Amyloid futures in the expanding pathology of brain aging and dementia

Positron emission tomography (PET) imaging studies of Alzheimer's disease (AD) patients show progressive increases of fibrillar A beta-amyloid. Because current PET ligands underestimate nonfibrillar forms, we assayed soluble A beta in AD and controls. To identify the mechanisms responsible for soluble A beta in AD brains, we examined lipid rafts (LRs), where amyloid precursor protein (APP) is enzymatically processed. Frontal cortex was compared with cerebellum, which has minimal AD pathology. Compared with cognitively normal controls (CTL; Braak 0-1), elevations of soluble A beta 40 and A beta 42 were similar for intermediate- and later-stage AD (Braak 2-3 and 4-6). Clinical-grade AD showed a greater increase in soluble A beta 40 than A beta 42 relative to CTL. LR raft yield per gram AD frontal cortex was 20% below that of controls, whereas cerebellar LR did not differ by Braak score. The extensive overlap of soluble A beta levels in controls with AD contrasts with the PET findings on fibrillar A beta. These findings further support fibrillar A beta as a biomarker for AD treatments and show the need for more detailed postmortem analysis of diverse soluble and insoluble A beta aggregates in relation to PET.

Automated summary

PET imaging studies of AD patients show progressive increases of fibrillar A beta-amyloid. This study analyzed soluble A beta levels in AD and controls, and found that soluble A beta levels overlapped significantly between AD and controls, in contrast to the PET findings on fibrillar A beta. These findings highlight the importance of further postmortem analysis to understand the relationship between diverse forms of A beta and PET.