Lifespan and Cardiovascular Health Effects on The Brain in Humans and Great Ape

Project Summary Humans and great apes share many similarities in age-related illnesses including cardiovascular and cerebrovascular diseases. Nevertheless, critical differences exist that may be key to understanding the precipitous age-based cognitive decline observed in some humans that is less evident in apes. For instance,

humans can live nearly twice as long as the oldest recorded great ape. Additionally, despite being our closest evolutionary relatives, the principal cause of heart disease differs between humans and great apes. The most frequent type of cardiovascular disease in elderly humans is coronary artery disease due to atherosclerosis,

whereas great apes are highly prone to cardiomyopathy-associated heart failure. Why heart disease varies between apes and humans and how it potentially relates to cerebrovascular disease and cognitive impairments are important unanswered questions, which may shed light on the unique human vulnerability to these

pathologies that affect lifespan. Here, we will examine the impact of cardiovascular health on longevity, the brain, and diseases of aging in humans and great apes including chimpanzees, bonobos, gorillas, and orangutans. In Aim 1, we will evaluate the effect of aging, cardiovascular disease, and neurovascular health on the brains of

humans and great apes. Using stereology and electron microscopy, we will measure neuron and glial cell densities, synapse and mitochondrial densities, and other age-related cerebrovascular pathology in humans and great apes across their lifespans and in individuals with cardiovascular and cerebrovascular diseases.

Multiplexed immunofluorescence imaging of age- and cerebrovascular-related neuropathology (e.g., cerebral amyloid angiopathy, Alzheimer’s disease lesions) also will be performed in each species. In Aim 2, the proposed studies will identify and determine if age-related vascular risk factors are associated with cognitive impairment

in great apes. We will use archival MRI brain scans to identify potential volumetric changes associated with age and cardiovascular and cerebrovascular diseases as well as evaluate for the presence of neurovascular-related lesions, such as white matter hyperintensities. Furthermore, we will quantify white matter microvessel,

endovascular cell, and vascular length densities from humans and apes to investigate associations with age, species, and disease status. We will investigate cellular localization of CD36, a protein involved in lipid metabolism that may differ between species, in fixed postmortem brains from humans and apes. In Aim 3, our

studies will examine how age and cardiovascular health influence cognition in chimpanzees compared to humans. This will include retrospective and prospective analyses between measures derived from transthoracic echocardiograms with cognitive and motor function as well as several biomarkers of cardiovascular and

cerebrovascular diseases in chimpanzees. Taken together, outcomes from our proposed studies will provide insights into how cardiovascular and cerebrovascular disease differentially contribute to the health, cognition, and lifespan of apes and humans.