The Effect of APOE-ε4 on Dementia is Mediated by Alzheimer Neuropathology

Abstract

The degree to which the association of ε4 with dementia is mediated by AD lesions in comparison with vascular lesions is controversial. The present study was undertaken to determine the roles of Alzheimer (AD) and vascular pathology in mediating the effect of APOE-ε4 alleles on dementia. Clinicopathologic correlations were studied in 267 Catholic sisters participating in the Nun Study. The extent to which AD and vascular pathologies mediated the effect of APOE-ε4 on dementia was investigated using multiple logistic regression. Adjusted for age at death and education, possession of one or more ε4 alleles was an important risk factor for dementia (OR=2.98, 95% CI: 1.62-5.48). This association was lost (OR=1.38, 95%CI: 0.68-2.80) when an index of the severity of AD-related neuropathology was added to the model, but changed little when measures of the severity of vascular pathology were added. The findings suggest that the effect of ε4 on dementia is mediated by the severity of AD pathology. While infarcts and atherosclerosis contribute to the occurrence of dementia, this contribution appears unrelated to APOE genotype.

Vascular Risk Factors and Dementia: 40-Year Follow-Up of a Population-Based Cohort

“…The ApoE ε4 allele is known to be associated with the development of atherosclerosis [26] and this association is presumably related to the higher levels of total cholesterol. In contrast, in a recent neuropathological study, the association of APOE ε4 with dementia was mediated by AD pathology and not by vascular lesions [27]. However, individuals with both APOE ε4 and vascular risk factors certainly have the highest risk of developing dementia, irrespective of the cause.…”

Genetic Associations of Autopsy-Confirmed Vascular Dementia Subtypes

“…The literature pertaining to APOE as a risk factor for VaD is highly inconsistent, with approximately equal numbers of studies supporting or refuting an association between VaD and the APOE- ε 4 genotype. The APOE- ε 4 allele has been found to be associated with increased Aβ load in AD, VaD, mixed VaD/AD and controls [6,16,17,18]. AD patients with the APOE- ε 4 allele have been shown to have an increased loss of choline acetyltransferase (ChAT) activity, as have controls [19,20].…”

The Effect of the APOE-ε4 Allele and ACE-I/D Polymorphism on Cognition during a Two-Year Follow-Up in First-Ever Stroke Patients

“…However, nowadays there is growing evidence of shared environmental and genetic risk factors between AD and VaD like hypertension, diabetes mellitus, and atherosclerosis [7,8,45] . Moreover, histopathological studies report the involvement of vascular lesions in AD and in VaD there is evidence for an increased accumulation of cerebral amyloid protein [17,46,47] .…”

“…It is hypothesized that in the pathophysiology of AD associated with disease onset late in life cognitive deterioration is caused by vascular pathology as a 'second hit' in addition to (a genetic predisposition for) increased amyloid deposition [51,52] . In the pathogenesis of VaD and mixed dementia an interaction between a facilitating effect of APOE-4 is suggested through an interaction between APOE-4 and AD-type pathology and vascular risk factors such as hypertension, atherosclerosis and diabetes [17,47,[53][54][55] . In stroke, APOE-4 carriers are reported to be more vulnerable to the damaging effect of ischaemia causing larger infarct sizes [56] .…”

“…APOE-4 is also associated with atherosclerotic changes and cardiovascular disease and brain infarctions [16] . Although an association between the presence of APOE-4 and VaD has been reported, evidence for a contribution in the pathophysiological mechanism of VaD still is equivocal [11,17] .…”