Objective The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer’s 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. Methods Cox proportional hazards analysis was used to compute hazards ratios (HR) 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 AD Neuroimaging Initiative. Results Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR=1.81 women; HR=1.27 men; interaction P=0.0106). The interaction remained significant in a pre-defined sub-analysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, male and female carriers were more likely to convert to AD (HR=2.16 women; HR=1.64 men). The effect was nominally stronger in women, but the interaction was not significant (P=0.136). In the sub-analysis restricted to APOE3/3 and APOE 3/4 genotypes, the interaction was significant (P= 0.022; HR=2.17 women; HR=1.51 men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients in total-tau and the tau-to-Abeta-ratio (P=0.0088 and P=0.020, respectively; more AD-like in women). Interpretation 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 major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested. METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima– media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen. RESULTS After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P = 0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P = 0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P = 0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum. CONCLUSIONS Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.)

The R(2) changes in white matter suggest that the healthy adult brain is in a constant state of change, roughly defined as periods of maturation continuing into middle age followed by progressive loss of myelin integrity. Clinically diagnosed AD is associated with more severe myelin breakdown. Noninvasive measures, such as the determination of the R(2), may have the potential to track prospectively the trajectory of deteriorating white matter integrity during normal aging and the development of AD and, thus, may be a useful marker for medication development aimed at the prevention of AD.

The authors explored the possibility that estrogen loss associated with menopause may contribute to the development of Alzheimer's disease by using a case-control study nested within a prospective cohort study. The Leisure World Cohort includes 8,877 female residents of Leisure World Laguna Hills, a retirement community in southern California, who were first mailed a health survey in 1981. From the 2,529 female cohort members who died between 1981 and 1992, the authors identified 138 with Alzheimer's disease or other dementia diagnoses likely to represent Alzheimer's disease (senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were individually matched by birth date (+/- 1 year) and death date (+1 year) to each case. The risk of Alzheimer's disease and related dementia was less in estrogen users relative to nonusers (odds ratio = 0.69, 95 percent confidence interval 0.46-1.03). The risk decreased significantly with increasing estrogen dose and with increasing duration of estrogen use. Risk was also associated with variables related to endogenous estrogen levels; it increased with increasing age at menarche and (although not statistically significant) decreased with increasing weight. This study suggests that the increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and that estrogen replacement therapy may be useful for preventing or delaying the onset of this dementia.

Four new 15-item versions of the Boston Naming Test (BNT), a 15-item version used by the Consortium To Establish a Registry for Alzheimer's Disease (CERAD), and three 30-item BNT versions were studied in 26 subjects with Alzheimer's disease (AD) and 26 nondemented, neurologically normal controls. The four 15-item versions were statistically equivalent. On each version, controls performed significantly better than AD subjects, and scores on each could be extrapolated to a complete 60-item BNT score. The CERAD version also differentiated between AD and control subjects, but it was not equivalent to our four versions and could not be as easily extrapolated to a 60-item score. Even and Odd 30-item BNT versions were confirmed to be equivalent, and we further validated a 30-item Empirical Version designed to maximally discriminate between AD and normal subjects. Equivalent 15- or 30-item versions of the BNT will be useful in repeated assessments requiring independent forms of a naming task, as well as in situations where administration of the complete BNT is not practical.

Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

ObjectiveTo examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort.DesignNationwide, population based cohort study.SettingAll Danish hospitals and hospital outpatient clinics from 1995 to 2013.Participants51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year.Main outcome measuresComorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis.ResultsHigher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 v 17 for myocardial infarction, 45 v 25 for ischaemic stroke, 11 v 6 for haemorrhagic stroke, 13 v 11 for peripheral artery disease, 27 v 18 for venous thromboembolism, 47 v 34 for atrial fibrillation or atrial flutter, and 19 v 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking.ConclusionsMigraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases.