to
address urgent ADRD research gaps.
Our overarching goal is to test the central hypothesis that sarcopenia is causally associated with
AD/ADRD risk in older adults. We will test this hypothesis using state-of-the-art quasi-experimental
methodologies to triangulate clinical, genetic, neuroimaging, and neuropathology data from several of the best
available sarcopenia and AD/ADRD datasets from around the world, including the UK Biobank (UKB).
The Aims will rigorously evaluate the relationship of evidence-based sarcopenia measures with key
AD clinical and neuropathological outcomes. The goal of Aim 1 (AD genetic risk) is to use genetic risk and
Mendelian randomization analyses with data from UKB and other observational cohorts to test the hypothesis that sarcopenia
is causally associated with AD-related phenotypes. The goal of Aim 2 (clinical mediators) is to use state-of-the-art decomposition analyses with
data from UKB and other leading observational cohorts to determine the extent to which obesity, physical activity,
sleep, and cardiovascular risk factors and conditions mediate the association between sarcopenia and AD
dementia risk.
