APOEɛ4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein

Abstract

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.

Association of apolipoprotein E gene polymorphism with small-vessel lesions and stroke type in moyamoya disease: a preliminary study

“…13 The APOE ε2 allele is known to be associated with fibrinoid necrosis, and the APOE ε4 allele has been associated with the loss of smooth muscle and vessel wall thickness, as well as with vascular Ab deposition. 2,16,28 Although there was no difference in APOE genotype between patients with MMD and the control group (Table 1), our results revealed a difference in APOE genotype according to the presence of microbleeds (Fig. 2B).…”

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

“…There is a strong association of APOE genotype with the risk for development of AD and CAA Holtzman, 2001;Chalmers et al, 2003;Ashford, 2004;Holtzman, 2004). However, the precise mechanism as to how ApoE3 or ApoE4 influences this risk for the development of sporadic AD and CAA is not well understood.…”

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

“…SVD had been scored as previously described 4, on a four‐point semiquantitative scale according to the extent of thickening of the arteriolar walls and associated narrowing of the vessel lumina: 0 = normal vessel wall thickness, 1 = slightly increased thickness, 2 = moderately increased thickness and 3 = markedly increased thickness such that for many arterioles the diameter of the lumen was <50% of the outer diameter of the blood vessel. CAA for all cases had also been previously graded semiquantitatively on a four‐point scale by a method adapted from that of Olichney et al 11, 42, ranging from “0” for vessels devoid of amyloid to “3” for extensive deposition. The left cerebral hemisphere had been sliced and frozen at −80°C until used for biochemical assessment.…”