Insula Structure and Function in a Nonhuman Primate Model of Induced Early Alzheimer's Disease

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Project Summary One in 10 adults who are aged 65 or older and 1 in 3 adults who are aged 85 or older meet the clinical diagnostic criteria for Alzheimer’s disease (AD), making AD a public health crisis. These statistics are certain to be underestimates of the disease’s total impact, given that disease onset precedes symptom onset by many years in all cases. With no known cure, the prevalence and impact of AD will only become more dire as the population ages. Effective intervention is contingent on the identification of behavioral and neurobiological markers that appear in preclinical AD. While most AD research has focused on declines in learning and memory, people with preclinical AD often have changes to their self-awareness of both physiological and psychological functions prior to any detectable impairments to learning and memory. Changes to the insular cortex, the putative neural correlate of self-awareness, have also been characterized in preclinical AD. Behaviors reflective of self- awareness, and their associated neurobiological substrates, are therefore important potential targets of study and intervention. The proposed work will characterize these behaviors alongside neurobiological changes in a highly tractable and translational animal model, where the onset of AD-related neuropathology can be tightly controlled. We will introduce amyloid beta oligomers (AβOs) into the brains of middle-aged rhesus monkeys—a manipulation that we have shown causes neuropathology consistent with early AD in humans. In the first aim, we will assess changes to behavioral indices of self-awareness of physiology (i.e., interoception) and self- awareness of cognition (i.e., metacognition). In the second aim, we will characterize changes to the structural integrity and functional connectivity of the insula using magnetic resonance imaging. In the third aim, we will examine the insula postmortem for known biomarkers of AD pathology. The aims of this proposal have been designed such that all experiments have direct translation to established behavioral tests and techniques available for use with human patients. The proposed experiments have also been designed to maximize training potential in behavioral, imaging, histological, and statistical techniques.