Synergistic Effect of β-Amyloid and Neurodegeneration on Cognitive Decline in Clinically Normal Individuals

IMPORTANCE Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE To determine whether neuroimaging markers of beta-amyloid (A beta) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES The A beta statuswas determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (A beta(-)/ND-), stage 1 (A beta(+)/ND-), stage 2 (A beta(+)/ND+), and suspected non-Alzheimer disease pathology (A beta(-)/ND+). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS The A beta(+) CN individuals were more likely to be classified as ND+: 59.6% of A beta(+) CN individuals were ND+, whereas 31.9% of A beta-CN individuals were ND+ (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both A beta and ND, whereas diminished practice effects were observed in CN individuals positive for either A beta or ND. Decline over time was observed only in CN individuals positive for both A beta and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between A beta and ND confirmed that this decline was greater than the additive contributions of A beta and ND (P = .04). CONCLUSIONS AND RELEVANCE The co-occurrence of A beta and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.