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Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the CD33 locus. It has been determined that the risk variant associated with AD increases the expression of the large isoform of CD33 (CD33M) in innate immune cells and alters its biological functions. CD33 is thought to signal via the interaction of its ITIM motif and the protein tyrosine phosphatase, SHP-1. Here, we utilize different molecular and computational approaches to investigate how AD-associated genetic variation in CD33 affects its interaction with SHP-1 in human microglia and microglia-like cells. Our findings demonstrate a genotype-dependent interaction between CD33 and SHP-1, which may functionally contribute to the AD risk associated with this CD33 variant. We also found that CD33-PTPN6 (SHP-1) gene–gene interactions impact AD-related traits, while CD33-PTPN11 (SHP-2) interactions do not. [ABSTRACT FROM AUTHOR]

ZCCHC17 is a putativemaster regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data fromhuman autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, amajority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. [ABSTRACT FROM AUTHOR]

Background: Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remain inconsistent in aging research. Objective: To determine the reliability and validity of the most frequently self-reported vascular risk factors: hypertension, diabetes, and heart disease. Methods: 1,870 individuals aged 65 years or older among African Americans, Caribbean Hispanics, and white non-Hispanic individuals were recruited as part of a community study of aging and dementia. We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use. The analyses were subsequently stratified by age, sex, education, and ethnic group. Results: Reliability of self-reported hypertension, diabetes, and heart disease was excellent. Agreement between self-reports and clinical measures was moderate for hypertension (kappa: 0.58), good for diabetes (kappa: 0.76–0.79), and moderate for heart disease (kappa: 0.45) differing slightly by age, sex, education, and ethnic group. Sensitivity and specificity for hypertension was 88.6% –78.1%, for diabetes was 87.7% –92.0% (HbA1c ≥6.5%) or 92.7% –92.8% (HbA1c ≥7%), and for heart disease was 85.8% –75.5%. Percent agreement of self-reported was 87.0% for hypertension, 91.6% –92.6% for diabetes, and 77.4% for heart disease. Conclusion: Ascertainment of self-reported histories of hypertension, diabetes, and heart disease are reliable and valid compared to direct measurements or medication use. [ABSTRACT FROM AUTHOR]

Objective: To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods: Genotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers. Results: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older. Interpretation: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐β plaques and tau neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD). Previously, genetic studies on amyloid‐β mediated AD pathogenesis dominated the field, and genetic studies on tau pathology are limited by comparison. Prior studies suggest that the spread of tau neurofibrillary tangles within the medial temporal lobe occurs following abnormal deposition of amyloid‐β, leading to cognitive impairment. Although amyloid‐β and tau both play a role in AD pathogenesis, exact genetic pathways associated with them are still unknown. Method: We performed genome‐wide association study (GWAS) with brain Tau standard uptake value ratios (SUVRs) measured from positron emission tomography (PET) images from the A4 ((N = 311 with preclinical AD;female = 62%;tau mean‐SUVR = 1.076±0.06) and ADNI studies (N = 375‐280 cognitively normal, 76 mild cognitively impaired and 19 AD;female = 53%;tau mean‐SUVR = 1.12±0.13). Models were adjusted for age, sex and APOE‐ε4 dosage. Additionally, we evaluated the association of amyloid‐β and tau SUVRs with AD polygenic risk scores (PRS). PRS was calculated using genome‐wide variants, excluding 1MB region flanking APOE, and effect sizes from Kunkle et al GWAS study of clinical AD. Result: Analysis of tau‐SUVR in 686 participants, identified five genome‐wide significant loci: rs78636169 (P = 1.37×10−9) in JARID2, rs114272033 (P = 7.87×10−9) in ISCA1P2, rs7292124 (P = 1.73×10−8) in RP1‐272J12.1, rs114742337 (P = 2.85×10−8) in RP4‐771M4.2, and rs138338441 (P = 3.91×10−8) in AC092684.1. Rs13412014 in AC007364.1 and rs9393067 in RP11‐314C16.1 were also associated with amyloid‐SUVR in a previous large GWAS. Two loci previously associated with clinical AD in a recent large GWA study, INPP5D (rs10933431) and SEC61G (rs76928645), were also nominally associated (P<0.05) with tau deposition in our study. Genes associated with Tau‐SUVR are enriched in the Schaffer axonal collaterals (P<1×10−05) that form synapses in hippocampus. Genome‐wide PRS of AD (excluding APOE region) was strongly associated with amyloid‐SUVR (P = 3.21×10−11;R2 = 0.077) but only weakly associated with tau‐SUVR (P = 1.38×10−04;R2 = 0.027). We are in the process of replicating our results in an independent cohort of 700 participants with measurements of tau deposition. Conclusion: We identified five novel genetic loci associated with tau pathology. Several genes involved in tau deposition were also associated with amyloid load in the brain. Taken together, our findings will clarify the genetic pathways that effect both amyloid and tau pathology in AD. [ABSTRACT FROM AUTHOR]

Background: Recent studies increased the number of genes that are associated with the co‐existence of vascular pathologies and Alzheimer's disease (AD). However, the biological functions and the mechanism of action by which they contribute to the disease pathology are still to be further elucidated. Therefore, animal models that allow streamlined large‐throughput functional screens in a biologically relevant manner are essential. Towards this goal, we generated adult zebrafish models of amyloid toxicity to functionally analyze candidate genes and how they relate to disease perturbations. Method: Through cerebroventricular injection of human amyloid‐beta42 monomers into the cerebrospinal fluid of the adult zebrafish brain, we inflict acute amyloid toxicity. By performing immunohistological analyses, single cell transcriptomics, gene editing for generating gene variants or full knockouts, transient functional knockdown of candidate genes, pharmacological intervention of selected signalling pathways and comparing the findings to human AD brain transcriptomics datasets, we determined the similarities and differences of the effects of amyloid pathology on the vasculature in zebrafish in relation to the human conditions. Results: We found that amyloid pathology in zebrafish brain shows histological and molecular similarities to human brains. Integration of single cell transcriptomics showed remarkable similarities in neurons to amyloid in humans and zebrafish. We identified several molecular mechanisms that underlie this pathology‐induced cellular response and translated to mammalian models including rodent brains. By performing genome‐wide association in AD patients, we identified that the FMNL2 links cerebrovascular disease and AD, by regulating the astroglial and blood vessel interactions and controlling the efficient clearance of toxic proteins from the brain. Our new single cell transcriptomics analyses of the gliovascular niche cells of the zebrafish brain revealed potential cellular interactions and the pathways perturbed in vascular disease and AD. Conclusion: We propose zebrafish as a useful model for functional investigation of vascular pathology and AD‐related genes identified in clinical studies by providing in vivo biological knowledge on disease mechanisms, on which novel drug development strategies can be based. [ABSTRACT FROM AUTHOR]

Background: Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer's disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alterations observed in AD brains are also detected in blood from living patients is unknown. Further, these GVU molecular perturbations require further investigation in different model systems to identify both human brain‐specific and cross‐species conserved alterations. In this study, we investigated prioritized GVU molecules altered in AD brains for their conservation in blood and cross‐species model systems. Methods: We performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in AD and control brains. We analyzed this data to detect cell‐specific GVU molecular perturbations and their interactions. We investigated molecular interactions between vascular and astrocyte clusters, the major cell types of the GVU of the BBB. To determine whether GVU transcriptional alterations detected in the brain are preserved in the blood, existing blood expression, genetic, and neuroimaging data from two longitudinal antemortem cohorts were analyzed. Using model systems, including mouse, drosophila, and zebrafish, we evaluated the cross‐species conservation of the top GVU alterations detected in AD brains. Results: Brain snRNAseq revealed transcriptional profiles of 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as pericytes, endothelia and perivascular fibroblasts. We identified differentially expressed genes and their enriched pathways within these clusters and observed the highest levels of transcriptional changes within pericytes. Vascular targets that interact with astrocytic ligands have biological functions in cell signaling, angiogenesis, amyloid ß metabolism, and cytoskeletal architecture. We discovered that genetic variants influencing blood expression levels of some of the prioritized GVU genes were associated with neuroimaging burden of cerebrovascular disease in living human cohorts. Our ongoing studies in model systems revealed conservation of some of the top prioritized molecular perturbations across species. Conclusion: Our findings prioritized by multiscale, cross‐tissue human data revealed GVU perturbations within interacting pericyte and astrocyte molecules, which are conserved across multiple cross‐species models. These results nominate new molecular targets and mechanistic insights for BBB disruptions in AD. [ABSTRACT FROM AUTHOR]

Background: Cardio and cerebrovascular diseases co‐exist in up to a third of the Alzheimer's disease (AD) patients, and the presence of cardiovascular/cerebrovascular risk factors (CVRFs) are associated with the risk of AD in middle age and later. The relationship between CVRFs such as hypertension, body mass index, diabetes and coronary heart disease, and AD is well known, but there has been limited mechanistic evidence directly linking these vascular risk factors in AD to the presence of ischemic microvascular pathology. Each of these vascular factors has the capacity to impair the blood‐brain barrier and glio‐vascular units. Arterial pulses and flow are required for glymphatic clearance of molecules including amyloid β. Few studies have directly linked genetic variation related to the risk factors and the molecular mechanisms underlying the interplay of CVRF and genetics in AD. APOE plays a role in the metabolism of cholesterol and other lipids in the brain. Other genetic variants that have been found to interact with cardio and cerebrovascular risk factors include the CLU, PICALM, CR1, BIN1, ACE, AGT, and ALDH2. Methods: We analyzed several large multi‐ethnic AD cohorts to understand the role of cardiovascular risk in the disease. We created a CVRF score comprised of hypertension, diabetes, heart disease and body‐mass‐index and tested the interaction of the score with genetic variants in conferring risk of AD. Results: We found that genetic variants in FMNL2, BRINP1, RFC2, and IGFN1 interact with enhanced risk score for CVRFs, to modify the risk of developing AD. FMNL2 and BRINP1 brain expression is increased in patients that have pathological hallmark of AD and have chronic infarcts. Causal mediation analysis found that both amyloid and tau pathology increased FMNL2 expression which in turn resulted in higher risk of AD, suggesting that AD brains enhance the activity of this gene. Conclusions: We propose that that FMNL2 is part of a larger set of genetic and molecular network that underlies the interaction between CVRF and AD. Clinical studies and basic science with animal models could be harmonized to discover new disease mechanisms, which could open new clinical directions and drug development efforts. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to identify additional genes that contribute to the interaction between CVRFs and AD. Method: A collection of eight multi‐ethnic cohorts was explored to study genome‐wide gene‐CVRF score interaction analysis for AD, in 7,441 AD patients and 10,453 controls. The cardiovascular risk factors score (CVRF score) was created from a first principal component of the four vascular risk factors; self‐reported history of hypertension, diabetes, and heart disease, and measured body mass index. Gene‐based interaction test was performed using the adaptive gene‐environment interaction (aGE) test. Results were summarized using a meta‐analysis. We investigated the association of gene expression with pathological AD and AD phenotype (amyloid‐β, tau, or brain infarcts) in 1,092 samples from the frontal cortex in ROSMAP. The pathway enrichment analysis was performed on the differentially expressed genes. Age and sex were adjusted in the models. Result: The previous interaction of CVRF score with FMNL2 (p = 3.64e‐07) was strengthened and additional genes were identified including BRINP1 (p = 2.45e‐06), CFAP99 (p = 3.3e‐06), and PRG3 (p = 3.71e‐06). FMNL2 encodes a formin‐related protein important in regulating actin and microtubules. FMNL2 and BRINP1 expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006, respectively). The expression level of BRINP1 interacted with brain infarcts on pathological AD (p = 0.02) and with amyloid‐β or tau on brain infarcts (p = 0.02 and p = 0.01, respectively). The pathways were relevant to cellular interactions between astrocytes and endothelia as well as the immune system reaction in the glio‐vascular niche. Conclusion: The four novel genes are likely to be involved in the complex interaction between Alzheimer's disease pathologies (amyloid and phosphorylated tau deposition) and cerebrovascular pathology, for example, at the glia‐vascular interface during AD progression. Understanding how these genes interfere with the mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain will be essential. [ABSTRACT FROM AUTHOR]

In order to provide a comprehensive evaluation of the non‐genetic factors involved in the development of Alzheimer's disease and related disorders it is necessary to develop a systematic process to capture the range of environmental and social influences. Exposomics has emerged as an approach to do this. Using high‐resolution mass spectrometry and geospatial techniques it is possible to evaluate thousands of external factors (chemical, nutritional, social, environmental) and their corresponding impact on biology. In this presentation, we will describe the steps we are taking to build the required infrastructure. The first aspect is to improve the identification of exogenous and endogenous chemical features by expansion of our high‐resolution mass spectrometry capabilities (automated liquid handling with ThermoFisher Orbitrap‐based technology: HFX, LC‐Exploris 240, GC‐Exploris 240, and IQX Tribrid Mass Spectrometer). We are in the process of analyzing thousands of samples from WHICAP, EFIGA, and RANN using our combined LC/GC Orbitrap platform, to identify significant associations with disease traits (existing and next generation biomarkers, pathology, imaging, clinical features). Initial results from these studies will be presented to demonstrate feasibility of the approach. We have also initiated a series of pilot studies for other AD cohorts, which cover a range of populations with diverse ethnicity, disease stage, and age. These studies have extensive clinical phenotyping and deep molecular phenotyping. The addition of exposomics will leverage these existing studies to uncover novel environmental contributors to AD. We also also developing a platform to distribute workflows via an online EXCEL AD Community Dashboard to other ADRCs and AD research groups interested in incorporating exposomics into their studies. We will also provide guidance on quality control materials, including providing standards as needed. The Community Dashboard would also compile information on ongoing AD studies that are incorporating exposomics, as well as relevant publications. Various tools will be developed to encourage the utilization of this new platform such as user manuals, training programs (in‐person, online) exposomics bootcamps, and scholar exchange through on‐site visits to laboratories. We will deploy an academic research consultancy that will help other interested laboratories to establish the exposomics workflow. [ABSTRACT FROM AUTHOR]

Background: Energy, amino acid, and lipid metabolism are dysregulated in Alzheimer's Disease. We investigated circulating plasma metabolites to capture systemic biochemical changes associated with Alzheimer's disease (AD) using the clinical diagnosis and followed by the addition of plasma‐based biomarkers. Method: Exogenous and endogenous metabolites in plasma were measured in 300 individuals with a clinical diagnosis of AD and 430 healthy individuals without dementia of Caribbean Hispanic ancestry using untargeted liquid‐chromatography, performed on HILIC (+ ionization) and C18 (‐ ionization) columns, coupled to a Thermo Orbitrap HF‐X mass spectrometer. Genome‐wide SNP data and plasma biomarkers including pTau181, Aβ40, Aβ42, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were obtained on all participants. Metabolite association with the clinical diagnosis of AD and for the AD biomarker, pTau‐181, levels were assessed after adjustment for age and sex. Result: More than 6000 metabolic features were measured with high accuracy in the sample. 270 metabolic features were associated with pTau‐181 levels and 66 metabolic features were associated with clinical AD status, after correction for multiple testing. Valyl‐Serine (p = 1.1e‐7) and creatinine (p = 9.6e‐7) were strongly associated pTau‐181 levels. When using a diagnostic cutoff of pTau181 levels for AD as the outcome (biological AD), we also observed significant associations with a lysophospholipid (p = 9.5e‐5). Malic acid (p = 4.2e‐4) and tryptophan (p = 3.9e‐4) were significantly associated with clinical AD status. Metabolites associated with pTau‐181 levels were enriched in glycan biosynthesis, energy, amino acid, urea cycle/amino group and carbohydrate metabolism pathways. Patients with both clinical and biological AD showed altered tyrosine and tryptophan metabolism. Conclusion: Metabolites, specifically amino acids and lipids, were associated with AD status and pTau181 levels. Metabolite profiling can identify perturbed pathways in clinical and pre‐clinical AD and integration with genome‐wide SNP data will identify mechanisms underlying genetic association with disease. [ABSTRACT FROM AUTHOR]

Background: Late‐Onset Alzheimer's Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. Short tandem repeats (STRs), which are hyper‐mutable sequences in the human genome could explain some of the missing heritability in LOAD. STRs are involved in several neuro‐degenerative disorders. We systematically evaluated the impact of 31 disease‐associated STRs on neuropathological LOAD features. Method: From whole‐genome sequencing (WGS) data in for 1,134 unrelated individuals of European ancestry from Religious Orders Study (ROS) and Rush Memory and Aging project (MAP) cohorts, we identified known pathogenic STRs in 31 loci using ExpansionHunter. WGS was generated from DNA extracted from blood and brain tissues. We tested the association of STRs with a) neuropathological LOAD status, b) beta‐amyloid levels, c) neurofibrillary tangle (NFT) burden, d) global measure of pathology based on the scaled scores of 5 brain regions and e) estimated slope of global cognition using longitudinal measurements. Regression models adjusting for age, sex and first three principal components. Subsequently, we examined if STRs influenced gene expression in dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC) and the anterior cingulate (AC) and tested if the association of STRs with neuropathological traits were mediated by altered gene expression. Result: TGC repeat in ATXN1 was associated with cognitive decline (b = ‐0.007, p = 0.014) and risk of clinical AD (b = 0.126, p = 0.03). Variation in CAG repeats in ATN1 was associated with cognition (b = 0.004, p = 0.022) and risk of pathological AD (b = ‐0.069, p = 0.035). Longer Repeats at ATXN1 increased gene expression in DLPFC (b = 0.012, p = 0.049) and PCC (b = 0.019, p = 0.006) and repeats in ATN1 altered DLPFC (b = 0.01, p = 0.016) and PCC (b = 0.01, p = 0.026) expression. Mediation analysis determined that the effect of the CAG repeats in ATN1 on tau was mediated by gene expression in PCC (p = 0.004). Conclusion: We demonstrate that disease causing STRs influence the underlying gene expression in brain and are associated with neuropathological and cognitive endophenotypes of AD. This suggests that STRs could explain some of the missing heritability in LOAD. [ABSTRACT FROM AUTHOR]

Background: Multi‐region brain transcriptomes uncover two subtypes of aging individuals with differences in the impact of APOEe4 Method: We preprocessed transcriptomic RNA sequencing profiles from three brain regions and deployed the canonical correlation analysis in the discovery set of individuals that have transcription profiles in all three regions. The subgroups of participants were identified through unsupervised k‐means clustering for each region and then integrated into "meta‐clusters" through a non‐negative matrix factorization. The clustering analysis was replicated in the remaining set of individuals that have data in only one or two of the three regions. To assess the clinicopathologic relevance of the meta‐clusters, we assessed whether clinical and pathologic features are different between the meta‐clusters by conducting a meta‐analysis of discovery and replication cohorts. We further investigated the mechanisms underlying the differences in clinical phenotypes between the two groups. Result: The clustering analysis revealed two stable subgroups of aging participants in each cohort. The empirically defined subgroups differ in their extent of the rate of cognitive decline and exhibit evidence of biological differences in the impact of APOEe4. Conclusion: These findings suggest that our population structure captures an aspect of the molecular state of the brain that affects cognition in a manner that may be independent of the underlying pathologies that accumulate with older age. [ABSTRACT FROM AUTHOR]

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes. Pathologic clustering suggests 8 subtypes within this cohort, and further analysis reveals that the previously described continuum from hippocampal predominant to hippocampal sparing is well represented in our data. Small vessel disease is overall highest in a cluster with a low hippocampal/cortical tau ratio, and across all clusters small vessel disease segregates separately from Lewy body disease. Two AD clusters are identified with extensive Lewy bodies outside amygdala (one with a high hippocampal/cortical tau ratio and one with a low ratio), and we find an inverse relationship between cortical tau and Lewy body pathology across these two clusters. Finally, we find that brains from persons of Hispanic descent have significantly more AD pathology in multiple neuroanatomic areas. We find that Hispanic ethnicity is not uniformly distributed across clusters, and this is particularly pronounced in clusters with significant Lewy body pathology, where Hispanic donors are only found in a cluster with a low hippocampal/cortical tau ratio. In summary, our analysis of recorded pathologic data across two decades of banked brains reveals new relationships in the patterns of AD-related proteinopathy, co-pathology, and ethnicity, and highlights the utility of pathologic subtyping to classify AD pathology., Competing Interests: Competing Interests: The authors declare no conflicts of interest

Background: Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD., Methods: We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses., Results: GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers., Conclusion: We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.

In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected because of the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously. Therefore, it is important to consider the role of covariates in genotype-specific distribution estimation using family history data. We propose an estimation method that permits more precise risk prediction by controlling for individual characteristics and incorporating interaction effects with missing genotypes in relatives, and thus, gene-gene interactions and gene-environment interactions can be handled within the framework of a single model. We examine performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in carriers of the LRRK2 G2019S mutation using first-degree relatives who are at genetic risk for PD. The utility of estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. Such sample size estimation is seen in the Huntington's disease literature using the length of abnormal expansion of a CAG repeat in the HTT gene but is less common in the PD literature. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)