Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer's disease.

The differential vulnerability of brain regions to Alzheimer's disease remains largely unexplained. Oh et al. report that regions with age-invariant metabolic rates and beta-amyloid-related hypermetabolism are more likely to undergo Alzheimer's disease-related degeneration. Temporal and regional dynamics of ageing, beta-amyloid pathology, and glucose metabolism interact to determine patterns of neurodegeneration.See Hansson and Gouras (doi:10.1093/aww146) for a scientific commentary on this article. The differential vulnerability of brain regions to Alzheimer's disease remains largely unexplained. Oh et al. report that regions with age-invariant metabolic rates and beta-amyloid-related hypermetabolism are more likely to undergo Alzheimer's disease-related degeneration. Temporal and regional dynamics of ageing, beta-amyloid pathology, and glucose metabolism interact to determine patterns of neurodegeneration.Although some brain regions such as precuneus and lateral temporo-parietal cortex have been shown to be more vulnerable to Alzheimer's disease than other areas, a mechanism underlying the differential regional vulnerability to Alzheimer's disease remains to be elucidated. Using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography imaging glucose metabolism and amyloid-beta deposition, we tested whether and how life-long changes in glucose metabolism relate to amyloid-beta deposition and Alzheimer's disease-related hypometabolism. Nine healthy young adults (age range: 20-30), 96 cognitively normal older adults (age range: 61-96), and 20 patients with Alzheimer's disease (age range: 50-90) were scanned using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography. Among cognitively normal older subjects, 32 were further classified as amyloid-positive, with 64 as amyloid-negative. To assess the contribution of glucose metabolism to the regional vulnerability to amyloid-beta deposition, we defined the highest and lowest metabolic regions in young adults and examined differences in amyloid deposition between these regions across groups. Two-way analyses of variance were conducted to assess regional differences in age and amyloid-beta-related changes in glucose metabolism. Multiple regressions were applied to examine the association between amyloid-beta deposition and regional glucose metabolism. Both region of interest and whole-brain voxelwise analyses were conducted to complement and confirm the results derived from the other approach. Regional differences in glucose metabolism between the highest and lowest metabolism regions defined in young adults (T = 12.85, P < 0.001) were maintained both in Pittsburgh compound B-negative cognitively normal older subjects (T = 6.66, P < 0.001) and Pittsburgh compound B-positive cognitively normal older subjects (T = 10.62, P < 0.001), but, only the Pittsburgh compound B-positive cognitively normal older subjects group showed significantly higher Pittsburgh compound B retention in the highest compared to the lowest glucose metabolism regions defined in young adults (T = 2.05, P < 0.05). Regional differences in age and amyloid-beta-dependent changes in glucose metabolism were found such that frontal glucose metabolism was reduced with age, while glucose metabolism in the precuneus was maintained across the lifespan (right hemisphere: F = 7.69, P < 0.001; left hemisphere: F = 8.69, P < 0.001). Greater Alzheimer's disease-related hypometabolism was observed in brain regions that showed both age-invariance and amyloid-beta-related increases in glucose metabolism. Our results indicate that although early and life-long regional variation in glucose metabolism relates to the regional vulnerability to amyloid-beta accumulation, Alzheimer's disease-related hypometabolism is more specific to brain regions showing age-invariant glucose metabolism and amyloid-beta-related hypermetabolism.