BackgroundMenopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.Methods and FindingsKEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes.On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importa...

Background Several studies have shown higher Alzheimer’s disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority. Objective Estimate the AA/CC rate ratio for AD incidence across all available studies. Methods We conducted a meta-analysis of population-based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter-study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs. Results There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR = 1.64 (95% CI 1.35–2.00)), with no evidence of heterogeneity. We estimated the current US AD prevalence for ages 65–90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56). Conclusion AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors.

Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.

Background/Objective Controversy exists over whether proton pump inhibitors (PPIs) increase risk for dementia. This study examined the risk associated with PPIs on conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer’s disease (AD). Design Observational, longitudinal study. Setting Tertiary academic Alzheimer Disease research centers funded by the National Institute on Aging. Participants Research volunteers ≥ 50 years old with 2 to 6 annual visits. Eight hundred and eighty four were taking PPIs at every visit, 1,925 took PPIs intermittently, whereas 7,677 never reported taking PPIs. All had baseline normal cognition or MCI. Analytic Plan Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition into MCI or dementia, or annual conversion of baseline MCI into dementia, controlling for demographics, vascular comorbidities, mood, and anticholinergics and histamine-2 receptor antagonists. Results Continuous (Always vs. Never) PPI use was associated with a decreased risk of decline in cognitive function (HR 0.78, 95% CI 0.66–0.93, p=.005) and decreased risk of conversion to MCI or dementia due to AD (HR 0.82, 95% CI 0.69–0.98, p=.026). Intermittent use was also associated with decreased risk of decline in cognitive function (HR 0.84, 95% CI 0.76–0.93), p=.001) and risk of conversion to MCI or dementia due to AD (HR 0.82, 95% CI 0.74–0.91), p=.001). This reduced risk was found for persons with either normal cognition or MCI. Conclusion PPIs were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and the lack of dispensing data. Prospective studies are needed to confirm these results in order to guide empirically based clinical treatment recommendations.

Women are at a higher risk than men to develop mood disorders and depression. The increased risk is associated with fluctuating estrogen levels that occur during reproductive cycle events, particularly during the menopausal transition, a time characterized by drastic fluctuations in estrogen levels and increases in new onset and recurrent depression. Conversely, recent data show that hormone therapy, particularly transdermal estradiol formulations, may prevent mood disorders or even serve as a treatment regimen for women with diagnosed mood disturbances via estrogen regulation. While the exact mechanism is unknown, there is compelling scientific evidence indicating the neuromodulatory and neuroprotective effects of estrogen, which are directly relevant to mood symptomotology. Specifically, affective regulation has been linked to neural structures rich in estrogen receptors and estrogenic regulation of neurotransmitters. While a wealth of basic science, observational and clinical research support this rationale, potential mediating variables, such as estrogen formulation, proximity of administration to menopause, and the addition of progestins should be considered. Furthermore, the nature of postmenopausal exogenous hormone formulations in relation to premenopausal endogenous levels, as well as the ratio of estrone to estradiol warrant consideration.

The current study investigated whether the androgenic activity of oral contraceptives (OC) mediates performance on sexually dimorphic cognitive tasks in 155 younger individuals. Participants were categorized by hormonal contraceptive use (user vs. nonuser) and the androgenic activity of each OC (OC generation). OC generation was determined based on previous research in which users are grouped based on the type of progestin contained in each OC. Cognitive tasks included the mental rotation task (MRT) and a recognition memory task. In addition, we examined the correlates of both menstrual cycle phase and OC use, such as mood, premenstrual syndrome, depression, blood pressure, and body fat using standardized measures. The main result was that OC androgenicity influenced MRT performance. Second generation OCs are the most androgenic. Thus, MRT performance was best in these OC users as compared to third generation users, Yasmin users and nonusers. On the other hand, Yasmin, a newer generation of OC, contains an "antiandrogenic" progestin, dropirenone. Yasmin users not only performed more poorly on the MRT in comparison to second and third generation pill users, but they performed significantly worse than OC nonusers. Results show that the androgenic activity in OCs influences MRT performance in the presence of static estrogen levels. Overall, the resulting pattern is consistent with a broad range of results demonstrating that visuospatial performance may be enhanced in women who are exposed to androgenic treatments. Furthermore, visuospatial performance is hindered with the introduction of antiandrogenic preparations.

Antihypertensives that modulate the renin-angiotensin system (RAS) on AD conversion in those with MCI has not been explored. Evidence suggests that blood-brain-barrier (BBB) permeability is necessary for these effects. We assessed the impact of RAS modulation on conversion to AD and cognitive decline in those with MCI, and the impact of BBB permeability and race on these associations. We analyzed data from the National Alzheimer’s Coordinating Center from the NIA-funded Alzheimer’s Disease Centers. We included individuals receiving antihypertensives with MCI at baseline and who had cognitive assessments on at least 2 follow-up visits. Outcomes included conversion to AD and cognitive and functional decline. Of 784 participants (M=75 years, 48% men), 488 were receiving RAS medications. RAS users were less likely to convert to AD (33% vs 40%; p=0.04) and demonstrated slower decline on the Clinical Dementia Rating sum-of-boxes (CDR-SOB, p<0.01) and Digit Span Forward (p=0.02) than non-RAS users. BBB-crossing RAS medications were associated with slower cognitive decline on the CDR-SOB, (p<0.01), the Mini Mental Status Examination, (p<0.01) and the Boston Naming test (p<0.01). RAS medications were somewhat associated with cognitive benefits in African Americans, more so than Caucasians. (MMSE (p=0.05) category fluency (p=0.04) and Digit Span Backwards, p=0.03)). RAS-modulating medications were associated with less conversion to AD. BBB permeability may produce additional cognitive benefit, and African Americans may benefit moreso from RAS-modulation than Caucasians. Results highlight the need for trials investigating RAS modulation during prodromal disease stages.

We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimer’s disease (AD). The trial was designed to evaluate the dose-dependent effects of transdermal 17-β estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera©), for 12 months in 43 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result of theWomen’s Health Initiative (WHI) and anticipated increased attrition, the protocolwas modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values < 0.030) and semantic memory (p-values < 0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD.