Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

Abstract

Fibrillar amyloid-beta (Abeta) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar Abeta burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Abeta burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele. The 8 epsilon4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Abeta was significantly associated with APOE epsilon4 carrier status and epsilon4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Abeta burden in cognitively normal older people is associated with APOE epsilon4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Abeta accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Abeta, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Abeta imaging in primary prevention trials.

Fig. 1.

Fibrillar Aβ burden in cognitively normal APOE ε4 noncarriers (NC), heterozygotes (HT), and homozygotes (HM) from our longitudinal study (white box), an HM with recent onset of MCI, and probable AD patients from a previous study (gray box). The data were generated from the ROIs shown in Fig. 3. The mean value in the HM group and statistical analyses in the text do not include data from the HM with MCI. P values correspond to the association between fibrillar Aβ burden and APOE ε4 gene dose (2-tailed linear trend) in the cognitively normal subjects.

Fig. 2.

Statistical brain maps showing higher cerebral-to-cerebellar PiB DVR, a measure of fibrillar Aβ, in the 8 cognitively normal APOE ε4 heterozygotes (A) and the 8 cognitively normal homoyzogotes (B) compared with the 12 cognitively normal noncarriers, and associations between higher PiB DVR and APOE ε4 gene dose in the 28 cognitively normal subjects (C). Statistical maps are superimposed onto horizontal sections from a spatially standardized MRI image and are shown in relationship to their distance above or below a horizontal plane through the anterior and posterior commissures.

Fig. 3.

Mean cortical PiB DVR (our primary outcome measure) generated using the frontal (including middle cingulate), posterior cingulate-precuneus, and lateral temporal ROIs.