HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

Abstract

HIV produces a chronic viral infection of the central nervous system that elicits chronic glial activation and overexpression of glial cytokines that are also implicated in Alzheimer disease (AD) pathogenesis. A genetic risk factor for AD is the E4 isoform for apolipoprotein E (APOE). Here we compare the frequency of neurologic symptoms for subjects with and without the E4 isoform (E4(+)and E4(-), respectively) in an HIV cohort. Compared with E4(-) subjects, twice as many E4(+) subjects were demented (30% compared with 15%) or had peripheral neuropathy (70% compared with 39%) at least once, and they had threefold more symptomatic examinations (13% compared with 3% and 42% compared with 14%, respectively)(P < 0.0001). Thus, neurologic symptoms for HIV-infection and AD are linked through an etiologic risk factor. Long-term survivors of HIV infection with E4 may be at high risk for AD; conversely, gene-viral interactions may speed AD pathogenesis.

Cell death in HIV dementia

“…Individuals with an apolipoprotein E4 allele are at an increased risk for Alzheimer's disease, and recent evidence suggests that the E4 allele also increases the risk of dementia in HIV-1-infected people. 88 Cutler et al 132 found evidence of dysregulated lipid and sterol metabolism in HIV dementia patients with an E4 genotype. Levels of sphingomyelin, ceramide and cholesterol were significantly increased in the medial frontal cortex, parietal cortex and cerebellum of HIV dementia patients with an E3/4 or E4/4 genotype compared to patients with an E3/3 genotype.…”

“…86 Although initial studies found no correlation between the risk of HIV dementia and ApoE genotype, 87 later findings suggested that HIV-infected patients with the E4 isoform of ApoE are more likely to suffer neurological complications including dementia and peripheral neuropathy. 88 The biophysical determinants of the E4 genotype that predispose neural tissue to malfunction and injury have not been determined, although a role for the regulation of redox balance by ApoE has been suggested. 89,90 Although the pathological consequences of cholesterol accumulation in brains of HIV patients with dementia remain to be determined, modification of cholesterol levels has been associated with poor cognitive function and may impair learning and memory.…”

The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol

“…The presence of the APOE4 gene has been established as a risk factor for Alzheimer's disease (AD) [16] and individuals who are heterozygous (3/4) or homozygous (4/4) for APOE4 demonstrate earlier cognitive changes and increased density of amyloid plaques and neurofibrillary tangles, characteristic neuropathological lesions in AD, than those individuals who do not carry an APOE4 gene [48;53]. The widespread association of APOE4 with enhanced risk and poorer outcomes in neurological diseases such as head injury, stroke and multiple sclerosis [9;24;29] suggests that the APOE4 gene may contribute to a common pathophysiological pathway in multiple types of CNS damage.…”

Role of apolipoprotein E polymorphism as a prognostic marker in traumatic brain injury and neurodegenerative disease: a critical review

“…28 Long-term survivors of human immunodeficiency virus (HIV) infection with the APOE e4 allele were found to be at higher risk for AD, and gene-virus interactions were postulated to speed AD development. 11 On the other hand, APOE e2 alleles were associated with a delayed age of onset of AD, 57,78 even in carriers of APP mutations. 69 These findings suggest that a protective role is conferred by APOE e2.…”