Metabolic interaction between ApoE genotype and onset age in Alzheimer's disease: implications for brain reserve

Abstract

Background: Clinically apparent Alzheimer's disease (AD) is thought to result when brain tissue damage exceeds a critical threshold of ''brain reserve'', a process possibly accelerated by the apolipoprotein E (ApoE) E4 allele. The interaction between onset age and ApoE genotype was investigated to assess whether early disease onset (,65 years) in patients carrying the E4 allele is associated with greater cerebral metabolic (regional cerebral metabolic rate of glucose utilisation, rCMRgl) reduction. Methods: AD patients, divided into early (EOAD; 27 patients) and late onset (LOAD; 65 patients) groups, both groups balanced as to the number of E4 carriers (E4+) and non-carriers (E42), and matched controls (NC; 35 cases) underwent 18 F-FDG PET ([ 18 F]fluorodeoxyglucose positron emission tomography) scanning. SPM'99 software was used to compare AD patients to NC and to perform a two way ANOVA with onset age and ApoE genotype as grouping factors. Results were considered significant at p,0.001, uncorrected. Results: AD patients demonstrated rCMRgl reductions compared to NC, with rCMRgl lower in association cortex and relatively higher in limbic areas in EOAD compared to LOAD subjects. rCMRgl was lower in the anterior cingulate and frontal cortex for E4+ compared to E42 subjects. A significant onset age by ApoE interaction was detected in the hippocampi and basal frontal cortex, with EOAD E4+ subjects having the greatest rCMRgl reduction. Conclusions: The interactive effects of early onset age, possibly reflecting lower brain reserve, and ApoE E4 allele, possibly leading to greater tissue damage, lead to reduced tolerance to the pathophysiological effects of AD in key brain regions.

FDG PET and the genetics of dementia

“…FDG PET studies in non-demented individuals report that, as compared to e4 non-carriers, ApoE e4 homozygotes (therefore, with a particularly high risk of developing AD) have a significantly reduced CMRglc in the same brain regions as clinically affected AD patients, including the posterior cingulate/precuneus, parietal, temporal and prefrontal regions [59]. As compared to e4 noncarriers, ApoE e4 heterozygotes show similar, but milder, hypometabolism within the same brain regions found to be affected in AD patients and in ApoE e4 homozygotes [59][60][61][62]. There is evidence that the metabolic reductions in ApoE e4 carriers are more progressive (25 % decline in CMRglc over a two-year interval) and correlate with the reductions in cognitive performance [63].…”

Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease

“…High e4/e4 Alzheimer's Bennett et al (2003), Corder et al (1993), Huang et al (2004), Hoyt et al (2005), Mosconi et al (2005), Roses et al (1995), Roses (1996), Rubinsztein and Easton, 1999 Alzheimer's + HSV Cheon et al (2001), Corder et al (1998a), Federoff (1999, Hendrie (1998), Itzhaki et al (1997); Itzhaki and Lin (1998), Itzhaki et al (2002); Lin et al (1996Lin et al ( , 2002 Corder et al (1993Corder et al ( , 1994, Farrer et al (1997), Hoyt et al (2005), Roses et al (1995), Roses (1996) e4 Protective effects of ApoE e3 and detrimental effects of ApoEe4 in neural tissue related to HSV-1 infection (Huang et al, 2004) The decline in androgen receptors could increase susceptibility to HSV-1 infection and/or neuroinvasiveness of HSV-1.…”

“…Furthermore, the risk association of the ApoE ε 4 allele and Alzheimer's disease (AD) has become almost universally accepted (Baxter et al, 2003;Bennett et al, 2003;Craig et al, 2004;Hoyt et al, 2005;Huang et al, 2004;Messier, 2003;Mosconi et al, 2005;Roses et al, 1995;Roses, 1996;Rubinsztein and Easton, 1999). This review will highlight clinical studies and experimental mouse studies that have shown significant disease risk (increased susceptibility) and/or protection (reduced susceptibility) associated with one of the three isoforms of apoE.…”

ApolipoproteinE ε4 allelic variant, cognitive decline and psychosis in Alzheimer disease: a review of the literature and suggestions for upcoming studies

“…In the same study, ApoE ε4 allele possession was associated with a decrease in age of onset. In fact, in the literature there is evidence that ApoE ε4 allele possession is associated with a more precocious age of onset (Reiss et al 2005, Mosconi et al 2005, Roses 1994, Lopez et al 1997, and several studies investigated its influence on determining the severity of memory disorder (Bondi et al 1995, O'Hara et al 1998, Mayeux et al 2001. Some research hypothesizes that presence and amount of ApoE ε4 alleles are predictors of impairment in cognitive performances .…”

“…Other studies reported that AD patients with familial aggregation compared with sporadic cases had more marked impairment of language, praxia, and graphia (Breitner & Folstein 1984). Finally, some genetic factors, underlying the pathogenesis of early onset AD (Zekanowski et al 2004, Lehtovirta et al 1996, Reiss et al 2005, Mosconi et al 2005 and late onset AD (Olin et al 2005, Bernardini et al 2005, Liang et al 2005, Saunders et al 1993, have been identified. Thus, neuropathological and genetic findings associated with the different forms of AD may explain different clinical manifestations (Lahiri et al 2004).…”