Biobanking and Collaborative Multicenter AD Research in Africa: Preliminary Experience from the Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the Alzheimer’s Disease Sequencing Project.

Background: The burden of Alzheimer’s disease and related dementias is growing fast in Africa. The Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the Alzheimer’s Disease Sequencing Project (READD‐ADSP) has commenced recruitment of 5000 African participants (AD and cognitively unimpaired individuals) to generate genomic and biomarker data to better characterize AD genetic architecture in Africa. Participating countries, part of the African Dementia Consortium (AfDC) include Nigeria, Ghana, Benin, Cameroon, Uganda, Kenya, Ethiopia, Tanzania, and Mozambique.

Challenges of Recruiting Persons with Alzheimer’s Dementia (AD) for Genetic Studies in Selected African Countries on the African Dementia Consortium (AfDC).

Background: Understanding the genetic underpinnings of Alzheimer’s disease is crucial for advancing research and developing targeted interventions. Genomic research in dementia in Africa is of utmost importance based on recent reports from studies in African Americans that African ancestral gene is associated with lower risk effect for developing AD. However, dementia related genetic study is an evolving research in sub‐Saharan Africa with peculiar challenges influencing participant recruitment.

Disparity in Resilience: The role of educational attainment and in Alzheimer Disease in a Puerto Rican cohort.

Background: Cognitive resilience research in African Americans (AA) shows that higher educational attainment (EA) can mitigate the impact of Alzheimer disease pathology (ADP). However, this mitigating effect is less pronounced in ε4 carriers. This finding suggests a disparity in resilience influenced by an interplay of educational and genetic factors.

Biomarker‐guided clustering in an Amish population older than 60 reveals subgroups featuring distinct Alzheimer Disease pathologies.

Background: Plasma amyloid‐beta (Aβ) 42/40 ratio and phosphorylated tau 181 (pTau181) are promising blood biomarkers for AD. Compared to heterogenous clinical phenotypes, they are more objective and proximal to the pathological hallmarks of Aβ plaques and tau tangles. Biomarker‐guided clustering using Aβ42/40 and pTau181 can potentially establish subpopulations that share similar mechanisms of AD and treatment responses.

Plasma biomarkers are stable for an extended period at –20°C: Implications for resource‐constrained environments.

Background: The Recruitment and Retention for Alzheimer’s Disease Diversity Cohorts in the Alzheimer’s Disease Sequencing Project (REAAD‐ADSP) aims to explore ADRD in diverse ancestral groups within the US and nine countries from sub‐Saharan Africa. While most laboratories store plasma samples ‐80°C for biomarkers, no studies at –20°C have been reported past 2 weeks. Only two sites in Africa possess ‐80°C freezers.

APOE ε4 genotype confers risk for Alzheimer Disease in Cuban Americans.

Background: The risk of Alzheimer Disease (AD) conferred by APOE and other genetic factors differ across populations. The Cuban American (CA) population is 3‐way admixed (European, African, and Amerindian) and vastly underrepresented in genetic studies. Previous genetic studies in this population have solely focused on APOE in AD and shown conflicting results regarding its effects.

Generalizability of Alzheimer’s disease plasma biomarkers phospho‐Tau and beta amyloid in individuals of diverse genetic ancestries.

Background: Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Aβ42/Aβ40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, assessment of the utility of these biomarkers has been in non‐Hispanic, European individuals. Given differences in AD risk across populations, generalizability of these findings is not assured in individuals of diverse ancestries.

AD plasma biomarkers are stable for an extended period at -20°C: implications for resource-constrained environments.

Standard procedures for measuring Alzheimer's disease (AD) plasma biomarkers include storage at -80°C. This is challenging in countries lacking research infrastructure, such -80°C freezer. To investigate stability of AD biomarkers from plasma stored at -20°C, we compared aliquots stored at -80°C and others at -20°C for two, four, six, fifteen, and thirty-five weeks.

Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.

Introduction: Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured.

Methods: In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aβ42/Aβ40.

Genetic analyses in multiplex families confirms chromosome 5q35 as a risk locus for Alzheimer's Disease in individuals of African Ancestry.

There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.

An Alzheimer's disease risk variant in modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

Unlabelled: A missense variant in the ( ) gene (rs377155188, p.S1038C, NM_003316.4:c.

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.

Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI.

Methods: A total of 1522 individuals screened for CI were genotyped.

Genetic architecture of RNA editing regulation in Alzheimer's disease across diverse ancestral populations.

Most Alzheimer's disease (AD)-associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the post-transcriptional modification of RNA bases, is a regulatory feature that is altered in AD patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are DNA variants that influence the level of RNA editing at a specific site.

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families.

Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds.

Introduction: Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences.

Methods: Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.

Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish.

Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment.

Immune and Inflammatory Pathways Implicated by Whole Blood Transcriptomic Analysis in a Diverse Ancestry Alzheimer's Disease Cohort.

Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer's disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes.

Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry.

Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2.

Whole exome sequencing and copy-number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop-gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein.

RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.

Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute to AD pathogenesis due to its roles in neuronal development and immune regulation. Here, we pursued one of the first transcriptome-wide RNA editing studies in AD by examining RNA sequencing data from individuals of both African-American (AA) and non-Hispanic White (NHW) ethnicities.

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations.

Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport.

Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD.

Objective: To search for rare variants contributing to the risk for EOAD.

mutations in early- and late-onset Alzheimer disease.

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor () gene.

Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with mutations were characterized based on clinical reviews of medical records.

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.

Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.