Angiotensin II type 1 receptor autoantibody as a Biomarker for Identification and Targeted treatment of Individuals at risk for Alzheimer’s Disease (ABIT-AD)
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ABSTRACT Early identification and treatment of individuals at increased risk for cognitive and physical decline due to Alzheimer’s disease and related dementias is of critical importance. Effective medication treatments are limited, associated with concerning side effects, or have generated mixed results. Medications that target the Renin Angiotensin System (RAS) such as Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) have been identified as potential treatments for Alzheimer’s disease and related dementias, however, results to date have been mixed. ACEi and ARBs act on the RAS system to decrease the activity of the Angiotensin II on the Angiotensin II type 1 receptor (AT1R). The AT1R site is a key driver of neurodegeneration in the brain RAS and promotes vasoconstriction and increased blood pressure in the peripheral RAS. Agonistic autoantibodies to the Angiotensin II type 1 receptor (AT1RaAb) have been observed in 53% of individuals with Alzheimer’s disease compared to 35% in healthy age-matched controls. Furthermore, while all RAS drugs work peripherally to decrease the activity of Angiotensin II, only some drugs cross the blood brain barrier (BBB) and act centrally on the brain RAS. A recent metanalysis suggested that central-RAS drugs(c-RAS) are associated with less memory decline. We have previously shown that older adults taking centrally acting ACEi manifested stronger grip strength and higher peak expiratory flow rate compared to those taking peripherally-acting ACEi. It remains unclear, however, whether the differential effects of RAS drugs on cognition and physical performance depend on their ability to cross the blood brain barrier and/or the presence of AT1RaAb. To address the utility of AT1RaAb as a novel dementia risk biomarker, we propose to measure baseline and again yearly (over a 3-year follow-up period) blood levels of AT1RaAb in existing and new participant samples. Participants taking RAS drugs will be stratified by the medication’s ability to cross the BBB (central, peripheral) and will be compared for prospective changes in measures of cognition (RBANs, MoCA), physical performance (grip strength, gait speed), and neurodegenerative and vascular brain pathologies. We hypothesize that high blood levels of AT1RaAb could serve a novel biomarker to identify patients at risk for Alzheimer’s disease who may benefit from targeted RAS drug therapy. The study aims to quantify the associations between AT1RaAb and measures of cognitive and physical performance using blood samples (n=335) of an existing cohort (Aim 1), compare associations between centrally-and peripherally-acting RAS drugs and cognition, physical performance and neurodegenerative and vascular brain pathologies as a function of AT1RaAb in a new cohort (n=210) (Aims 2&3). Our proposal has the potential to provide valuable insights into the targeted use of readily available medications to slow declines in cognitive and physical performance in individuals at risk who may benefit the most.
