Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration

Objective:To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of -amyloid (A) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.Methods:A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A-) and baseline hippocampal volume (N+ or N-). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups.Results:At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A-N-), 29 (12%) amyloid negative and neurodegeneration positive (A-N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N-), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of A accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+.Conclusions:We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging-Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of A accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, A pathophysiology increases or catalyzes neurodegeneration.