Association of Epigenetic Age Acceleration with Incident Mild Cognitive Impairment and Dementia among Older Women

Background: Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia. Methods: This prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated. Results: IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99-1.53), dementia (HR, 1.10; 95% CI, 0.88-1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia. Conclusions: IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.46 ppm

We present the first results of the Fermilab Muon g-2 Experiment for the positive muon magnetic anomaly $a_\mu \equiv (g_\mu-2)/2$. The anomaly is determined from the precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency $\omega_a$ between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ${\tilde{\omega}'^{}_p}$ in a spherical water sample at 34.7$^{\circ}$C. The ratio $\omega_a / {\tilde{\omega}'^{}_p}$, together with known fundamental constants, determines $a_\mu({\rm FNAL}) = 116\,592\,040(54)\times 10^{-11}$ (0.46\,ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both $\mu^+$ and $\mu^-$, the new experimental average of $a_\mu({\rm Exp}) = 116\,592\,061(41)\times 10^{-11}$ (0.35\,ppm) increases the tension between experiment and theory to 4.2 standard deviationsComment: 10 pages; 4 figure

Mild cognitive impairment: baseline and longitudinal structural MR imaging measures improve predictive prognosis.

Results of this study demonstrate that patient-specific estimates of the risk of conversion from mild cognitive impairment to Alzheimer disease can be derived from quantitative measures of brain atrophy obtained from single-time-point and serial MR imaging examinations. Purpose To assess whether single-time-point and longitudinal volumetric magnetic resonance (MR) imaging measures provide predictive prognostic information in patients with amnestic mild cognitive impairment (MCI). Materials and Methods This study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from all participants or the participants’ legal guardians. Cross-validated discriminant analyses of MR imaging measures were performed to differentiate 164 Alzheimer disease (AD) cases from 203 healthy control cases. Separate analyses were performed by using data from MR images obtained at one time point or by combining single-time-point measures with 1-year change measures. Resulting discriminant functions were applied to 317 MCI cases to derive individual patient risk scores. Risk of conversion to AD was estimated as a continuous function of risk score percentile. Kaplan-Meier survival curves were computed for risk score quartiles. Odds ratios (ORs) for the conversion to AD were computed between the highest and lowest quartile scores. Results Individualized risk estimates from baseline MR examinations indicated that the 1-year risk of conversion to AD ranged from 3% to 40% (average group risk, 17%; OR, 7.2 for highest vs lowest score quartiles). Including measures of 1-year change in global and regional volumes significantly improved risk estimates (P = 001), with the risk of conversion to AD in the subsequent year ranging from 3% to 69% (average group risk, 27%; OR, 12.0 for highest vs lowest score quartiles). Conclusion Relative to the risk of conversion to AD conferred by the clinical diagnosis of MCI alone, MR imaging measures yield substantially more informative patient-specific risk estimates. Such predictive prognostic information will be critical if disease-modifying therapies become available