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INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late‐ and early‐onset and familial late‐onset AD, but not in familial early‐onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind.AD PRS influences memory aspects in DS individuals, independently of APOE genotype.These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population.APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex‐dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. METHODS: Thirty‐three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face‐name associative memory functional magnetic resonance imaging (fMRI) task with a 2‐year follow‐up. We acquired baseline carbon 11‐labeled Pittsburgh compound B ([11C]PiB) positron emission tomography (PET) and T2‐weighted fluid‐attenuated inversion recovery (T2‐FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively. RESULTS: Males had increased hippocampal‐prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. DISCUSSION: These findings suggest sex‐dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females. [ABSTRACT FROM AUTHOR]

Introduction: Plasma biomarkers—cost effective, non‐invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)—have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population‐based cohort to determine whether they could identify an at‐risk group, independently of brain and cerebrospinal fluid biomarkers. Methods: We measured plasma phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ)42/40 ratio in 847 participants from a population‐based cohort in southwestern Pennsylvania. Results: K‐medoids clustering identified two distinct plasma Aβ42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p‐tau181, NfL, and GFAP were inversely correlated with Aβ42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group. Discussion: Abnormal plasma Aβ42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening. Highlights: Population‐based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data.In the Monongahela‐Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age.Plasma amyloid beta (Aβ)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups.Plasma Aβ42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group.Plasma biomarkers can enable relatively affordable and non‐invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don't provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes. Method: Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline). Result: Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women. Conclusion: We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? We investigated whether the presence of small vessel disease (SVD) (measured as significant WMH burden) altered the associations between brain amyloid-beta (Aβ) and hippocampal functional connectivity during associative encoding in cognitively normal older adults. • What is the main finding of this study? In older adults with significant WMH burden (WMH+), greater Aβ burden was associated with a more localized pattern of hippocampal-medial temporal lobe (MTL) hyperconnectivity, but not in individuals with minimum WMH burden (WMH-). This local hippocampal-MTL hyperconnectivity is associated with local MTL atrophy. • What is the meaning of the finding? These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in pre-clinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD. Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. This study included 61 cognitively normal older adults (age range: 65–93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aβ, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. We found that, in WMH (+) older adults greater Aβ burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aβ burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD. [ABSTRACT FROM AUTHOR]

Background: Only a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer's disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels. Methods: We performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives. Results: Our genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release. Conclusion: This genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer's disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS. Methods: We constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals. Results: The PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE. Conclusions: Our study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer's disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS. Methods: We constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals. Results: The PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE. Conclusions: Our study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS. [ABSTRACT FROM AUTHOR]

Background: Incidence of dementia increases exponentially with age; little is known about its risk factors in the ninth and 10th decades of life. We identified predictors of dementia with onset after age 85 years in a longitudinal population-based cohort.Methods: On the basis of annual assessments, incident cases of dementia were defined as those newly receiving Clinical Dementia Rating (CDR) ≥1. We used a machine learning method, Markov modeling with hybrid density-based and partition-based clustering, to identify variables associated with subsequent incident dementia.Results: Of 1439 participants, 641 reached age 85 years during 10 years of follow-up and 45 of these became incident dementia cases. Using hybrid density-based and partition-based, among those aged 85+ years, probability of incident dementia was associated with worse self-rated health, more prescription drugs, subjective memory complaints, heart disease, cardiac arrhythmia, thyroid disease, arthritis, reported hypertension, higher systolic and diastolic blood pressure, and hearing impairment. In the subgroup aged 85 to 89 years, risk of dementia was also associated with depression symptoms, not currently smoking, and lacking confidantes.Conclusions: An atheoretical machine learning method revealed several factors associated with increased probability of dementia after age 85 years in a population-based cohort. If independently validated in other cohorts, these findings could help identify the oldest-old at the highest risk of dementia. [ABSTRACT FROM AUTHOR]

Background: Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. There have been over 40 genetic loci associated with AD but genome‐wide associations (GWA) underlying VaD remain incompletely identified. The proportion of VaD differs across studies based on study‐specific definitions. We hypothesize that common forms of dementia (AD, VaD) will share genetic risk factors. We conducted the largest GWAS to date of VaD and examined the genetic overlap with "all‐cause dementia" (ACD). Method: A total of 293,544 participants from 9 population‐based CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) cohorts, 2 national case‐control consortia (ADGC, MEMENTO) and the UKBB contributed 23,986 and 2,935 cases of ACD and VaD, respectively. We ran study‐specific analyses adjusting for age, sex, and population structure and meta‐analyzed summary statistics using the sample size weighted method implemented in METAL, followed by conditional analyses, fine‐mapping and bioinformatic exploration of loci. Result: Genome‐wide associations with VaD were identified at the APOE locus and at 5 additional loci. One locus has been previously associated with hippocampal volume, verbal memory and CSF amyloid levels (ASTN2); others were near genes associated with hypertension, diabetes and hyperlipidemia (Figures 1 and 2). In addition to previously identified AD loci, we identified novel variants associated with ACD. VaD‐related loci also showed sub‐threshold associations with ACD that were congruent in direction of effect, thus suggesting additional biological targets underlying ACD. We will additionally present results of an ongoing multiethnic GWAS and insights from pathway analyses and bioinformatic parsing of the identified loci. Conclusion: Although VaD is the second most common cause of dementia, the identification of associated genetic loci has been hindered by the heterogeneity of its definition, which necessitates a large sample size to reach genome‐wide significance. The newly identified loci could provide novel insights into the pathophysiological mechanisms of dementia and point to new prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: We compared risk of progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) in an academic memory clinic versus a population‐based study. Methods: Older adults presenting at a memory clinic were classified as SCD (n = 113) or as noncomplainers (n = 82). Participants from a population study were classified as SCD (n = 592) and noncomplainers (n = 589) based on a memory complaint score. Annual follow‐up performed for a mean of 3 years. Results: The adjusted hazard ratio for SCD was 15.97 (95% confidence interval: 6.08–42.02, P <.001) in the memory clinic versus 1.18 (95% confidence interval: 1.00–1.40, P =.047) in the population study, where reported "worry" about memory further increased SCD‐associated risk for MCI. Discussion: SCD is more likely to progress to MCI in a memory clinic than the general population; participants' characteristics vary across settings. Study setting should be considered when evaluating SCD as a risk state for MCI and dementia. [ABSTRACT FROM AUTHOR]

Background: Cognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures. Method: To identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains. Result: Genome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF/FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell (Viruses 2021;13:384; J Biol Chem 2021; 296:100135). Conclusion: We have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection (Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings. [ABSTRACT FROM AUTHOR]

Introduction African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. Methods We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7 , identified previously in a LOAD GWAS of AAs. Results Two SNPs at novel loci, rs112404845 ( P = 3.8 × 10 −8 ), upstream of COBL , and rs16961023 ( P = 4.6 × 10 −8 ), downstream of SLC10A2 , obtained genome-wide significant evidence of association with the posterior liability. Discussion An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS. [ABSTRACT FROM AUTHOR]

Background: Dementia broadly describes conditions that affect a person's memory, cognition, and behavior with Alzheimer's disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome‐wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above. Method: We performed a genome‐wide association study (GWAS) on the genome‐wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non‐demented subjects (mean age ± sd = 84.55±3.23). Result: The established association of APOE*4 with AD was confirmed in this community‐based sample of older subjects (OR = 2.22; P = 9.36E‐14). In addition, a genome‐wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E‐08). Sex‐stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E‐10) than in males (P = 2.43E‐05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome‐wide significance (OR = 4.51; P = 3.72E‐08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance. Conclusion: The use of community‐based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case‐control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD. [ABSTRACT FROM AUTHOR]

Background: A rare missense APOE variant (L28P; APOE*4Pittsburgh) has been reported to be a risk factor for Alzheimer's disease (AD). However, sinceL28P has been observed only among APOE*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect. Method: Samples were derived from three sources: University of Pittsburgh, Alzheimer's Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE*4‐background and 3/4 is the most common genotype containing the APOE*4 allele. Result: A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80. Conclusion: Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology. [ABSTRACT FROM AUTHOR]

Background Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations of common CETP variants with variation in plasma lipid levels, and/or CETP mass/activity have been extensively studied and well-documented; however, the effects of uncommon/rare CETP variants on plasma lipid profile remain undefined. Hence, resequencing of the gene in extreme phenotypes and follow-up rare-variant association analyses are essential to fill this gap. Objective To identify common and uncommon/rare variants in the CETP gene by resequencing the entire gene and test the effects of both common and uncommon/rare CETP variants on plasma lipid traits in two genetically distinct populations. Methods and results The entire CETP gene plus flanking regions were resequenced in 190 individuals comprising 95 non-Hispanic whites (NHWs) and 95 African blacks with extreme HDL-C levels. A total of 279 sequence variants were identified, of which 25 were novel. Selected variants were genotyped in the entire samples of 623 NHWs and 788 African blacks and 184 QC-passed variants were tested in relation to plasma lipid traits by using gene-based, single-site, haplotype and rare variant association analyses (SKAT-O). Two novel and independent associations of rs1968905 and rs289740 with HDL-C were identified in African blacks. Using SKAT-O analysis, we also identified rare variants with minor allele frequency < 0.01 to be associated with HDL-C in both NHWs ( P = 0.024) and African blacks ( P = 0.009). Conclusions Our results point out that in addition to the common CETP variants, rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an irreversible neurodegenerative brain disease with varying disease progression rates among individuals. This study aims to identify possible underlying genetic variants associated with AD progression using a whole‐genome sequencing approach. Method: Whole‐genome sequencing at 30x coverage was performed on 416 late‐onset AD patients (mean baseline age ± sd) = 76.47 ± 6.10) having at least two Mini‐Mental State Examination (MMSE) scores ranged from 0 to 30. Since the study subjects had varying time points of visit and MMSE records, we defined AD progression phenotypes in four ways, including differentially specified progression rates and time to pre‐defined events in genome‐wide association analyses. Genetic association analyses between single‐nucleotide variants (SNVs) and phenotypes were adjusted for baseline age, sex, year of education, baseline MMSE measures, and the first four principal components. Result: Six novel genome‐wide statistically significant associations (p<5E‐08) were observed in our study. Two associations were detected with the same SNVs on chromosomes 2 (SLC4A10/rs13036052) and 7 (chr7:58053009[Hg38] near ZNF716) with overall progression rates. One genetic variant on chromosome 6 (chr6:3127309[Hg38] near BPHL) was associated with annual progression rate. In addition, three associations were seen on chromosomes 1 (rs199560872), 14 (chr14:9600158[Hg38] near TUNAR), and 18 (rs34718969) with time‐to‐event phenotypes. All top variants were present either in introns or intergenic regions. Conclusion: Our initial whole‐genome sequencing analyses have identified several independent associations with AD progression, which need to be confirmed in larger sequencing samples. [ABSTRACT FROM AUTHOR]

Background: The APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Method: Baseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available. Result: As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09). Conclusion: We have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to examine the effect of mixing fiber cocktail on cracking strength of concrete. The research work has been carried out to evaluate the effect of “cocktail fibers” on reinforced concrete. Cocktail fiber is a mixture of steel fibers (SF) and polypropylene fibers (PPF). Comparison was carried out by preparing and testing 30 specimens of plain & reinforced concrete incorporating different ratios of fibers. Monofilament polypropylene fibers and undulated steel fibers were used in various dosages and their effect on the cracking strength in terms of compressive strength as well as ultimate load capacity was observed. For this purpose cubes (150 x 150 x 150mm) and beams (150 x 225 x 1975mm) were cast for compressive strength test on cubes and two point loading test on beams. The cubes and beams were cast in groups, such as, group A (concrete without any fiber), group B (steel fibers @ 60kg/m3), group C (PP fibers @ 0.7kg/m3), group D (PP fibers @ 1.5kg/m3), group E (cocktail fibers @ 60kg/m3 of steel fibers + 0.7kg/m3 of PP fibers) and group F (cocktail fibers @ 60kg/m3 of steel fibers + 1.5kg/m3 of PP fibers). From test results, it was concluded that the addition of polypropylene, steel and cocktail fibers enhanced the initial cracking and post cracking behaviour of reinforced concrete. However, with the addition of steel fibers the compressive strength of concrete reduced which is a trade-off between the initial cracking strength and compressive strength. [Copyright &y& Elsevier]

Background: Recently developed immuno‐precipitation mass spectrometry (IP‐MS) assays to measure blood‐based amyloid‐β with high accuracy holds exciting potential. Adoption of amyloid‐β measurement will be especially valuable in large population studies where not previously feasible. We evaluated the correspondence between a new IP‐MS assay developed on a commercially available platform with brain amyloid PET imaging as the gold standard. Method: N=99 older participants without dementia, active in the population‐based Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) study, underwent blood draws at the time of brain amyloid imaging with PiB‐PET (50‐70 minutes post‐injection, SUVR with cerebellar reference). Adapting methods of Nakamura et al. (2018), immunoprecipitation from plasma was followed by time‐of‐flight MS, using a benchtop mass spectrometer, to measure relative amounts of endogenous peptides Aβ1‐40, Aβ1‐42, APP669‐711, and a stable‐isotope‐labeled internal standard. A composite plasma biomarker was calculated as the mean of the normalized ratios APP669711/Aβ142 and Aβ140/Aβ142. Result: n= 24 (24%) of participants were PiB‐positive by a global cutoff, 7 (7%) were CDR 0.5, and 13 (13%) were APOE*4 carriers. Higher global PiB SUVR was associated with older age, higher CDR (0.5 vs. 0) and APOE*4 genotype (p's <.05), while higher plasma composite biomarker was similarly associated with CDR and APOE*4 but not age. ROC analysis yielded an AUC of 0.78 (SE 0.05) for the composite plasma biomarker predicting PiB‐PET status, with an optimized cut‐point corresponding to sensitivity of 0.75 and specificity of 0.69. Including age and APOE*4 into the model yielded an overall AUC of 0.89, and plasma biomarker sensitivity of 0.91 and specificity of 0.77. Conclusion: This IP‐MS assay was successfully implemented using a commercially‐available, benchtop MALDI‐TOF instrument that is easy to operate and already used in clinic settings. Concurrent prediction of amyloid status from plasma amyloid alone was significant, with moderately high accuracy. Combining plasma amyloid with age and APOE genotype improved prediction to high accuracy. Planned follow‐up of the sample with repeat PiB scans will yield yet further information about prospective prediction of brain amyloid status. This non‐invasive approach using a peripheral biomarker could be highly useful and feasible to apply in large population studies of AD risk. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) have identified approximately 40 risk loci associated with Alzheimer's disease (AD). However, only a fraction of heritability has been explained. In large meta‐analysis, smoking was associated with AD dementia. In this study, we sought to identify interactions between smoking and single‐nucleotide polymorphisms (SNPs) to further characterize AD genetic architecture. Method: We used a subset of datasets of individuals of European ancestry from the Alzheimer's Disease Genetic Consortium (ADGC) that had smoking information available from parent studies. The presence of any past or current smoking habit was considered to be positive smoking exposure. In each dataset, we ran a genome‐wide case‐control analysis including SNP and smoking main terms, and a SNP‐smoking interaction term. Models were adjusted for age, sex, and principal components of population substructure. Results from each dataset were meta‐analyzed using the inverse variance method. Pathway analysis of top SNPs was run using Ingenuity. Result: The sample included 6,916 total individuals, including 2,862 AD cases and 4,054 controls. Although no interaction terms reached genome‐wide significance, there were two suggestive loci: top SNP rs3734416 [minor (C) allele frequency (MAF) = 0.27; interaction P = 7.2 × 10−6; OR for C allele in smokers = 1.23; OR for C allele in non‐smokers = 0.86] on chromosome 6 within the gene MTHFD1L and 95kb downstream of PLEKHG1, and top SNP rs693951 [MAF (G) = 0.27; interaction P = 1.3 × 10−6; OR for major A allele in smokers = 1.31; OR for A allele in non‐smokers = 0.83] on chromosome 8, 70kb upstream of ANGPT1. Pathway analysis implicated cellular development, cellular growth and proliferation and nervous system development and function. MTHFD1L has been implicated in candidate gene studies of AD and PLEKHG1 has been implicated in a GWAS of white matter hyperintensities. ANGPT1 has been implicated in recovery after ischemic stroke in candidate gene, transcriptomic and blood‐based biomarker studies. Conclusion: We found suggestive evidence of a smoking‐SNP interaction associated with AD risk at 2 loci previously linked with AD and cerebrovascular disease, but that were not identified in the largest AD GWAS to date. Expansion of the sample and replication are underway. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline is a major characteristic of aging and neurogenerative diseases such as Alzheimer's disease (AD), Parkinson's disease and other dementias. With worldwide increases in life‐expectancy and elderly population, cognitive decline is a major public health concern. Understanding genetic contributors to age‐related decline in cognition may facilitate identification of the molecular mechanisms of cognitive decline. Method: To discover genetic influences on cognitive decline, we conducted genome‐wide meta‐analyses on longitudinal performance of five cognitive domains (attention, language, executive function, visuospatial, memory) and the global domain, constructed from five domains, using 3068 individuals aged 65 and above across three longitudinal cohorts: the Gingko biloba Memory Evaluation Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). A linear mixed effect model was used to find individual specific slopes by adjusting for baseline age, years of education and sex. Results: APOE*4 (rs429358), a well‐known risk factor for AD, demonstrated a genome‐wide significant association with the memory (P= 1.37E‐09) and global (P= 9.26E‐10) domains. Previous studies have also reported APOE*4 's association with memory decline. In addition to APOE*4, multiple suggestive associations of gene loci with cognition were also observed for each domain as follows: attention on chromosome 9 near RASEF/FRMD3 (P = 8.29E‐08), memory on chromosome 6 near ID4/MBOAT1(P = 1.27E‐07), visuospatial function on chromosome 11 near PAMR (P = 2.74E‐07), language on chromosome 9 near PSAT1 (P = 4.08E‐07), executive function on chromosome 4 near SNHG27 (P = 6.49E‐07), and global function on chromosome 4 near LINC00290 (P=8.80E‐07). Conclusion: Our result suggests that in addition to APOE, multiple genetic loci affect cognitive decline in older individuals. These findings may offer new insights into understanding the genetic architecture of cognitive decline. [ABSTRACT FROM AUTHOR]