Evidence for an Interaction between Apolipoprotein E Genotype, Gender, and Alzheimer Disease

Bretsky, Philip; Buckwalter, J. Galen; Seeman, Teresa E.; Miller, C A; Poirier, Judes; Schellenberg, Gerard D.; Finch, Caleb E.; Henderson, Victor W.

doi:10.1097/00002093-199910000-00007

Cited by 170 publications

(125 citation statements)

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“…In the context, it is worth noting research on the apolipoprotein E (APOE: 19q13.2) 34 allele, which represents an established genetic risk factor for AD (Corder et al, 1993); in the healthy older population, those with the 34 allele also present with poorer cognitive performance, especially on memory tests (Soininen and Riekkinen, 1996); and importantly, it is linked directly with poorer animal fluency in healthy elderly 34 carriers (Rosen et al, 2005). Although still controversial, the APOE genotype is believed to affect the probability of developing AD to a greater extent in women than men (Bretsky et al, 1999;Gomez Isla et al, 1996;Payami et al, 1996), possibly by impacting on hippocampal atrophy in female AD sufferers (Fleisher et al, 2005); and that the effect exerted by APOE genotype on cognitive performance in the general population is also more pronounced in women than men (Bartres-Faz et al, 2002;Hyman et al, 1996). In accordance with these findings, our study points to a particular vulnerability in female AD sufferers to develop a profound lexical-semantic impairment.…”

Section: Discussionmentioning

confidence: 99%

The impact of dementia, age and sex on category fluency: Greater deficits in women with Alzheimer's disease

Moreno-Martínez¹,

Laws

Schulz

2008

Cortex

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AgingCategory specific Semantics Sex differences APOE a b s t r a c t A category specific effect in naming tasks has been reported in patients with Alzheimer's dementia. Nonetheless, naming tasks are frequently affected by methodological problems, e.g. ceiling effects for controls and ''nuisance variables'' that may confound results.Semantic fluency tasks could help to address some of these methodological difficulties, because they are not prone to producing ceiling effects and are less influenced by nuisance variables. One hundred and thirty-three participants (61 patients with probable AD; and 72 controls: 36 young and 36 elderly) were evaluated with semantic fluency tasks in 14 semantic categories. Category fluency was affected both by dementia and by age: while in nonliving-thing categories there were differences among the three groups, in living thing categories larger lexical categories produced bigger differences among groups. Sex differences in fluency emerged, but these were moderated both by age and by pathology. In particular, fluency was smaller in female than male Alzheimer patients for almost every subcategory.

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Section: Discussionmentioning

confidence: 99%

The impact of dementia, age and sex on category fluency: Greater deficits in women with Alzheimer's disease

Moreno-Martínez¹,

Laws

Schulz

2008

Cortex

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“…An additional interaction that modifies AD risk is sex and APOE genotype. Clinical data indicate that the APOE4-induced risk for AD is significantly greater, perhaps exclusive to, females compared with males (77)(78)(79). Mechanistically, APOE4 may increase AD risk in women via multiple pathways involving the cardiovascular system (80), cellular aging (81), and importantly, A␤ accumulation.…”

Section: E4fad-hpmentioning

confidence: 99%

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Tai

Koster

Luo

et al. 2014

Journal of Biological Chemistry

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Background: Human APOE effects on RXR agonist activity are unclear. Results: In RXR agonist-treated EFAD mice, beneficial effects in APOE4 hippocampus include ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. Detrimental effects in APOE3 and APOE4 cortex might be from systemic hepatomegaly. Conclusion: A␤ pathology and APOE genotype modulate RXR agonist effects. Significance: Although promising for later stage Alzheimer disease, detrimental side effects limit translational application of RXR agonists.

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“…A meta analysis of 40 studies of ApoE genotype, sex, age of onset of AD, and ethnic background for 5,930 patients and 8,607 controls indicated that at most ages and across all genotypes women are more likely to develop AD (50). Moreover, the presence of one or more ApoE4 alleles conferred a substantially greater risk of AD to women than to men (51). Epidemiological data indicate that women are particularly susceptible to the adverse effects of a single copy of ApoE4 isoform in that women with the ApoE3͞4 allele had the same risk of AD as the women with the ApoE4͞4 allele (50,52,53).…”

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 99%

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Wang

Irwin

Brinton

2006

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease ͉ estrogen therapy ͉ risk factor regulation ͉ Alzheimer's disease prevention A polipoprotein E (ApoE) is a 34-kDa lipid binding protein that functions in the transport of triglycerides and cholesterol in multiple tissues, including brain, by interacting with lipoprotein receptors on target cells (1-4). Three ApoE isoforms exist in humans: ApoE2, ApoE3, and ApoE4, which differ from one another by single amino acid substitutions at positions 112 and 158, ApoE2 (Cys-112, Cys-158), ApoE3 (Cys-112, Arg-158), and ApoE4 (Arg-112, Arg-158) (5). Substitution of cysteine at position 158 in ApoE2 results in hypocholesterolemia caused by low levels of low-density lipoprotein (LDL), cholesterol (6). In contrast, substitution of cysteine with arginine at position 112 in ApoE4 results in elevation of plasma cholesterol and LDL levels and predisposes the carrier to cardiovascular disease and neurodegenerative disorders, including Alzheimer's disease (AD) (7,8).Statistically, individuals with one copy of the ApoE4 allele show a 4-fold increase in the risk of AD, whereas those with two copies of the ApoE4 allele exhibit a 15-fold increase in risk coupled with a significantly lower age of onset compared with AD patients carrying ApoE2͞3 alleles (9). The ApoE4 allele itself appears to account for as much as 50% of the populationattributable AD risk in the United States (for reviews see refs. 10 and 11). Thus, ApoE4 is considered a risk factor for late-onset AD, whereas ApoE2 and ApoE3 are associated with decreased risk of AD (10,12,13).Previous in vitro and in vivo analyses indicate that 17␤-estradiol (E 2 ) increased ApoE expression in astrocytes and microglia and in neurons (14, 15). Further, ApoE synthesis was required for E 2 -induced neuroprotection and neurotrophism, including neurite outgrowth (16,17).Recently, we discovered that in HT-22 cells ectopically transfected with full-length estrogen receptor (ER) (ER␣ or ER␤), E 2 -induced an opposite effect on ApoE expression depending on the transfected ER subtype. Based on our own data and others (17-19), we hypothesized that ApoE expression is differentially regulated by ER subtypes. To test this hypothesis, we investigated the impact of ER␣ versus ER␤ on ApoE gene expression by using real-time RT-PCR with confirmation of protein levels by Western blot in primary cultured rat hippocampal neurons. To determine the in vivo significance of our in vitro findings, we conducted in vivo analyses in ovariectomized (OVX) female rats treated with either the ER␣-selective ligand, propylpyrazole triol (PPT) or the ER␤-selective ligand, diarylpropionitrile (DPN). Results of these analyses demonstrated that the expression of ApoE is differentially regulated by ER␣ and ER␤. Activation of ER␣ increased, whereas activation of ER␤ decreased ApoE mRNA and protein expression in vitro and in vivo in rat hippocampus. Results Differential ApoE Expression in HT-22 Cells Transfected with ER␣ orER␤. To determine the ER subtype mediating E 2 regulation of ApoE, mouse hybrid HT-22 cel...

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Evidence for an Interaction between Apolipoprotein E Genotype, Gender, and Alzheimer Disease

Cited by 170 publications

References 0 publications

The impact of dementia, age and sex on category fluency: Greater deficits in women with Alzheimer's disease

The impact of dementia, age and sex on category fluency: Greater deficits in women with Alzheimer's disease

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

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