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Background: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel., Methods: The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [ 11 C] PiB PET, [ 18 F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers., Results: NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype., Conclusions: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD., (© 2024. The Author(s).)

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women., Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women ( n  = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori ); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status., Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4 -stratified analyses, these interactions were driven by non- APOE4 carriers., Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non- APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause., Competing Interests: RT reported receiving personal fees from Astellas Pharma, Bayer, Hello Therapeutics, Happify Health, and Vira Health outside the submitted work. HA reported receiving personal fees from Eisai outside the submitted work. PM reported receiving personal fees from Astellas Pharma, Bayer, Estrigenix, Alloy, and MidiHealth outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wugalter, Schroeder, Thurston, Wu, Aizenstein, Cohen, Kamboh, Karikari, Derby and Maki.)

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aβ PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aβ in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aβ (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aβ differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Blood-based biomarkers are gaining grounds for Alzheimer's disease (AD) detection. However, two key obstacles need to be addressed: the lack of methods for multi-analyte assessments and the need for markers of neuroinflammation, vascular, and synaptic dysfunction. Here, we evaluated a novel multi-analyte biomarker platform, NULISAseq CNS disease panel, a multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA) targeting ~120 analytes, including classical AD biomarkers and key proteins defining various disease hallmarks., Methods: The NULISAseq panel was applied to 176 plasma samples from the MYHAT-NI cohort of cognitively normal participants from an economically underserved region in Western Pennsylvania. Classical AD biomarkers, including p-tau181 p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were also measured using Single Molecule Array (Simoa). Amyloid pathology, tau pathology, and neurodegeneration were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and MRI, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA biomarkers and AD pathologies. Spearman correlations were used to compare NULISA and Simoa., Results: NULISA concurrently measured 116 plasma biomarkers with good technical performance, and good correlation with Simoa measures. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET+ participants, including TIMP3, which regulates brain Aβ production, the neurotrophic factor BDNF, the energy metabolism marker MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET+ participants. Markers with tau PET-dependent longitudinal changes included the microglial activation marker CHIT1, the reactive astrogliosis marker CHI3L1, the synaptic protein NPTX1, and the cerebrovascular markers PGF, PDGFRB, and VEFGA; all previously linked to AD but only reliably measured in cerebrospinal fluid. SQSTM1, the autophagosome cargo protein, exhibited a significant association with neurodegeneration status after adjusting age, sex, and APOE ε4 genotype., Conclusions: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Introduction: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes., Methods: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P)., Results: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations., Discussion: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development., Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies., (© 2024. The Author(s).)

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 ([ 11 C]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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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, PRS APOE , p = 2.84 × 10 -4 ; PRS excluding APOE, PRS nonAPOE , p = 1.60 × 10 -2 ). PRS APOE 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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years., Methods: We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments., Results: By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster ( p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years)., Discussion: There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Introduction: Cognitive abilities have substantial heritability throughout life, as shown by twin- and population-based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains., Methods: We conducted a meta-analysis on 3045 individuals aged ≥65, derived from three population-based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene-based and functional bioinformatics analyses., Results: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E-09) and global cognitive function (p = 1.84E-08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E-08), near RASEF. Gene-based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS-CoV-2, to be associated with the decline in global cognitive function (p = 4.28E-07)., Discussion: Domain-specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains., Highlights: rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS-CoV-2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk., (© 2023. The Author(s).)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10 -311 , MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10 -09 , MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10 -10 , MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10 -09 , MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10 -08 , MAF = 0.006, sex-interaction P = 9.8 × 10 -07 ) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10 -08 , MAF = 0.004, sex-interaction P = 1.3 × 10 -03 ). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies., (© 2023. The Author(s).)

Objective: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: DISCLOSUREs The authors declare no competing interests in relation to the work described., (Copyright © 2022. Published by Elsevier Inc.)

A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD., Competing Interests: Disclosure Statement The authors have no actual or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Structural variations such as copy number variants (CNVs) have been associated with multiple autoimmune diseases. In this study, we explored the association of the Fc gamma receptor 3B gene ( FCGR3B ) copy number variation (CNV) with rheumatoid arthritis (RA) susceptibility and related serological traits in the Pakistani population. We also performed a meta-analysis of four published FCGR3B CNV studies along with the current study. A total of 927 subjects (597 RA cases, 330 healthy controls) were recruited from three rheumatology centers in Pakistan. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured in RA patients. FCGR3B copy number was assayed using the TaqMan ® CN assay (Hs04211858&#95;cn, Applied Biosystems, Foster City, CA, USA) and the copy number was estimated by using CopyCaller ® software (version 2.1; Applied Biosystems, USA). Logistic regression was applied to calculate the odds ratio (OR) of RA risk associated with FCGR3B CNV using sex and age as covariates in R. Meta-analysis on four previously published studies and the current study was performed using the random-effect model. We observed a significant association between FCGR3B copy number < 2 and RA susceptibility (OR = 1.53; 95% CI: 1.05 to 2.22; p = 0.0259) and anti-CCP seropositivity (OR 2.56; 95% CI: 1.34 to 4.89; p = 0.0045). A non-significant association of FCGR3B copy number < 2 was also observed between increased rheumatoid factor (RF) seropositivity (OR = 1.74; 95% CI:0.93 to 3.26; p = 0.0816). Meta-analysis on 13,915 subjects (7005 RA cases and 6907 controls) also showed significant association of copy number < 2 with the increased risk of RA (OR = 1.30; 95% CI: 1.07 to 1.56; p = 0.00671). FCGR3B copy number < 2 is associated with increased RA risk and anti-CCP seropositivity.

The number of people suffering from Alzheimer's disease (AD) is increasing rapidly every year. One aspect of AD that is often overlooked is the disproportionate incidence of AD among African American/Black populations. With the recent development of novel assays for lipidomics analysis in recent times, there has been a drastic increase in the number of studies focusing on changes of lipids in AD. However, very few of these studies have focused on or even included samples from African American/Black individuals samples. In this study, we aimed to determine if the lipidome in AD is universal across non-Hispanic White and African American/Black individuals. To accomplish this, a targeted mass spectrometry lipidomics analysis was performed on plasma samples ( N = 113) obtained from cognitively normal (CN, N = 54) and AD ( N = 59) individuals from African American/Black ( N = 56) and non-Hispanic White ( N = 57) backgrounds. Five lipids (PS 18:0&#95;18:0, PS 18:0&#95;20:0, PC 16:0&#95;22:6, PC 18:0&#95;22:6, and PS 18:1&#95;22:6) were altered between AD and CN sample groups ( p value < 0.05). Upon racial stratification, there were notable differences in lipids that were unique to African American/Black or non-Hispanic White individuals. PS 20:0&#95;20:1 was reduced in AD in samples from non-Hispanic White but not African American/Black adults. We also tested whether race/ethnicity significantly modified the association between lipids and AD status by including a race × diagnosis interaction term in a linear regression model. PS 20:0&#95;20:1 showed a significant interaction ( p = 0.004). The discovery of lipid changes in AD in this study suggests that identifying relevant lipid biomarkers for diagnosis will require diversity in sample cohorts.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5-10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder., (© 2021. The Author(s).)

Background: Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for., Objective: 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 aged 75 and above., Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects., Results: The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p = 9.36E-14) and was stronger in females (OR = 2.72; p = 1.74E-10) than in males (OR = 1.88; p = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR = 3.31; p = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR = 4.51; p = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR = 3.76; p = 6.93E-08)., 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 studies of these regions and genes will help to provide a clearer picture for their role in AD.

The clinical diagnosis of Alzheimer's disease, at its early stage, remains a difficult task. Advanced imaging technologies and laboratory assays to detect Aβ peptides Aβ42 and Aβ40, total and phosphorylated tau in CSF provide a set of biomarkers of developing AD brain pathology and facilitate the diagnostic process. The search for biofluid biomarkers, other than in CSF, and the development of biomarker assays have accelerated significantly and now represent the fastest-growing field in AD research. The goal of this study was to determine the differential enrichment of noncoding RNAs (ncRNAs) in plasma-derived extracellular vesicles (EV) of AD patients and Cognitively Normal controls (NC). Using RNA-seq, we profiled four significant classes of ncRNAs: miRNAs, snoRNAs, tRNAs, and piRNAs. We report a significant enrichment of SNORDs - a group of snoRNAs, in AD samples compared to NC. To verify the differential enrichment of two clusters of SNORDs - SNORD115 and SNORD116, localized on human chromosome 15q11-q13, we used plasma samples of an independent group of AD patients and NC. We applied ddPCR technique and identified SNORD115 and SNORD116 with a high discriminatory power to differentiate AD samples from NC. The results of our study present evidence that AD is associated with changes in the enrichment of SNORDs, transcribed from imprinted genomic loci, in plasma EV and provide a rationale to further explore the validity of those SNORDs as plasma biomarkers of AD., (Copyright © 2021. Published by Elsevier Inc.)

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10 -8 ) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10 -8 ), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

A true understanding of the distribution and functional correlates of Alzheimer's disease pathology in dementia-free older adults requires a population-based perspective. Here we report initial findings from a sample of 102 cognitively unimpaired participants (average age 77.2 years, 54.9% women, 13.7% APOE*4 carriers) recruited for neuroimaging from a larger representative population-based cohort participating in an ongoing longitudinal study of aging, the Monongahela-Youghiogheny Healthy Aging Team (MYHAT). All participants scored < 1.0 on the Clinical Dementia Rating (CDR) Scale, with 8 participants (7.8%) scoring CDR = 0.5. Participants completed a positron emission tomography scan using the tracers [C-11]Pittsburgh Compound-B (PiB) and [F-18]AV-1451 to estimate amyloid and tau deposition. PiB positivity was defined on a regional basis using established standardized uptake value ratio cutoffs (SUVR; cerebellar gray matter reference), with 39 participants (38.2%) determined to be PiB(+). Health history, lifestyle, and cognitive abilities were assessed cross-sectionally at the nearest annual parent MYHAT study visit. A series of adjusted regression analyses modeled cognitive performance as a function of global PiB SUVR and [F-18]AV-1451 SUVR in Braak associated regions 1, 3/4, and 5/6. In comparison to PiB(-) participants (n = 63), PiB(+) participants were older, less educated, and were more likely to be APOE*4 carriers. Global PiB SUVR was significantly correlated with [F-18]AV-1451 SUVR in all Braak-associated regions (r = .38-0.53, p < .05). In independent models, higher Global PiB SUVR and Braak 1 [F-18]AV-1451 SUVR were associated with worse performance on a semantic interference verbal memory test. Our findings suggest that brain amyloid is common in a community-based setting, and is associated with tau deposition, but both pathologies show few associations with concurrent cognitive performance in a dementia-free sample., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders., (Copyright © 2021. Published by Elsevier Inc.)

Genome-wide association studies (GWAS) have identified multiple type 2 diabetes (T2D) loci, mostly among populations of European descent. There is a high prevalence of T2D among Pakistanis. Both genetic and environmental factors may be responsible for this high prevalence. In order to understand the shared genetic basis of T2D among Pakistanis and Europeans, we examined 77 genome-wide significant variants previously implicated among European populations. We genotyped 77 single-nucleotide polymorphisms (SNPs) by iPLEX® Gold or TaqMan® assays in a case-control sample of 1,683 individuals. Association analysis was performed using logistic regression. A total of 16 SNPs (TCF7L2/rs7903146, GLIS3/rs7041847, CHCHD9/rs13292136, PLEKHA1/rs2292626, FTO/rs9936385, CDKAL1/rs7756992, KCNJ11/rs5215, LOC105372155/rs12970134, KCNQ1/rs163182, CTRB1/rs7202877, ST6GAL1/rs16861329, ADAMTS9-AS2/rs6795735, LOC105370275/rs1359790, C5orf67/rs459193, ZBED3-AS1/rs6878122 and UBE2E2/rs7612463) showed statistically significant associations after controlling for the false discovery rate. While KCNQ1/rs163182 and ZBED3-AS1/rs6878122 showed opposite allelic effects, the remaining significant SNPs had the same allelic effects as reported previously. Our data indicate that a selected number of T2D loci previously identified among populations of European descent also affect the risk of T2D in the Pakistani population., (Copyright © 2021. Published by Elsevier B.V.)

Background: African American/Black adults have a disproportionate incidence of Alzheimer's disease (AD) and are underrepresented in biomarker discovery efforts., Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults., Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates., Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD., Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers.

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11 C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated., Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel., Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019., Main Outcomes and Measures: Diagnosis of Alzheimer disease., Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration., Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Common variants in the hepatic lipase (LIPC) gene have been shown to be associated with plasma lipid levels; however, the distribution and functional features of rare and regulatory LIPC variants contributing to the extreme lipid phenotypes are not well known. This study was aimed to catalogue LIPC variants by resequencing the entire LIPC gene in 95 non-Hispanic Whites (NHWs) and 95 African blacks (ABs) with extreme HDL-C levels followed by in silico functional analyses. A total of 412 variants, including 43 novel variants were identified; 56 were unique to NHWs and 234 were unique to ABs. Seventy-eight variants in NHWs and 89 variants in ABs were present either in high HDL-C group or low HDL-C group. Two non-synonymous variants (p.S289F, p.T405M), found in NHWs with high HDL-C group were predicted to have damaging effect on LIPC protein by SIFT, MT2 and PP2. We also found several non-coding variants that possibly reside in the circRNA and lncRNA binding sites and may have regulatory potential, as identified in rSNPbase and RegulomeDB databases. Our results shed light on the regulatory nature of rare and non-coding LIPC variants as well as suggest their important contributions in affecting the extreme HDL-C phenotypes., Competing Interests: The authors have declared that no competing interests exist.

Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10 -5 and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10 -27 ). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10 -5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

Objective: Copy number variation (CNV) is a structural variation in the human genome that has been associated with multiple clinical phenotypes. B cells are important components of rheumatoid arthritis- (RA-) mediated immune response; hence, CNV in the regulators of B cells (such as VPREB1) can influence RA susceptibility. In this study, we aimed to explore the association of CNV in the VPREB1 gene with RA susceptibility in the Pakistani population., Methods: A total of 1,106 subjects (616 RA cases, 490 healthy controls) were selected from three rheumatology centers in Pakistan. VPREB1 CNV was determined using the TaqMan® CN assay (Hs02879734&#95;cn, Applied Biosystems, Foster City, CA, USA), and CNV was estimated by using CopyCaller® (version 2.1; Applied Biosystems, USA) software. Odds ratio (OR) was calculated by logistic regression with sex and age as covariates in R ., Results: A significant association between >2 VPREB1 CNV and RA risk was observed with an OR of 3.92 (95% CI: 1.27 - 12.12; p = 0.01746) in the total sample. Whereas <2 CNV showed a significantly protective effect against RA risk in women with an OR of 0.48 (95% CI: 0.29-0.79; p = 0.00381)., Conclusion: CNV > 2 of VPREB1 is a risk factor for RA in the total Pakistani population, while CNV < 2 is protective in women., Competing Interests: All the authors declared that they have no conflict of interest., (Copyright © 2020 Muhammad Muaaz Aslam et al.)

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.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR-DNA binding protein of 43kDA (TDP-43) in Alzheimer's disease (AD) patients., Methods: The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA-Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37-95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP-43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE-4 allele, and presence of Lewy bodies (LB)., Results: HS was present in 18% (n = 64) and TDP-43 in 51.5% (n = 185) of the patients. HS and TDP-43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP-43. Age at onset was not associated with TDP-43 or HS. HS was associated with duration of symptoms and LB, TDP-43, and atherosclerosis in the CW. TDP-43 was associated with duration of symptoms, LB, and HS., Interpretation: HS and TDP-43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP-43 are part of the later neuropathological changes in AD., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To explore long-term predictors of avoiding β-amyloid (Aβ) deposition and maintaining unimpaired cognition as outcomes in the oldest old., Methods: In a longitudinal observational cohort study, 100 former participants of the Ginkgo Evaluation of Memory Study (GEMS; 2000-2008) completed biannual Pittsburgh compound B-PET imaging and annual clinical-cognitive evaluations beginning in 2010. Most recent Aβ status and cognitive status were selected for each participant. Longitudinal outcomes included change in serial Aβ and cognitive tests. Baseline predictors from GEMS included neuropsychological tests, daily functioning, APOE genotype, lifestyle variables, occupational measures, health history, sleep, subjective memory, physical and cognitive activities, depressive symptoms, and physical performance and health indices, among others., Results: Mean age at the last cognitive evaluation was 92.0 (range 86-100) years. Mean follow-up time from baseline to last measured Aβ status was 12.3 (SD 1.9) years and to last cognitive evaluation was 14.1 (SD 1.9) years. The APOE*2 allele predicted last Aβ status (n = 34 Aβ negative vs n = 66 Aβ positive). Baseline cognition predicted cognitive status (n = 30 unimpaired vs n = 70 impaired). Predictors of cognitive status among Aβ-positive participants only (n = 14 normal cognition vs n = 52 impaired) were baseline cognitive test scores and smoking history. Baseline pulse pressure predicted longitudinal Aβ increase; paid work engagement and life satisfaction predicted less cognitive decline., Conclusions: The APOE*2 allele and lower pulse pressure predict resistance to Aβ deposition in advanced aging. Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ. Several lifestyle factors appear protective., (© 2020 American Academy of Neurology.)

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs ( LINC00824 /rs1516971, PADI4 /rs2240336, CEP57 /rs4409785, CTLA4 /rs3087243, STAT4 /rs13426947, HLA-B/MICA /rs2596565, C5orf30 /rs26232, CCL21 /rs951005, GATA3 /rs2275806, VPS37C /rs595158, HLA-DRB1 /rs660895, EOMES /rs3806624, SPRED2 /rs934734, and RUNX1 /rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73 E -06 to 3.48 E -02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways., Competing Interests: All authors declared no competing interests., (Copyright © 2020 Muhammad Muaaz Aslam et al.)

Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic models PLG /rs4252120 ( p = 0.0078), KIAA1462 /rs2505083 ( p = 0.005), and SLC22A3 /rs2048327 ( p = 0.045) and two with recessive models SORT1 /rs602633 ( p = 0.005) and UBE2Z /rs46522 ( p = 0.03). PLG /rs4252120 was in LD with two functional PLG variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, KIAA1462 /rs2505083 was in LD with a functional SNP, KIAA1462 /rs3739998, having a RegulomeDB score of 2b. In the GTEx database, KIAA1462 /rs2505083, SLC22A3 /rs2048327, SORT1 /rs602633, and UBE2Z /rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Asma Naseer Cheema et al.)

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

The genetics of late-onset Alzheimer's disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and controls from the Alzheimer's Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE/rs7412 (odds ratio (OR) = 0.40; p = 5.46E-24), TOMM40/rs157581 (OR = 1.49; p = 4.04E-07), and TREM2/rs75932628 (OR = 4.00; p = 1.15E-07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p = 2.88E-07). NSF was also significant in the gene-based analysis (p = 1.20E-05). In the GTEx data, NSF/rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-β accumulation. Further characterization of genes that are affected by NSF/rs199533 may help to shed light on the roles of these genes in AD etiology.

To identify novel loci that affect cognitive decline in older adults free of dementia, we conducted genome-wide and gene-based meta-analyses on longitudinal slopes of 5 cognitive domains (memory, executive function, language, attention/processing speed, and visuospatial ability) derived from 2 population-based cohorts. For decline over time in each cognitive domain, we normalized intraindividual slopes within each cohort, accounting for baseline age, sex, and years of education. Normalized slope for each domain was used in cohort-specific genome-wide analyses after including top principal components as covariates followed by genome-wide and gene-based meta-analyses. Both analyses revealed a novel WDFY2 locus at genome-wide (p = 3.37E-08) and gene-wide (p = 7.10E-07) significance levels for the attention/processing speed domain. In the GTEx eQTL analysis, genome-wide significant single-nucleotide polymorphism was associated with RNA expression levels of WDFY2 in several brain regions: cerebellar hemisphere (p = 1.07E-04), cerebellum (p = 6.92E-04), hippocampus (p = 2.18E-03) and cortex (p = 2.29E-02), and in whole blood (p = 4.41E-05). Our results suggest that WDFY2 genetic variation may affect individual differences in decline over time on tests of attention/processing speed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity exercise is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of skepticism and debate because of the absence of large, comprehensive, Phase III clinical trials. Here we describe the protocol for such a randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise), a study capable of more definitively addressing whether exercise influences cognitive and brain health in cognitively normal older adults. We are conducting a 12-month, multi-site, randomized dose-response exercise trial in 639 cognitively normal adults between 65 and 80 years of age. Participants are randomized to (1) a moderate intensity aerobic exercise condition of 150 min/week (N = 213), (2) a moderate intensity aerobic exercise condition at 225 min/week (N = 213), or (3) a light intensity stretching-and-toning control condition for 150 min/week (N = 213). Participants are engaging in 3 days/week of supervised exercise and two more days per week of unsupervised exercise for 12 months. A comprehensive cognitive battery, blood biomarkers and battery of psychosocial questionnaires is assessed at baseline, 6 and 12-months. In addition, brain magnetic resonance imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and positron emission tomography of amyloid deposition are assessed at baseline and at the 12-month follow-up. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Associations between whole blood transcriptome and clinical phenotypes in vitamin D-deficient overweight and obese children can provide insight into the biological effects of vitamin D and obesity. We determined differentially expressed genes (DEGs) in relation to body mass index (BMI) in vitamin D-deficient black children with a BMI ≥ 85th percentile and ascertained the cardiometabolic phenotypes associated with the DEGs. We examined whole-blood transcriptome gene expression by RNA sequencing and cardiometabolic profiling in 41, 10- to 18-year-old children. We found 296 DEGs in association with BMI after adjusting for age, race, sex, and pubertal status. Cardiometabolic phenotypes associated with the BMI-related DEGs, after adjusting for age, sex, pubertal status, and %total body fat, were (i) flow-mediated dilation (marker of endothelial function), (ii) c-reactive protein (marker of inflammation), and (iii) leptin (adipocytokine). Canonical pathways of relevance for childhood obesity and its phenotypes that were significantly associated with the BMI-related DEGs affected immune cell function/inflammation, vascular health, metabolic function, and cell survival/death; several immune and inflammatory pathways overlapped across the three phenotypes. We have identified transcriptome-based biomarkers associated with BMI in vitamin D-deficient, overweight and obese black children. Modulating effects of vitamin D supplementation on these biomarkers and their related phenotypes need further exploration.

Objective: Type 1 diabetes (T1D) and rheumatoid arthritis (RA) are autoimmune diseases. It is known that certain genetic loci and factors that increase the overall autoimmunity risk can be shared among different autoimmune diseases. We sought to replicate seven T1D-related SNPs (single nucleotide polymorphisms) that have been previously reported to be associated with RA susceptibility in a small set of mixed family-based and case-control Pakistani sample in a relatively large and independent RA case-control sample from the same population. Seven T1D-associated SNPs (GLIS3/rs7020673, BACH2/rs11755527, SKAP2/rs7804356, GDSMB/rs2290400, C6orf173/rs9388489, LOC399716/rs947474 and DLK1-MEG2/rs941576) were genotyped in a large Pakistani RA case-control sample (n = 1959) using TaqMan ® SNP genotyping assays., Results: None of the tested SNPs showed statistically significant association with RA susceptibility; however, one SNP (GLIS3/rs7020673) showed a trend for association (OR = 0.88, p = 7.99E-02). Our study has failed to replicate the previously reported association of seven T1D-associated SNPs with RA risk in a large sample from the same population. Thus, our results do not support a major role of these T1D SNPs in affecting RA susceptibility in the Pakistani population.

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65-93 years old). We found that men and women showed different associations between Aβ load and hippocampal functional connectivity. During associative memory encoding, in men greater Aβ burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aβ burden. For resting-state data, the interaction of gender × Aβ on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest-based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aβ load in men and was negatively correlated with Aβ load in women. The observed Aβ-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women., (Copyright © 2018 Elsevier Inc. All rights reserved.)