Autoantibodies, Frailty and Cognitive Decline

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Abstract Alzheimer's disease (AD) and frailty are interacting age-related disorders with a high level of morbidity and mortality that both lack biomarkers for prognosis and drugs that can delay and/or prevent disease progression. In older patients, chronic inflammation commonly accompanies frailty and increases risk of cognitive decline and the progression of AD. Autoantibodies (aAbs) angiotensin type 1 receptor (AT1RaAb) are agonistic and increase receptor signaling, which may increase inflammatory burden and thus potentially accelerate the development of AD in frail patients. The presence of circulating AT1RaAbs may facilitate disease development and progression and the levels of these aAbs may be markers of at-risk status. In a study we recently completed of 255 community dwelling adults, Logistic regression analysis of frailty revealed that individuals with AT1RaAb levels above 8.2 µg/ml were 3.9 (95% CI 1.38 - 11.0) times more likely to be frail after controlling for age (p < 0.05). Logistic regression of falls as a function of AT1RaAb levels yielded an odds ratio of 1.33 (95% CI 1.06 to 1.66) for an age, gender, BMI and BP adjusted model. For every 1 µg/ml change in AT1RaAb levels, the odds of falling increased approximately 30%. Regression analysis of the natural logarithm of time to death in a smaller validation group (n=60) yielded a βAT1RaAb of -0.096 (95% CI -0.255 to -0.036) with P < 0.01 after adjusting for age, gender and BMI. For every 1 µg/ml increase in AT1RaAbs, the time to death decreased by 9% after controlling for age, gender, BMI and BP. A case control study of 120 serum samples from subjects with normal cognition on enrollment and later classified as either cognitively normal or diagnosed with AD found baseline AT1RaAb levels were associated with the rate of cognitive decline. We hypothesize that (a) physical frailty is associated with increased levels of AT1RaAb and that, in frail elderly, the highest baseline levels of AT1RaAbs are associated with worsening cognitive status and the development of AD; and (b) ARB treatment would have a positive effect of lessening cognitive decline and delaying the progression to AD in frail subjects. To test these hypotheses we will perform a prospective study assessing the association of baseline aAb levels with longitudinal outcomes (rate of cognitive decline, incidence of frailty and of AD), and determine the capacity of AT1RaAb to predict progression to AD. We will also carry out an exploratory study to investigate the impact of ARB treatment on rate of cognitive decline. The proposed research uses 500 samples from the Rush Alzheimer's Disease Center Repository and core expertise of the Johns Hopkins Biostatistics Center to evaluate a biomarker that could be used to stratify the risk of frail patients for cognitive decline and progression to AD and to identify patients who might benefit from angiotensin receptor blocker treatment.