Association Between Amyloid-β, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals

BACKGROUND: We estimated the prevalence and incidence of amyloid-β deposition (A), small-vessel disease (V), and neurodegeneration (N) biomarker positivity in community-dwelling cognitively normal individuals (CN). We determined the longitudinal association between the respective biomarker indices with progression to all-cause mild cognitive impairment (MCI) and its amnestic and nonamnestic subtypes. METHODS: CN participants, recruited by advertising, underwent brain [C-11]Pittsburgh Compound-B (PiB)-positron emission tomography (PET), magnetic resonance imaging, and [F-18]fluoro-2-deoxy-glucose (FDG)-PET, and were designated as having high or low amyloid-β (A+/A-), greater or lower white matter hyperintensities burden (V+/V-) and diminished or normal cortical glucose metabolism (N+/N-). MCI was adjudicated using clinical assessments. We examined the association between A, V, and N biomarker positivity at study baseline and endpoint, with progression to MCI using linear regression, Cox proportional hazards and Kaplan-Meier analyses adjusted for age and APOE-ε4 carrier status. RESULTS: In 98 CN individuals (average age 74 years, 65% female), A+, V+, and N+ prevalence was 26%, 33%, and 8%, respectively. At study endpoint (median: 5.5 years), an A+, but not a V+ or N+ scan, was associated with higher odds of all-cause MCI (Chi-square = 3.9, p = .048, odds ratio, 95% confidence interval = 2.6 [1.01-6.8]). Baseline A+, V+, or N+ were not associated with all-cause MCI, however, baseline A+ (p = .018) and A+N+ (p = .049), and endpoint A+N+ (p = .025) were associated with time to progression to amnestic, not nonamnestic, MCI. CONCLUSION: Longitudinal assessments clarify the association between amyloid-β and progression to all-cause MCI in CN individuals. The association between biomarker positivity indices of amyloid-β and neurodegeneration, and amnestic MCI reflects the underlying pathology involved in the progression to prodromal Alzheimer's disease.