Association of Low Plasma Aβ42/Aβ40 Ratios With Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease

Background To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. Objective To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. Design Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. Setting Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels. Main Outcome Measures The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. Results During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI or AD ( P  = .04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline ( P  = .02). Conclusion The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.