Risk Of Alzheimer's Disease In Women Research Articles

Prior infections are associated with smaller hippocampal volume in older women.

Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD), however, mechanism is unclear, as multiple pathways may be involved. One possibility is that infections could contribute to neurodegeneration directly by promoting neuronal death. We explored relationships between history of infections and brain hippocampal volume (HV), a major biomarker of neurodegeneration, in a subsample of the UK Biobank (UKB) participants. Infectious disease diagnoses were based on ICD10 codes. The left/right HV was measured by the magnetic resonance imaging (MRI) in cubic millimeters and normalized. Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found that HV was significantly lower in women aged 60-75, as well as 65-80, years, with history of infections, compared to same age women without such history. The effect size increased with age faster for the left vs. right HV. Results for males didn't reach statistical significance. Results of our study support a major role of adult infections in neurodegeneration in women. The detrimental effect of infections on HV became stronger with age, in line with declining resilience and increasing brain vulnerability to stressors due to aging. The faster increase in the effect size observed for the left vs. right HV may indicate that female verbal memory degrades faster over time than visual-spatial memory. The observed sex difference may reflect a higher vulnerability of female brain to infection-related factors, which in turn may contribute to a higher risk of AD in women compared to men.

Increased ERb expression during ageing could be neuroprotective against Alzheimer's disease development in the male but not the female brain.

Age is the biggest risk factor for Alzheimer's disease (AD) with cases doubling every 5 years after 65 years. Increased risk is also associated with being female. This gender difference in AD incidence could be partly explained by menopause-related hormone deficiencies during ageing. Clinical studies concluded that the age when hormone replacement therapy was started, especially after the menopause, was critical in delaying AD development. Deposition of b-amyloid (Ab) in the hippocampus and cortex is the key pathological feature in AD. Much evidence has demonstrated that oestrogen activation of oestrogen receptors (ER) in neurones decreases Ab accumulation and antagonizes its cytotoxic effects in AD. ERb is an ER subtype highly expressed in the nervous system. In vivo studies reported that ERb activation reduces the cytotoxic effect of Ab through the Akt pathway and improves learning and memory capacity in AD models. However, this finding has not yet been investigated in the clinic. We hypothesised that the increased risk of AD in women could be partly explained by alterations in the levels of oestrogen, its receptors and downstream signalling pathways in the female brain during ageing affecting the expression of AD biomarkers. Levels of ERb, phosphorylated and total Akt, APP, its secretases and metabolites were measured using immunoblotting and ELISA in frontal cortical brain samples from young (20-30), middle-aged (45-55) and old (70-90) men and women with no history of dementia. In female brains significant age-related increases in APP and the secretases were observed but were not seen in male samples. bCTF and the Aβ42:40 ratio also showed age-related increases only in women. Aβ42 levels were higher in elderly female samples compared to male. In contrast, significant age-related increases in ERb and pAkt:total Akt were only seen in male samples. We demonstrate for the first time a sex difference in the expression of AD biomarkers with ageing with a novel age-related increase in APP in the ageing female brain. The increase in ERb expression in male but not female samples could result in a neuroprotective effect against Aβ cytotoxicity. Our findings could partly explain female vulnerability for AD development.

Dietary sugar intake and risk of Alzheimer's disease in older women

ABSTRACT Background Despite some reports of cardiometabolic disorders associated with the risk of Alzheimer's disease (AD), limited studies have been conducted to examine the association between excessive sugar intake (a risk factor for cardiometabolic disorders) and AD risk. Aim The purpose of our study was to evaluate if excessive sugar intake has a significant long-term effect on the risk of AD. Methods A population sample of 37,689 participants, who enrolled in the United States (US) Women's Health Initiative – Dietary Modification Trial (WHI-DM) in 1993–2005 and its extended observational follow-up study through 1 March 2019, were analyzed. Dietary sugar intake was measured using food frequency questionnaires. AD was classified by reports using a standard questionnaire. A dietary pattern that explained the maxima variations in sugar intake was constructed using reduced rank regression (RRR) technique. Associations of RRR dietary pattern scores and sugar intake (g/day) by quartiles (Q1 through Q4) with AD risk were examined using Cox proportional hazards regression analysis with adjusting for key covariates. Results During a mean follow-up of 18.7 years, 4586 participants reported having incident AD. The total incidence rate (95% confidence interval [CI]) of AD was 6.5 (6.3–6.7) per 1000 person-years (PYs). The incidence rates (95% CI) of AD by total sugar intake were 6.2 (5.8–6.6), 6.4 (6.0–6.8), 6.6 (6.3–7.0), and 6.9 (6.5–7.3) per 1000 PYs among those in quartiles (Q) 1 to Q4 (toward higher sugar consumption) of total sugar intake, respectively (test for trend of AD incident rates, p < 0.001). Individuals in Q4 of total sugar intake had a 1.19 higher risk of incident AD than those in Q1 (hazard ratio [HR] = 1.19, 95% CI: 1.05–1.34, p = 0.01). An estimated increase of 10 g/day in total sugar intake (about 2.4 teaspoons) was associated with an increased AD risk by 1.3–1.4%. Of six subtypes of sugar intake, lactose was significantly associated with AD risk. Conclusions Our study indicates that excessive total sugar intake was significantly associated with AD risk in women. Of six subtypes of sugar intake, lactose had a stronger impact on AD risk.

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.

Biological sex and DNA repair deficiency drive Alzheimer's disease via systemic metabolic remodeling and brain mitochondrial dysfunction.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

Does Gender Influence the Relationship Between High Blood Pressure and Dementia? Highlighting Areas for Further Investigation.

Gender differences have been noted in studies linking blood pressure to all-cause dementia, and the two most common forms of dementia: Alzheimer's disease (AD) and vascular dementia (VaD). However, how gender modifies the relationship between blood pressure and dementia remains unclear. To review evidence for a gender modifying effect on the link between blood pressure and all-cause dementia. A systematic review was conducted according to PRISMA guidelines. Sixteen out of 256 reviewed articles met inclusion criteria. For women, higher midlife systolic blood pressure (SBP) and hypertension were both associated with greater risk of all-cause dementia, AD, and VaD, in six out of seven studies. Two of these studies reported higher midlife SBP/hypertension were associated with greater risk for all-cause dementia in women, but not men. One study reported higher midlife SBP associated with greater AD risk in women, but not men. However, another study reported that midlife hypertension associated with AD risk in men, but not women. No clear gender differences were reported in the relationship between late-life high blood pressure/hypertension with all-cause dementia or AD. Studies rarely, and inconsistently, analyzed or reported gender effects. Therefore, interpretation of available evidence regarding the role of gender in blood pressure associated dementia was difficult. Several studies indicated higher midlife SBP was associated with greater risk of all-cause dementia for women, compared to men. Future studies should evaluate women-specific aging processes that occur in midlife when considering the association between blood pressure and dementia risk.

Accelerated Ovarian Failure as a Unique Model to Study Peri-Menopause Influence on Alzheimer's Disease.

Despite decades of extensive research efforts, efficacious therapies for Alzheimer’s disease (AD) are lacking. The multi-factorial nature of AD neuropathology and symptomatology has taught us that a single therapeutic approach will most likely not fit all. Women constitute ~70% of the affected AD population, and pathology and rate of symptoms progression are 2–3 times higher in women than men. Epidemiological data suggest that menopausal estrogen loss may be causative of the more severe symptoms observed in AD women, however, results from clinical trials employing estrogen replacement therapy are inconsistent. AD pathological hallmarks—amyloid β (Aβ), neurofibrillary tangles (NFTs), and chronic gliosis—are laid down during a 20-year prodromal period before clinical symptoms appear, which coincides with the menopause transition (peri-menopause) in women (~45–54-years-old). Peri-menopause is marked by widely fluctuating estrogen levels resulting in periods of irregular hormone-receptor interactions. Recent studies showed that peri-menopausal women have increased indicators of AD phenotype (brain Aβ deposition and hypometabolism), and peri-menopausal women who used hormone replacement therapy (HRT) had a reduced AD risk. This suggests that neuroendocrine changes during peri-menopause may be a trigger that increases risk of AD in women. Studies on sex differences have been performed in several AD rodent models over the years. However, it has been challenging to study the menopause influence on AD due to lack of optimal models that mimic the human process. Recently, the rodent model of accelerated ovarian failure (AOF) was developed, which uniquely recapitulates human menopause, including a transitional peri-AOF period with irregular estrogen fluctuations and a post-AOF stage with low estrogen levels. This model has proven useful in hypertension and cognition studies with wild type animals. This review article will highlight the molecular mechanisms by which peri-menopause may influence the female brain vulnerability to AD and AD risk factors, such as hypertension and apolipoprotein E (APOE) genotype. Studies on these biological mechanisms together with the use of the AOF model have the potential to shed light on key molecular pathways underlying AD pathogenesis for the development of precision medicine approaches that take sex and hormonal status into account.

Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study

Background: We investigated the global and age-specific association between Apolipoprotein E (APOE) genotype and Alzheimer's disease (AD) in a large multicentric case-control study, using cerebrospinal fluid (CSF) biomarkers-based diagnostic criteria for AD. Methods: In this case-control design, data on 1,599 Caucasian AD cases with abnormal values of CSF biomarkers came from 9 European memory clinics and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. AD cases were compared to 11,724 dementia-free controls, drawn from two longitudinal cohort studies (Whitehall II and 3-City). Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were reported, overall and by 5-year age categories. Findings. 63*4% of CSF biomarker-defined AD patients and 22*6% of population controls carried at least one APOE e4 allele; respective percentages for APOE e4 homozygotes were 16*7% and 1*4%. Compared to none4 carriers, heterozygous e4 carriers had a 4*6 (95% confidence interval: 4*1 - 5*2) and e4/e4 homozygotes a 25*4 (20*5 - 31*3) higher OR of AD. This association was strongly modified by age (p for interaction < 0*001). The PAF associated with carrying at least one e4 allele was greatest in the 65-70 age group (69*7%), and weaker before 55 years (14*2%) and after 85 years (22*6%). There was some evidence of a stronger effect of APOE on AD risk in women. Interpretation: Incorporating biomarkers for diagnosis of AD led to a stronger association with APOE e4 than previously reported, perhaps due to better diagnostic accuracy. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE e4 at the population level. Funding Statement: US National Institutes of Health, Fondation Plan Alzheimer. Declaration of Interests: ASM is supported by NIH/NIA R01AG056477. IZ is supported by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). KB reports consulting fees from Fujirebio Europe, IBL International, Roche Diagnostics. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, and Servier. All other authors declare no competing interests. Ethics Approval Statement: Ethical clearance was obtained by the institutional review boards of all participating sites (European memory centers and ADNI Study sites) and all participants provided written, informed consent.

To What Extent Does Age at Death Account for Sex Differences in Rates of Mortality From Alzheimer Disease?

Our objective was to compare sex-specific rates of death with Alzheimer disease (AD) or dementia as the underlying or associated cause of death using death records. Deidentified individual records on causes of death for all people aged 60 years or more who died in Australia during 2006-2014 (n = 1,104,684) were analyzed. There were 184,562 records with International Classification of Diseases, Tenth Revision, codes for dementia (AD, vascular dementia, or unspecified dementia). Death rate ratios for women versus men were estimated using Poisson regression. Women had a greater crude rate of death from all types of dementia than men (5.9 deaths per 1,000 person-years as compared with 3.8 deaths per 1,000 person-years), which disappeared after adjustment for age. For AD, the age-adjusted rate was higher among women (rate ratio = 1.14, 95% confidence interval: 1.12, 1.16), while for vascular dementia age-adjusted rates were higher for men (rate ratio = 0.80, 95% confidence interval: 0.78, 0.82). There was no evidence of a differential bias in coding of dementia type between men and women. Women's older age at death explained much of the sex-related difference in rates of death from AD or dementia. However, excess numbers of AD deaths among women and vascular dementia deaths among men remained, providing support for the hypothesis of greater biological risk of AD in women.

APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice.

Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E ( APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD). EFAD mice were fed either control (10% fat, 7% sugar) or WD (45% fat, 17% sugar), and both metabolic and neuropathologic outcomes were determined. Although E4FAD mice generally exhibited poorer metabolic status at baseline, E3FAD mice showed greater diet-induced metabolic impairments. Similarly, E4FAD mice exhibited higher levels of AD-related pathology overall, but only E3FAD showed significant increases on select measures of β-amyloid pathology after exposure to WD. These data demonstrate a gene-environment interaction between APOE and obesogenic diets in females. Understanding how AD-promoting effects of obesity are modulated by genetic factors will foster the identification of at-risk populations and development of preventive interventions.-Christensen, A., Pike, C. J. APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice.

Sex modifies the APOE-related risk of developing Alzheimer disease.

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women). APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.

The sex-specific associations of the aromatase gene with Alzheimer’s disease and its interaction with IL10 in the Epistasis Project

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

Aromatase Variants Modify Risk for Alzheimer's Disease in a Multiethnic Female Cohort

Background/Aims: Few studies of gene variants that affect estrogen activity investigate their association with risk for Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with individual ethnicity assessed by genetic population ancestry informative markers (AIMs) as well as by self-identified ethnicity. Methods: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project, association with risk for AD was assessed for 41 single nucleotide polymorphisms (SNPs) on the CYP19 gene using multivariable logistic regression, adjusting for age, presence of an APOE ε4 allele, years of education, and body mass index. Results: Risk for AD was associated with 6 SNPs in women of predominantly Caucasian AIMs-defined ancestry. Of these, 2 were also associated with decreased risk of AD in women of admixed/Hispanic AIMs ancestry. Two separate SNPs were found to be protective in women of predominantly African AIMs-based ancestry. Conclusions:CYP19 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry. These effects are possibly due to linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors mediating the SNP effect on risk for AD by group.

P4‐133: Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort

Genetic variants that affect estrogen activity may influence risk for Alzheimer's disease (AD). However, most studies have been conducted in Caucasian ethnic groups, and few polymorphisms have been assessed in a multi-ethnic cohort in which the members have all been evaluated in a consistent manner. Examination of polymorphisms in multiethnic groups which are evaluated without taking ancestry into account may have several limitations, including a loss of significant association due to different allele frequencies, different linkage disequilibrium patterns between ethnicities, or differences in the distribution of comorbid conditions and risk factors by ethnic group. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with ethnicity assessed by genetic population ancestry markers (AIMs) as well as by self-identified ethnicity. W e hypothesized that genetic variants would affect risk for AD differently in groups with different population ancestries due to varying allele frequencies as well as disparate exposure environmental factors. 1686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), were followed at 18–24 month intervals. Data from standardized assessments, including neurological examination and a neuropsychological battery, were used to make an AD diagnosis. Using multivariate logistic regression, we examined risk for AD associated with 41 single-nucleotide polymorphisms (SNPs) on the CYP19 gene, controlling for age at time of evaluation, BMI, APOE status, current smoking, and current or past diabetes mellitus. Risk for AD was associated with six SNPs in women of predominantly Caucasian AIMs-defined ancestry (rs4775935, rs727479, rs17647719, s1902586, rs10163138, and rs7168331). Of these, rs4775935 and rs727479 were also associated with decreased risk of AD in women of admixed/ Hispanic AIMs ancestry. Two separate SNPs (rs6493495 and rs11070843) were found to be protective in women of predominantly African AIMs-based ancestry. Our findings suggest that CYP19 genetic variants play a role in risk for AD in women and that the risk alleles vary by population ancestry and self-identified ethnicity, possibly due to different linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors for AD.

Variants in CYP17 and CYP19 Cytochrome P450 Genes are Associated with Onset of Alzheimer's Disease in Women with Down Syndrome

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model

Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

Estrogen receptor α and APOEɛ4 polymorphisms interact to increase risk for sporadic AD in Italian females

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease-related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER-alpha gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER-alpha p allele and APOE epsilon4 allele was observed in women, taking subjects who had neither the p allele nor epsilon4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22-23.60]. For women carrying the ER-alpha x allele together with APOE epsilon4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73-40.06). The data suggest that the p and x alleles of polymorphic ER-alpha gene interact synergistically with the APOE epsilon4 allele to increase the risk of AD in women but not in men in this Italian cohort.

Estrogen receptor beta gene variants are associated with increased risk of Alzheimer's disease in women

We investigated the association of five intronic single-nucleotide polymorphism (SNP) at the estrogen receptor beta (ESR2) gene locus and the susceptibility of developing Alzheimer's disease (AD) in 387 subjects with clinically diagnosed probable AD and 467 cognitively normal individuals derived from eastern Finland. According to our results, variation in the ESR2 gene is associated with an increased risk of AD in women, whereas it does not contribute to the disease susceptibility in men. More specifically, in women, the allele T and the genotype T/T of two of the studied ESR2 gene SNPs (SNP2 and SNP3) were more frequent in AD women than in cognitively normal control women (P=0.012 and P=0.016, respectively). The ESR2 SNP2 T/T genotype and the SNP3 T/T genotype were associated with a significant, nearly two-fold increase in the risk of AD in women (OR=1.87, 95% CI=1.21-2.90), and remained significant after adjustment with the APOE genotype and age (OR=1.63, 95% CI, 1.00-1.68). The combined effect of the ESR2 SNP2 T/T or SNP3 T/T genotype and female gender increases the risk of the disease (OR=3.2, 95% CI=1.3-7.7). Consistent with these results, also the frequency of the haplotype containing the two above ESR2 gene risk alleles was elevated in AD women (P=0.027, OR=1.3, 95% CI=1.02-1.65). Results show that variation in ESR2 gene may be linked with increased AD susceptibility and furthermore, this association is gender specific.