Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration

Abstract

Objective: To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) 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 Aβ 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 Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.

Figure 1. Relating 2-feature biomarker classification to operationalized National Institute on Aging–Alzheimer's Association preclinical staging

Illustration of how the operationalized National Institute on Aging–Alzheimer's Association preclinical staging criteria correspond to the 2-feature biomarker classification. SNAP = suspected non-Alzheimer pathophysiology.

Figure 2. Rates of atrophy and amyloid accumulation by 2-feature biomarker classification

Box plots of Alzheimer disease (AD)–signature atrophy rate (A) and amyloid PET accumulation rate (B) by baseline biomarker group: amyloid negative and neurodegeneration negative (A−N−), amyloid negative and neurodegeneration positive (A−N+), amyloid positive and neurodegeneration negative (A+N−), and amyloid positive and neurodegeneration positive (A+N+). AD-signature atrophy rate is a measure of annualized log Jacobian values multiplied by 100, which can be interpreted as approximately the annualized percentage change in volume in the AD-signature regions. Amyloid PET accumulation is a measure of annual rate of change in amyloid PET in standardized uptake value ratio per year.

Figure 3. Rates of atrophy and amyloid accumulation by continuous total intracranial volume–adjusted hippocampal volume and amyloid PET positivity

Scatterplots show Alzheimer disease (AD)–signature atrophy rate (A) and amyloid PET accumulation rate (B) vs baseline total intracranial volume–adjusted hippocampal volume (HVa) by amyloid PET positivity. Amyloid PET-positive subjects are represented by plus signs and amyloid PET-negative subjects by open circles. The solid line represents the mean AD-signature atrophy or amyloid PET accumulation rate by baseline HVa level for amyloid PET-positive subjects and the dashed line represents the mean rate for amyloid PET-negative subjects.