Relationship between Amyloid-β positivity and progression to mild cognitive impairment or dementia over 8 years in cognitively normal older adults

Background: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (A+β) in cognitively normal (CN) older adults. Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to A+, APOE ϵ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. Results: 17.7% A+ and 8.1% A-progressed over 8 years (OR: 2.43). Risk of progression for A+ was 65-104% greater than A-. A+ APOE ϵ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in A+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ϵ4 carriage (HR: 2.63); only age was a significant risk factor in A-(HR: 1.09). A-progressors were not near the threshold for A+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: A+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ϵ4 carriage provides further predictive value in the presence of A+. These data suggest that A-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated A deposition may be the result of neuropathological processes other than AD that accumulate with age.