Changes in Aβ biomarkers and associations with APOE genotype in 2 longitudinal cohorts

Abstract

Apolipoprotein E (APOE) genotype influences onset age of Alzheimer's disease but effects on disease progression are less clear. We investigated amyloid-β (Aβ) levels and change in relationship to APOE genotype, using 2 different measures of Aβ in 2 different longitudinal cohorts. Aβ accumulation was measured using positron emission tomography (PET) imaging and (11)C-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and cerebral spinal fluid (CSF) Aβ1-42 assays in 207 BIOCARD study participants (mean age 62 years; 195 normal, 12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3-2.4). PET-PiB retention increased and CSF Aβ1-42 declined longitudinally. APOE ε4 was significantly associated with higher PET-PiB retention and lower CSF Aβ1-42, independent of age and sex, but APOE genotype did not significantly affect Aβ change over time. APOE ε4 carriers may be further along in the disease process, consistent with earlier brain Aβ deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease.

Keywords: Apolipoprotein E genotype; Biomarkers; CSF Aβ(1-42); Longitudinal; PET amyloid imaging.

Figure 1

Observed values of Aβ over time for (a) PET-PiB mean cortical DVR (cDVR) and (b) CSF Aβ_1–42. Within-individual changes are shown by connecting lines. Individuals who are cognitively normal at baseline evaluation are shown in black, mild cognitive impairment (MCI) and Alzheimer disease in red, and “cognitively impaired, not MCI” in blue. Threshold for detection of elevated PiB retention is shown as a gray line in (a).

Figure 2

Observed values of Aβ over time stratified by APOE ε4 carrier status for (a) PET-PiB mean cortical DVR (cDVR) and (b) CSF Aβ_1–42. Within-individual changes are shown by connecting lines. APOE ε4 negative individuals are shown in black and APOE ε4 positive in red. Threshold for detection of elevated PiB retention is shown as a gray line in (a).

Figure 3

Cross-sectional effect of age on (a) PET-PiB mean cortical DVR (cDVR) and (b) CSF Aβ_1–42, showing stronger association of age with Aβ for APOE ε4 carriers compared with non-carriers. This interaction reached significance for PET-PiB (p = 0.047) and was at trend level for CSF Aβ_1–42 (p = 0.076).