Gender differences in the incidence of AD and vascular dementia

Andersen, Kjeld; Launer, Lenore J.; Dewey, Martin; Letenneur, Luc; Ott, Alewijn; Copeland, J. R. M.; Dartigues, Jean‐François; Kragh‐Sörensen, P.; Baldereschi, Marzia; Brayne, Carol; Lobò, Antonio; Martínez‐Lage, J. M.; Stijnen, Theo; Hofman, Albert

doi:10.1212/wnl.53.9.1992

Cited by 570 publications

(380 citation statements)

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“…This might have been observed because we included mild cognitive impairment participants. The prevalence of cognitive impairment in women (46.4%) was three times as high as that in men (15.6%), which is consistent with previous studies (Andersen et al, 1999). There were no significant differences of the frequency distributions of the CC, CT, and TT genotypes of the SNP rs189037 between the cognitively impaired and control groups.…”

Section: Discussionsupporting

confidence: 91%

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

et al. 2015

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ABSTRACT. The aim of this study was to explore the existence of a relationship between the rs189037 single nucleotide polymorphism (SNP) of the ataxia telangiectasia mutated (ATM) gene and cognitive impairment in the elderly (aged 60 years and above). In a cohort, 505 residents of Suinung City were consecutively recruited and their cognitive function was measured using a 30-point Mini-Mental State Examination (MMSE). The subjects were divided into cognitive impairment group and control group on the basis of MMSE scores. Presence of the rs189037 SNP variant was examined using polymerase chain reaction-restriction fragment length polymorphism. The prevalence rates of cognitive impairment were 32.7% in the whole 4585 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4584-4592 (2015) Association between ATM and cognitive impairment sample. The genotype frequencies of the rs189037 polymorphism were 33.5% (CC), 50.7% (CT), and 15.8% (TT); the C and T allele frequencies were 58.8 and 41.2%, respectively. No significant differences in the frequency distributions of the CC, CT and TT genotypes were observed between cognitively impaired and control groups. We found that the rs189037 SNP was not directly correlated with cognitive impairment among the elderly Chinese Han population.

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Section: Discussionsupporting

confidence: 91%

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

et al. 2015

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“…In addition, lack of education is found to be negatively associated with AD risk. However, the female prevalence in AD remains after adjusting for age and education (24)(25)(26) and female hormone may, in part, also contribute to gender-related differences in AD. After menopause, the decline of estrogen levels in the brain may make neurons more susceptible to age-related neurodegenerative processes (27).…”

mentioning

confidence: 99%

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Yue

Lu²,

Lancaster³

et al. 2005

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

327

304

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Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age-and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased ␤ amyloid peptide (A␤) deposition. These mice also exhibited increased A␤ production, and microglia cultures prepared from the brains of these mice were impaired in A␤ clearance͞degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.amyloid deposition ͉ aromatase ͉ transgenic animal N europathological hallmarks of Alzheimer's disease (AD) include significant deposition of extracellular ␤ amyloid peptide (A␤) and presence of neurofibrillary tangles in the brain (1). A␤ is derived from the two-step enzymatic processing of amyloid precursor protein (APP) in which ␤-secretase (BACE) cleaves the ␤-site of APP to release the N terminus of A␤, and the ␥-secretase protein complex cleaves the ␥-site of APP to release the C terminus of A␤ (2, 3). Overproduction and progressive deposition of A␤ are known to underlie, in part, A␤ plaque formation, a key pathologic feature of AD. The initial cleavage of APP by BACE is critical for A␤ associated with AD neuropathology (4). Recent studies have shown that BACE activity increases with age and is elevated in AD brains (5, 6).Impaired A␤ clearance and͞or degradation may also contribute to A␤ plaque formation. Our previous findings support this hypothesis: Microglia isolated from AD brains have impaired phagocytic activity, leading to reduced A␤ clearance (7). Other groups have found that cytoplasmic A␤ granules in the plaque-associated glia and microglia participate in the clearance of A␤ in A␤-immunized AD patients and APP transgenic mice (8, 9).Two enzymes are involved in A␤ degradation and clearance: insulin-degrading enzyme (IDE) and neprilysin (NEP). IDE is expressed in high concentrations in the brain. Besides degrading insulin and several regulatory peptides, IDE also degrades the intracellular domain of APP and is responsible for degrading and clearing A␤ from the brain (10, 11). Indeed, genetic linkage studies have shown that late-onset AD loci on chromosome 1...

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“…However, recent studies showed that women carry an innate higher risk for AD (2). The precipitous decline and loss of neuroprotective effects of estrogens in postmenopausal women-in contrast to the gradual decline of androgens in aging men-are offered as an explanation.…”

mentioning

confidence: 99%

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

Papasozomenos

Shanavas

2002

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

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We have shown previously that glycogen synthase kinase-3␤ (GSK-3␤), cyclin-dependent kinase 5, and c-Jun NH2-terminal kinase become overactivated and hyperphosphorylate in heat-shocked female rats. This hyperphosphorylation of is estrogen-independent, prevented by androgens, and similar to Alzheimer's disease. In this study, ovariectomized (OVX) Sprague-Dawley rats (n ‫؍‬ 75) received daily injections of 10 g of 17␤-estradiol benzoate (EB), or 250 g of testosterone propionate (TP), or both EB and TP, or sesame oil (SO) vehicle for 4 -6 weeks. In kinase assays of forebrain homogenates, overactivation of GSK-3␤ at 0 -6 h after heat shock toward human recombinant , bovine , and phosphoglycogen synthase peptide 2 was prevented in OVX ؉ TP and OVX ؉ (EB ؉ TP) but not in sham-OVX ؉ SO, OVX ؉ SO, and OVX ؉ EB. Abs against inactive (pSer 9 ) and activity-enhanced (pTyr 216 ) GSK-3␤ showed marked increase of pSer 9 -and decrease of pTyr 216 -GSK-3␤ in both OVX ؉ TP and OVX ؉ (EB ؉ TP) but not in sham-OVX ؉ SO, OVX ؉ SO, and OVX ؉ EB. EB enhanced the overactivation of cyclin-dependent kinase 5. The activity of c-Jun NH2-terminal kinase was gonadal hormone-independent. The serum concentrations of testosterone and 17␤-estradiol were 2.53 ng͞ml and 201 pg͞ml in OVX ؉ TP and OVX ؉ EB, respectively. These findings demonstrate that testosterone prevents the hyperphosphorylation of by inhibiting the heat shock-induced overactivation of GSK-3␤ and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer's disease.A bout two times more women than men have Alzheimer's disease (AD) (1), partly because women with AD live longer. However, recent studies showed that women carry an innate higher risk for AD (2). The precipitous decline and loss of neuroprotective effects of estrogens in postmenopausal women-in contrast to the gradual decline of androgens in aging men-are offered as an explanation. However, recent studies showed no beneficial effects of estrogens on mild-to-moderate AD (3). On the other hand, a possible advantageous role of androgens in the prevention and͞or treatment of AD has not been tried yet despite their neuroprotective effects (4), the century-old suggestion that they may rejuvenate aged men (5), lower serum testosterone concentration in men with AD (6), the increasing evidence that stressful stimuli play a role in the etiopathogenesis of AD (7,8), and inhibition of stress response by androgens (9).The cause of AD is not known, but it seems to be a syndrome resulting from an interplay among a genetic predisposition, environmental stress factors, and the aging process. The histologic hallmarks of AD are the senile plaques made of A␤ amyloid, dystrophic neurites, and reactive glial cells, and the neurofibrillary tangles composed of bundles of abnormal filaments, the so-called paired-helical filaments, the major component of which is hyperphosphorylated (10-12). However, the earliest manifestation of hyperphosphorylated is a granular form in...

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Gender differences in the incidence of AD and vascular dementia

Abstract: Compared with men, women have an increased risk for AD. There are no gender differences in risk for vascular dementia.

Cited by 570 publications

References 36 publications

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

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Gender differences in the incidence of AD and vascular dementia

Abstract: Compared with men, women have an increased risk for AD. There are no gender differences in risk for vascular dementia.

Cited by 570 publications

References 36 publications

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

Association between the rs189037 single nucleotide polymorphism in the ATM gene promoter and cognitive impairment

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH 2 -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

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Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease