The Biofluid Biomarkers Best Practices Workgroup of the National Alzheimer's Coordinating Center-Alzheimer's Disease Research Center (ADRC) Biomarker Core Steering Committee was convened to update pre-analytical handling guidelines for biofluid biomarkers, focusing on cerebrospinal fluid (CSF) and blood. We reviewed current literature pertinent to best practices for biomarker studies and surveyed the ADRCs for biomarker analytes, platforms, and protocols used at each center. Across 37 ADRCs, 16 CSF and 28 plasma/serum analytes were reported to be studied at multiple centers. The pre-analytical handling steps and concerns related to each, as supported by empirical studies and expert opinion, were integrated to generate a revised guideline document. The guideline aimed to standardize steps in biospecimen and biomarker analyte collection, storage, and pre-analytical handling across the ADRCs. The 2025 ADRC guidelines represent the current working knowledge on biomarker best practices, providing guidance and harmonized protocols, and promoting robust analysis and reporting of composite data.

Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

ABSTRACT Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementias marked by progressive declines in behavior, cognition, and/or movement. FTLD neuropathologies, including TDP-43 proteinopathies and primary tauopathies, do not have reliable fluid biomarkers for in-vivo diagnosis nor biomarkers that directly correspond to FTLD clinical features. Fluid biomarkers that forecast and track FTLD clinical progression, irrespective of pathology or clinical syndrome, are urgently needed to improve clinical trial designs. We previously identified the ratio between two cerebrospinal fluid (CSF) synaptic proteins, YWHAG and NPTX2, as a prognostic biomarker of cognitive decline in Alzheimer’s disease (AD), independent of core AD pathologies, amyloid and tau. Here, we evaluate its utility in sporadic and familial FTLD compared to other neurodegenerative diseases. Using CSF assays from four independent cohorts (UCSF-MAC, ALLFTD, GENFI, PDBP), we find CSF YWHAG:NPTX2 is substantially elevated across all sporadic and familial FTLD syndromes, AD, and dementia with Lewy bodies. CSF YWHAG:NPTX2 robustly correlates with clinical severity across sporadic and familial FTLD ( C9orf72 , GRN , or MAPT mutations), independent of current gold-standard neurodegeneration biomarker neurofilament light (NfL). In presymptomatic familial FTLD, CSF YWHAG:NPTX2 is estimated to rise roughly a decade before symptom onset and improves prediction of imminent symptomatic conversion by 1.7-fold compared to plasma NfL alone, more than halving the estimated sample size required for an FTLD prevention clinical trial. These findings underscore CSF YWHAG:NPTX2 as a cross-dementia synaptic biomarker of cognitive decline and a promising biomarker for disease staging and prognosis across the clinico-pathological continuum of FTLD.

Background and Objectives:Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods:This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results:Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion:C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

The ADSP is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD). Initial phases (Discovery and Discovery Extension) were predominantly non-Hispanic Whites of European Ancestry (NHW-EA). The ADSP expanded the population diversity in the Follow Up Study (ADSP-FUS), and the current phase, ADSP-FUS 2.0: The Diverse Population Initiative, focusing on whole genome sequencing (WGS) of non-European populations including Hispanic/Latino (HL), non-Hispanic Black with African Ancestry (NHB-AA) and Asian populations. Support for these efforts include newly funded initiatives such as The DAWN Project, focused on recruitment of African, African-American and Hispanic American populations, and the Asian Cohort for Alzheimer’s Disease (ACAD). ADSP cohorts consist of studies of AD, dementia, and age-related conditions. Clinical classifications are assigned based on standard criteria and derived from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, APOE genotyping is available for all ADSP samples. The ADSP currently consists of 40 cohorts comprised of ∼36,300 individuals, with plans to sequence >110,000 individuals from diverse race/ethnicity. Genotyping, sequencing, and clinical adjudication has been performed on 36,361 participants (cases N = 12,133, median age = 72; cognitively-unimpaired(CU) individuals N = 17,116, median age = 74; ADRD N = 7,112, median age = 71). Mean ages for cases and controls vary across cohorts, 57.0+5.6 to 86.5+4.2 cases and 63.3+7.8 to 90.0+0 controls. 61% participants female, distributed as follows: cases(60.3%), CU(63.7%), and ADRD(55.8%). APOE genotype proportions differ considerably across reported race/ethnicity, for example highest for APOE ε 4/ ε 4 carriers observed in Non-Hispanic whites participants (7.4%) and the lowest in Asians (1.7%) The results provide an overview of clinical features in ADSP cohorts. The growth of the ADSP-FUS 2.0 is central to the ADSP and expanding the size and diversity of this genomic resource available via NIAGADS. WGS data will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP-FUS 2.0 will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.

NCRAD is a National Institute on Aging (NIA) cooperative grant, awarded to Indiana University since 1990, whose purpose is to serve as a biorepository for AD/ADRD researchers. With 74 participating across 150 unique institutions, NCRAD links specimens to clinical research data. NCRAD maintains over 2 million aliquots from more than 126,000 research participants spanning a wide range of AD/ADRD related phenotypes as well as healthy controls. To ensure standardization and uniformity, NCRAD develops a manual of procedures specific to each study protocol that includes detailed pictures, schematics, and flow charts for each sample type collected. NCRAD conducts web-based training for site staff and provides supplemental training videos to ensure Researchers receiving samples from NCRAD agree to share the data generated from the samples. Since its inception, NCRAD has distributed over 410,000 samples to more than 200 researchers. NCRAD biospecimens and data have been reported in more than 850 publications. NCRAD’s mission is to maintain uniformity in collection and processing of samples sites involved in each study. Centralized biobanking and broad sharing of biospecimens has accelerated research discovery. Using standardized biospecimen collection, processing, shipping, storage, and distribution procedures established at NCRAD, in conjunction with attention to detail, strict compliance with regulations, and oversight from the NIA, has resulted in a biorepository with highest quality samples available to researchers investigating the etiology, early detection and therapeutic development for AD/ADRD.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Late-Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short-read WGS, combined with Sniffles2 calls from 4 ONT-sequenced genomes and an external SV call set from HGSVC on 32 PacBio-sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project-level VCF. We identified 45,251 insertions and 76,566 deletions genome-wide. Variants were tested for segregation and pathogenicity using Annot-SV, cadd-SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

The National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) is continuing to develop a bank of induced pluripotent stem cells (iPSCs) that are available by request to the Alzheimer’s disease (AD) research community. As part of the pipeline for quality control of received cell lines, DNA was extracted for all lines and was submitted for whole genome sequencing (WGS). Paired-end WGS data was generated using the Illumina NovaSeq 6000 and processed following GATK best practices using the Sentieon pipeline. WGS data was annotated with Annovar, and data was reviewed for reported cell line variants and checked with Varsome and Franklin. Sequencing data was reviewed for all nonsynonymous and splicing variants in the APP , PSEN1 , PSEN2 , GRN , and MAPT genes. Additionally, DNA from cell lines was genotyped in-house by NCRAD to generate apolipoprotein E (APOE) genotypes, and this data was compared with the WGS to confirm sample identity. Basic clinical and demographic data was also collected, including sex, case/control status, age, race, and ethnicity. To date, DNA has been extracted and genotyped at NCRAD for lines from 183 participants including generation of APOE genotypes passing quality control. Of these, 120 cell lines have returned WGS data passing quality control. Table 1 describes the demographic and clinical features for these lines, which include data for lines from 90 individuals as well as data for 30 isogenic lines. Of the 120 lines with available WGS, there are 13 case APP variant carriers, 13 case MAPT variant carriers, 8 case PSEN1 variant carriers, and 2 case PSEN2 variant carriers. Additionally, these cell lines included two control carriers of variants of uncertain significance (VUS) in GRN or PSEN2 , as well as two cases carrying VUS in PSEN1 or APP . NCRAD continues to expand iPSCs for the research community; adding WGS data to this resource provides an expanded scope for pre-screening as well as functional research. Future directions include review of variants being tested in the Model Organism Development & Evaluation for Late-Onset AD (MODEL-AD) to provide additional value to researchers.

The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) was established in 2002 to support research on the genetics of Alzheimer's disease. NCRAD quickly became a central resource, banking samples from numerous studies and distributing them to researchers worldwide. As genetic risk variants were identified, NCRAD prepared for functional studies by expanding its collections to include peripheral blood mononuclear cells (PBMCs), RNA, and biofluids. Over the past decade, NCRAD's extensive repository of plasma, serum, and cerebrospinal fluid was essential to the development of fluid biomarkers. NCRAD's rigorous best practices for sample collection, processing, and distribution ensure biospecimens are of the highest quality for a broad range of experimental approaches. Currently, NCRAD banks samples from 91 studies representing over 135,000 unique, well-characterized participants, and has distributed over 440,000 aliquots to more than 300 researchers. Data from NCRAD-supported studies have contributed to over 1100 publications and numerous key discoveries in Alzheimer's disease and related dementias (ADRD) genetics and biomarkers. HIGHLIGHTS: Centralized Biobanking for ADRD Research: National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports over 90 National Institute on Aging (NIA) -funded studies by providing standardized, high-quality biospecimens and longitudinal sample collections, enabling reproducible and scalable research into Alzheimer's disease and related dementias (ADRD). Enabling Genetic Discovery and Functional Genomics: NCRAD partnerships with numerous research initiatives has facilitated major advances in gene discovery, while also supporting downstream functional studies using induced pluripotent stem cells (iPSCs), transcriptomics, and post mortem brain tissue. Rigorous QA/QC and Automation Infrastructure: NCRAD employs comprehensive quality assurance/quality control (QA/QC) systems and cutting-edge automation-including robotic liquid handling, automated nucleic acid extraction, and ultra-low temperature storage-to ensure biospecimen integrity and reduce preanalytical variability. Unique Sample Distribution and Data Sharing Model: NCRAD's blinded sample distribution system and emphasis on returning data to public repositories ensure broad research access, maximize scientific output, and promote transparency and reproducibility. Collaborative, Scalable Repository Ecosystem: As part of Indiana University's integrated biobanking infrastructure, NCRAD supports efficient cross-study and cross-repository research, enabling large-scale multi-omic and biomarker analyses across diverse neurodegenerative diseases.

Biorepositories play an integral role in the advancement of our understanding of neurodegenerative diseases and improving human health outcomes. Research efforts are accelerated when access to high-quality clinical specimens is made available from a large, diverse participant group. Indiana University is home to three important neurodegenerative disease-focused biorepositories including the NIA-funded National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), the NINDS-funded Biospecimen Exchange for Neurological Disorders (BioSEND), and the Michael J. Fox Foundation (MJFF) biorepository. Having all three repositories in one location presents a unique opportunity to leverage common protocols and shared resources to provide researchers with access to a wide breadth of specimens, facilitating broad specimen sharing and standardization across studies and repositories. All three repositories provide exceptional data and study coordination, data management, scientific support, and technical resources. Uniform best practice standard operating procedures (SOPs) and materials for collection and processing of samples yield consistently high-quality specimens across studies from all repositories. Banked specimen types include DNA, RNA, whole blood, plasma, serum, cerebrospinal fluid, urine, stool, brain tissue, peripheral blood mononuclear cells (PBMCs), fibroblasts, and induced pluripotent stem cells (iPSCs). Online catalogs are available for specimen selection along with project management that can assist in the selection and approval of specimens across studies and repositories. Among the three repositories, over 4 million specimen aliquots from more than 150 studies have been banked. This collection represents over 142,000 unique participants across a diverse array of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Lewy Body Dementia, Concussion, Traumatic Brain Injury, Huntington’s Disease, Spinocerebellar Ataxia and other neurodegenerative proteinopathies. More than 600,000 specimen aliquots have been distributed to over 370 investigators, resulting in almost 1,000 publications. NCRAD, BioSEND, and MJFF serve as crucial resources for investigators requiring high-quality clinical specimens collected and processed in accordance with best practice SOPs. The centralized location at Indiana University provides the opportunity to synergize and align common study objectives to provide shared resources with broader sample diversity, increased statistical power, improved reproducibility, and enhanced opportunities for broad specimen sharing, thereby fostering collaborative research initiatives.

BACKGROUND:Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer's disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling. METHODS:Using genome sequencing data from 197 families in The NIA Alzheimer's Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS:Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of families APOE-e4 was the only variant segregating. However, in 60.3% of families neither APOE-e4 nor missense or LoF variants were found within the GWAS loci. DISCUSSION:Although APOE-ε4 and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.

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.

The iDA Project (iPSCs to Study Diversity in Alzheimer’s and Alzheimer’s Disease-related Dementias) is generating 200 induced pluripotent stem cell lines from Alzheimer’s Disease Neuroimaging Initiative participants. These lines are sex balanced, include common APOE genotypes, span disease stages, and are ancestrally diverse. Cell lines and characterization data will be shared openly.

INTRODUCTION:Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS:The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS:ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION:ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS:The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non-Hispanic Whites of European Ancestry (NHW-EA) populations. Given the lack of diversity in the ADSP, the ADSP-FUS was designed to whole genome sequence (WGS) existing ethnically diverse and unique cohorts. The upcoming phase ADSP- FUS 2.0: The Diverse Population Initiative, focuses on inclusion of Hispanic/Latino (HL), non-Hispanic Black with African Ancestry (NHB-AA), and Asian populations. ADSP-FUS cohorts consist of studies of AD, dementia, and age-related conditions. Clinical classifications are assigned based on standard criteria from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, genome-wide array and APOE genotyping is acquired or performed for all ADSP-FUS samples. The ADSP-FUS currently consists of 38 cohorts comprised of ∼40,000 individuals, with plan to sequence >100,000 individuals from diverse ancestries. Genotyping, sequencing, and clinical adjudication has been performed on 23,428 participants (cases N = 6,961, median age = 73; controls N = 13,007, median age = 72; ADRD N = 3,460, median age = 77. More participants are female (62.3%) than male and are evenly distributed across cases (61.0%), controls (63.1%), and ADRD (61.8%). As expected, the most prevalent APOE genotype is APOE 3/3 (% by cases/controls for 2/2 = 0.2,0.4; 2/3 = 4.3, 8.2; 2/4 = 2.2, 1.8; 3/3 = 43.8, 64.4; 3/4 = 39.5, 23.0; 4/4 = 10.1, 2.2). These proportions vary greatly between ethnicities, with the highest for APOE 4/4 observed in Asian participants (8.8%) and the lowest in Hispanic participants (2.5%), for example. Mean Braak stage for AD cases is higher (5.1+1.2) than controls (2.6+1.3) and ADRD participants (3.5+1.6). The results provide an overview of features of ADSP-FUS cohorts. As the ADSP-FUS expands in size and diversity, this genomic resource, available via NIAGADS, will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP-FUS will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.

Much of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cognitive impairment may carry pathogenic, potentially causative variants in Parkinson’s disease (PD) genes. Whole exome sequencing data for cognitively impaired LEADS participants (N = 301) was processed using the GATK best practices pipeline with Sentieon software; joint-called VCFs were annotated with Annovar, and the results were filtered to prioritize amino acid code-altering variants with minor allele frequencies <1% that have not been reported as benign or likely benign in ClinVar. Variants in the acid beta-glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), Parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN-induced putative kinase 1 (PINK1), protein kinase, interferon-inducible double-stranded rna-dependent activator (PRKRA), and Parkinson disease 7, autosomal recessive early-onset (PARK7) were reviewed. Heterozygous or homozygous carriers of variants meeting these criteria in GBA and LRRK2, as well as homozygous or potentially compound heterozygous variant carriers in the other genes, were reviewed for the presence of PD-related symptoms documented with the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected at baseline (N = 283). There were no variants meeting inclusion criteria for PINK1, PARK7, PRKN, or PRKRA. However, we observed 21 individuals with predicted or reported functional variant(s) in GBA or LRRK2. The mean screening visit age for these carriers was 59 (range 53-64), and all but two were amyloid positive. While only one case was documented with motor symptoms, several participants had peripheral nervous symptoms such as neuropathy. 17 carriers had amnestic-type dementia, with similar frequency to non-carriers. While there are a small subset of individuals carrying functional variants in PD genes, they do not appear to substantially influence the phenotype of most cases at baseline. Future planned research efforts include assessing alpha synuclein pathology via alpha synuclein seeding assays, which will help clarify the potential role of mixed genetic etiology and pathology in risk for non-familial early onset dementia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.