Grant Abstract: COCOA PAD II Trial: Cognition Ancillary Study

Grant Number: 3R01AG068458-01A1
PI Name: McDermott
Project Title: COCOA PAD II Trial: Cognition Ancillary Study

Abstract: Approximately 10-15% of people age 65 and older in the U.S. have lower extremity peripheral artery disease (PAD). Our work and that of others has shown that people with PAD have significantly greater functional impairment and faster functional decline, compared to people without PAD. People with PAD also have an increased prevalence and incidence of Alzheimer’s Disease and Related Dementia (ADRD). Because PAD is associated with systemic atherosclerosis, people with PAD are at increased risk for vascular contributions to cognitive impairment and dementia. However, effective therapeutic interventions to prevent or slow onset of ADRD have not been identified. Identifying effective, safe, and widely available therapeutic interventions to prevent or slow ADRD is an important public health priority. Cocoa flavanols, from the seeds of theobroma cacao, the “cocoa” tree, have therapeutic properties that may improve, prevent, or slow the onset of ADRD and improve cognitive function. Cocoa flavanols may prevent or slow the onset of ADRD by improving vascular function and cerebral blood flow, via signaling pathways that improve neural function, through improved beta-amyloid processing, or through anti-oxidant actions. However, data on the effects of cocoa flavanols on prevention and treatment of ADRD are conflicting. We propose a supplemental study to our multi-centered double blinded randomized trial, the COCOA- PAD II Trial (R01-AG068458). The primary aim of the COCOA-PAD II Trial, currently funded by the NIA, is to determine whether cocoa flavanols, compared to placebo, significantly improve 6-minute walk distance at six- month follow-up in 190 older people with PAD. Secondary outcomes in the funded COCOA-PAD II Trial include brachial artery flow-mediated dilation and gastrocnemius muscle perfusion (measured by MRI). We now request supplemental funding to add outcome measures related to ADRD and plasma measures of tau and amyloid β42/40 to the COCOA PAD II Trial, in order to delineate potential benefits of cocoa flavanols for slowing the onset or progression of ADRD in people with PAD. Prior studies suggest beneficial and dose dependent benefits of cocoa flavanols on general cognition, executive function, attention, processing speed, and working memory. Therefore, we will add measures of verbal fluency and working memory to the COCOA PAD II Trial, including the Digit Symbol Substitution Test and the Trail-Making Test. We will test the hypotheses that among 190 older people with PAD, cocoa flavanols will prevent or slow onset of ADRD by improving cognitive measures and plasma measures of tau and the Aβ42/40 ratio, compared to placebo. If our hypotheses are correct, results have the potential to prevent or slow the onset of dementia, by improving understanding of the biologic pathways and therapies that prevent Alzheimer’s Disease and Related Dementia in the large and growing number of people disabled by PAD. PUBLIC HEALTH RELEVANCE: We propose a supplemental study to our funded multi-centered double blinded randomized trial, the COCOA-PAD II Trial (R01-AG068458). The proposed supplemental study will assess whether cocoa flavanols have effects that may prevent or slow progression of Alzheimer’s disease or related dementias, compared to placebo, in 190 people with PAD.

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