van Dyck C, Barcelos N, Brück A, Planeta-Wilson B, Benincasa A, MacAvoy M, Gelernter J, Carson R.
Amyloid-Beta Burden and Neuropsychological Test Performance in Cognitively Normal First-Degree Relatives at Varying Genetic Risk for Alzheimer's Disease.
Human Amyloid Imaging Abstract. 2012 Jan 1;
In Alzheimer's disease (AD) there is strong evidence that brain amyloid deposition precedes the emergence of dementia by many years. This study investigated the relationship between APOE-e4 genotype, amyloid deposition, and neuropsychological test performance in pre-symptomatic individuals at varying genetic risk for AD.
Methods: Cognitively normal subjects aged0-66 with a first-degree family history for AD were genetically screened to select three groups: APOEgenotype e4e4 (n=15), e3e4 (n=15), and e3e3 (n=15), matched for age and sex. Subjects were then studied with C-11-Pittsburgh Compound B ([C-11]PiB) PET, MRI, and neuropsychological testing. PET and MR images were co-registered for application of a ROI template (AAL for SPM2) to generate regional time-activity curves with cerebellum as reference region. Parametric BPND images were then generated using SRTM2 such that BPND=0 reflected no specific binding. BPND was computed for a mean cortical ROI consisting of frontal, posterior cingulate-precuneus, lateral parietal, and lateral temporal ROIs.
Results: APOE-e4 carriers demonstrated significantly greater BPND (.16±.19) in comparison to non-carriers (.04±.09; F=7.00, p=.012, ANCOVA controlling for age and sex), with no dosage effect between e4e4 (.19±.13) and e3e4 (.14±.23) groups (Figure). Significant cortical [C-11]PiB uptake was observed in APOE-e4 carriers throughout the age range studied (as young as age1 in a e4e4 subject, Figure). There was no significant effect of APOEgenotype on neuropsychological test performance. There were also no significant associations between mean cortical [C-11]PiB BPND and neuropsychological test performance in the overall sample.
Conclusions: In cognitively normal individuals at high-risk for AD, significant amyloid deposition begins earlier than has been previously reported. Neuropsychological test results suggest minimal cognitive consequences of amyloid burden in these middle-aged “at risk” subjects. Detection of AD pathogenesis at a fully presymptomatic stage of disease may be necessary to enable the earliest therapeutic intervention for prevention trials.