Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease

Abstract

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Figure 1

Examples of PET images (comparable parietal lobe levels viewed from below head) coregistered to each subject's baseline MRI scan for an 81-year-old nondemented woman (APOE 3/3 genotype; Top), a 76-year-old nondemented woman (APOE 3/4 genotype; Middle), and 79-year-old woman with AD (APOE 3/4 genotype; Bottom). The last column shows 2-year follow-up scans for the nondemented women. Compared with the nondemented subject without APOE-4, the nondemented APOE-4 carrier had 18% (Right) and 12% (Left) lower inferior parietal cortical metabolism, whereas the demented woman's parietal cortical metabolism was 20% (Right) and 22% (Left) lower, as well as more widespread metabolic dysfunction due to disease progression. Two-year follow-up scans showed minimal parietal cortical decline for the woman without APOE-4, but bilateral parietal cortical decline for the nondemented woman with APOE-4, who also met clinical criteria for mild AD at follow-up. MRI scans were within normal limits.

Figure 2

Differences in cerebral metabolism in nondemented subjects according to genetic risk (SPM analysis). Lower metabolic levels are seen for the APOE-4 group (yellow and red areas) in left lateral temporal (P < 0.001), posterior cingulate (P < 0.001), and inferior parietal (P < 0.006) cortex. The region of peak significance (z = 3.24) lies in the temporal cortex in Brodmann's areas 20 and 21. Images are MRI structural images with superimposed SPM findings from PET.

Figure 3

The plot of the Buschke-Fuld recall change score (last to first) versus baseline right inferior parietal cortical metabolism indicated that lower baseline metabolism correlated with memory decline after 2 years in nondemented APOE-4 subjects (Pearson's r = 0.69, P = 0.026) but not in subjects without APOE-4. Other baseline regional metabolic rates correlating with memory change scores in APOE-4 subjects included left posterior cingulate cortex versus delayed paragraph recall (r = 0.67, P = 0.049) and right posterior cingulate cortex versus delayed paragraph recall (r = 0.71, P = 0.034). Baseline regional metabolic rates did not correlate with memory change scores in the nondemented subjects without APOE-4.

Figure 4

Regions showing the greatest metabolic decline after 2 years of longitudinal follow-up in nondemented subjects with APOE-4 (SPM analysis) included the right lateral temporal and inferior parietal cortex (brain on the left side of figure). Voxels undergoing metabolic decline (P < 0.001, before correction) are displayed in color, with peak significance (z = 4.35) occurring in Brodmann's area 21 of the right middle temporal gyrus.

Figure 5

Right lateral temporal metabolism (normalized to a mean voxel value of 50 for each brain and labeled adjusted response) for the APOE-4 subjects declined 5% at follow-up 2 years after baseline scans. Individual values (●) at the voxel of most significant decline (Talairach coordinates 68 −30 0) uniformly decreased, with no overlap for the two points in time (z = 4.35, P = 0.022, corrected for multiple comparisons). Although single voxels were initially defined for a volume of 8 mm³, as the image data were preprocessed with a Gaussian-weighted three-dimensional smoothing filter of 16 mm FWHM (full width at half maximum) before statistical analysis, the data represent cerebral activity extending well beyond the confines of the brain tissue represented by the specific voxel location described by the given coordinates. Histograms represent means at each time point.