BASELINE CARDIOVASCULAR RISK AND AMYLOID BURDEN SYNERGISTICALLY PREDICT LONGITUDINAL COGNITIVE DECLINE IN CLINICALLY NORMAL ELDERLY: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

Abstract

Neuropathological studies indicate that vascular brain changes commonly co-occur with Alzheimer's disease (AD) pathology in late-onset dementia and are likely contributors to cognitive decline. Given the overlap of cardiovascular and cerebrovascular risk factors, we examined whether well-validated cardiovascular (CV) risk scores would predict cognitive decline alone or synergistically with amyloid burden in clinically normal elderly. 205 clinically normal older adults (mean age = 72.5; range = 65 - 89) in the Harvard Aging Brain Study underwent baseline β-amyloid imaging with Pittsburgh compound-B (PiB)-PET and annual neuropsychological testing for up to 6 years (mean follow-up of 3.77+/-1.2y). QRISK2 2016 and Framingham Heart Study cardiovascular (FHS-CVD) risk scores were calculated from baseline demographic, blood pressure, and cholesterol data. We used linear mixed models (controlled for age, sex, and education) to assess CV risk, amyloid burden, and their interaction as predictors of longitudinal cognitive decline as measured by the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid burden and CV risk each predicted longitudinal cognitive decline (p < 0.0001). We observed a strong synergistic effect of CV risk and amyloid burden on prediction of cognitive decline (Figure 1; p < 0.0001). Follow-up analyses revealed CV risk predicted cognitive decline in both high and low amyloid groups (amyloid positive: p < 0.0001; amyloid negative: p = 0.0191), whereas, amyloid burden predicted decline only among individuals with moderate to high CV risk (low CV risk: p > 0.05; moderate CV risk: p < 0.0005; high CV risk: p< 0.0001). Individuals with high amyloid burden and high CV risk showed the steepest cognitive decline (Figure 1). Results using QRISK2 or FHS-CVD were highly similar. Well-validated measures of baseline CV risk were strong predictors of longitudinal cognitive decline in clinically normal elderly, both alone and synergistically with baseline amyloid burden. The co-occurrence of high amyloid burden with moderate to high levels of CV risk was an especially potent predictor of cognitive decline. These results highlight the potential utility of CV risk scores in AD clinical research, especially in understanding and stratifying risk for cognitive decline in the preclinical phase of AD. Cardiovascular Risk Interacts with Amyloid Burden to Predict Longitudinal Cognitive Decline. Illustration of rates of longitudinal cognitive decline (assessed by declines in the PACC) at varying levels of CV Risk (FHS-CVD) and amyloid burden (PiB PET). All scales have been converted to z-scores. Red axis tick corresponds to a PiB FLR SUVR of 1.2, a previously published, data-driven cutoff to separate high and low- Aβ groups in the Harvard Aging Brain Study. PACC = Preclinical Alzheimer Cognitive Composite; FHS-CVD = Framingham Heart Study cardiovascular disease risk score; PiB PET = Pittsburgh Compound-B PET; FLR = composite cortical region of interest from frontal, lateral, and parietal regions; SUVR = Standardized Uptake Value Ratio.