APOE and Alzheimer's Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Abstract

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer's Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In the current mini-review article, we summarize the known effects of APOE on cerebral metabolism and cerebrovascular function, with a special emphasis on recent findings via neuroimaging approaches.

Keywords: Alzheimer’s Disease (AD); ApoE; apolipoprotein E; brain; cerebral; imaging; metabolism; neurodegeneration.

Figure 1

Neuroimaging approaches to study the effects of the Apolipoprotein E (ApoE) isoforms on cerebral metabolism. Left: traditional neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been invaluable in characterizing the metabolic and cerebrovascular deficits associated with APOE4, the strongest genetic risk factor for late onset Alzheimer’s disease (AD). ¹⁸F-Fluorodeoxyglucose positron emission topography (FDG-PET) imaging has consistently shown a pattern of brain glucose hypometabolism in individuals with E4, while amyloid PET imaging shows increased amyloid deposition. Some, but not all, blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies in E4 individuals have shown decreased cerebral blood flow (CBF). Right: other alternative, or non-imaging methods of visualizing vascular and metabolic changes may prove instrumental in elucidating apoE isoform-specific effects on AD risk and progression. Magnetic resonance spectroscopy (MRS), metabolomics and lipidomics studies have implicated E4 in multiple pathways of lipid and glucose metabolism (effects of E4 denoted by red arrows).