ELEVATED CENTRAL AND PERIPHERAL INFLAMMATORY PROFILES IN A POPULATION AT RISK FOR ALZHEIMER’S DISEASE

Abstract

Mid-life obesity and hypertension, two interconnected healthcare epidemics, increase the risk of cognitive decline and age-related neurodegeneration. These vascular risk factors are most common in women and African Americans, who are also at higher risk for Alzheimer's disease (AD). Elevated inflammatory signaling cascades are a primary characteristic of obesity and hypertension. Peripheral inflammation has been linked to cognitive decline and neurodegeneration. However, the mechanistic links remain unknown. Here we tested the hypothesis that obesity and hypertension are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking into the brain thereby leading to chronic inflammation. Cognitively normal, middle aged participants with a parental history of Alzheimer's disease were enrolled. Blood and CSF were centrifuged for isolation of immune cells for immunophenotyping by multicolor flow cytometry; supernatant biofluids were collected for measurement of inflammatory factors by multiplexed immunoassays. Deep immunophenotyping analysis of CSF revealed that individuals with high blood pressure displayed altered brain immune cell profiles, including elevated central memory T cells, compared to those with normal blood pressure. This same T cell population was altered in obese (BMI >30) compared to non-obese individuals (BMI 18.5–23.9). Altered immune cell profiles were also detected in participants who suffered from disturbed sleep, a common complaint of those who suffer from Alzheimer's disease. Profiling immune cell populations in the CSF is a novel approach in the neurodegeneration field that may reveal opportunities for therapeutic intervention with targeted immunomodulatory therapies. AD risk factors associated with hypertension correlate with altered central and peripheral immune cell profiles in cognitively normal middle-aged participants. Our results demonstrate that immune cell dysfunction is detectable in cognitively intact hypertensive individuals at risk for AD and suggest that RAS-targeted interventions may afford therapeutic benefit to delay onset of AD.