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IntroductionClinical 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.MethodsThe 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.ResultsACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception.DiscussionACAD'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.HighlightsThe 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.

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Background: Asian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer's disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer's Disease (ACAD), the first large dementia genetics cohort currently focuses on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: The ACAD pilot study has 7 recruiting sites (5 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and a centralized data management system in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure the protocol consistency, ACAD implemented a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. Result: As of December 2022, ACAD's pilot study has consented 606 participants, 527 participants have complete DCP data submitted to REDCap (448 Chinese, 54 Korean, and 25 Vietnamese), and more than 1,500 people have expressed interests in ACAD. The majority 66.2%)women. The age range of the sample is 60‐93 years. 47.3% have college or graduate level education. 451 participants provided a saliva (274) or a blood (177) sample. Feedback in pilot indicates a need to adapt the Early Life Enrichment inventory further to apply to wartime deprivation conditions for this population, as well as more cultural tailored neuropsychological tests. Conclusion: ACAD has learned valuable experience in interactions with ASACs and shown the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on minority, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. [ABSTRACT FROM AUTHOR]

Background: As the first large Alzheimer's Disease (AD) genetics cohort for Asians in the United States and Canada, the Asian Cohort for Alzheimer's Disease (ACAD) has adapted existing instruments to collect data on sex, genetics, medical history, and lifestyle risk factors. We hypothesize that any and all of these factors impact AD risk differently for Asians. Initially ACAD focuses on US and Canadian participants of Chinese, Korean, and Vietnamese ancestry. Method: ACAD's Clinical Workgroup reviewed commonly used dementia research questionnaires, including the NACC Uniform Data Set, Religious Order Study, and NIA‐Late‐Onset AD to select, and in some cases adapt, questions that are most appropriate for ACAD. A combination of AD clinical researchers and community outreach specialists reviewed the data collection packet, administration procedures, and consensus diagnosis process for cultural sensitivity without sacrificing scientific rigor to gather non‐genetic and lifestyle risk factor data. Result: We designed the ACAD Data Collection Packet (DCP) to create a friendly dialogue with participants through a socio‐culturally and linguistically sensitive 3‐part process. The DCP consists of some instruments already validated in Chinese, Vietnamese and Korean languages to screen for cognitive impairment (Cognitive Abilities Screening Instrument (CASI) and Modified Mini‐Mental State (3MS)). Part A collects origins, Mediterranean diet compliance, and Clinical Dementia Rating scores. The self‐administered Part B uses an adaptation of the Rush Cognitive Activity Questionnaire on early‐life enrichment. Part C structures the collection of medical history and cognitive testing with CASI vs 3MS, the Common Objects Memory Test, Category (not Letter) Fluency, and the 15‐item Clock Drawing Task. This assessment is designed to be administered either remotely or face to face. Conclusion: Over the next year, we will pilot the ACAD Data Collection Packet, to set a community standard for dementia screening among Asian Americans and Canadians that can support data harmonization across epidemiological studies. While ACAD translation accommodates Chinese, Korean, and Vietnamese at this stage, we look forward to implementing additional major Asian languages. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Variant Portal (ADVP, https://advp.niagads.org) is a curated and harmonized interactive platform providing the research community with a unified way to access and visualize the largest up‐to‐date collection of Alzheimer's disease (AD) genetic findings from >200 genome‐wide association studies (GWASs). In this study, we aim to characterize the regulatory roles and mechanisms underlying these genetic signals in AD. Methods: We analyzed all Caucasian genome‐wide significant signals in ADVP (348 genetic variants and 186 loci) using FILER (Kuksa et al., 2021) and SparkINFERNO (Kuksa et al., 2020). The SparkINFERNO high throughput system analyses framework is coupled with the FILER (https://lisanwanglab.org/FILER), a rich resource of >50,000 harmonized functional genomic datasets across many different sources including ENCODE, FANTOM5, GTEx, Roadmap, DASHR2 and others. With this systematic, hypothesis‐free analysis approach, we analyzed and ranked relevant tissue categories by quantifying the significance and enrichment of tissue‐specific enhancer overlaps with ADVP variants compared to the empirical overlap distribution for matching background (non‐AD) variants. Further integration with the AMP‐AD expression quantitative trait loci (eQTL) datasets from three brain regions (dorsolateral prefrontal cortex, cerebellum and temporal cortex), enable us to discover the potentially causal genes affected by these variants. Results: The ADVP variants were enriched in regulatory elements profiled by FANTOM5 and Roadmap Epigenomics (ChromHMM). Top tissues enriched in Roadmap enhancers include blood (OR=3.7), digestive (OR=3.5), brain (OR=2.8), and skeletal muscles (OR=2.6). 31% of the analyzed ADVP variants were identified as significant eQTLs in at least one of the three AMP‐AD eQTL datasets (FDR<0.01), and 32% among these were eQTLs in all three brain regions. Altogether, these variants targeted 130 genes (including HLA regions), of which 31 were also the nearest genes reported in ADVP. These target genes (e.g. ACE, PVR, KANSL1, NARS2) were enriched in cell junction organization, DNA repair (nucleotide‐excision repair) and acetyltransferase activity (cholinergic system), which recapitulated some of the molecular and cellular mechanisms underlying the pathogenesis of AD. Conclusions: Conducted analysis of genetic associations across >200 GWASs in ADVP and identified known AD culprit genes, relevant tissue/cell type categories, and regulatory mechanisms. [ABSTRACT FROM AUTHOR]

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud-based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimer's disease.

To better capture the polygenic architecture of Alzheimer's disease (AD), we developed a joint genetic score, MetaGRS. We incorporated genetic variants for AD and 24 other traits from two independent cohorts, NACC ( n = 3,174, training set) and UPitt ( n = 2,053, validation set). One standard deviation increase in the MetaGRS is associated with about 57% increase in the AD risk [hazard ratio (HR) = 1.577, p = 7.17 E-56], showing little difference from the HR for AD GRS alone (HR = 1.579, p = 1.20E-56), suggesting similar utility of both models. We also conducted APOE-stratified analyses to assess the role of the e4 allele on risk prediction. Similar to that of the combined model, our stratified results did not show a considerable improvement of the MetaGRS. Our study showed that the prediction power of the MetaGRS significantly outperformed that of the reference model without any genetic information, but was effectively equivalent to the prediction power of the AD GRS., Competing Interests: C-LL would like to note that the analysis in this manuscript was conducted during his stay at the University of Pennsylvania any opinion expressed in the manuscript does not reflect the view of the Analysis Group. 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 © 2023 Clark, Fu, Liu, Ho, Wang, Lee, Chou, Wang and Tzeng.)