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.
Highlights
Apolipoprotein E (ApoE) plays an critical role in the metabolism of lipoproteins and redistribution of cholesterol, and has long been studied in relation to atherosclerosis and cardiovascular disease (Mahley and Rall, 2000; Eichner et al, 2002; Pendse et al, 2009)
The neuropathological characterization of Alzheimer’s Disease (AD) has expanded beyond the classic descriptions of amyloid and tau pathology to include metabolic and vascular dysfunction
The metabolic and cerebrovascular dysfunction described by these studies includes reductions in brain glucose uptake, blunted insulin signaling, alterations in brain lipid metabolism, loss of BBB integrity and deficits in CBF
Summary
Apolipoprotein E (ApoE) plays an critical role in the metabolism of lipoproteins and redistribution of cholesterol, and has long been studied in relation to atherosclerosis and cardiovascular disease (Mahley and Rall, 2000; Eichner et al, 2002; Pendse et al, 2009). The cerebrovascular pathology observed in diabetic patients and in individuals with E4 show significant overlap (Walker and Harrison, 2015) and both IR and E4 have been independently associated with brain glucose hypometabolism and reduced cerebral blood flow (CBF; Thambisetty et al, 2010; Filippini et al, 2011; Pallas and Larson, 1996; Chung et al, 2015) These two risk factors appear to interact to impair cognition and drive neurodegeneration (Peila et al, 2002; Dore et al, 2009; Salameh et al, 2016; Johnson et al, 2017a,b). Could deposition of Aβ in the microvascular walls be a primary cause of the decreased CBF in E4 individuals? Questions such as these highlight the need for further studies examining CBF in the context of CAA
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