An X chromosome‐wide DNA methylation study of Alzheimer’s disease.

Background: Sex is an important factor that contributes to both clinical and biological heterogeneity in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex differences in AD are still not well understood. DNA methylation (DNAm) is an epigenetic modification that regulates gene transcription and is known to be involved in AD. However, due to analytical and biological complexity, few previous DNAm studies analyzed the X chromosome, where many genes influencing cognitive abilities and immune functions are located.

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.

Association of markers of endothelial function with blood‐based biomarkers of Alzheimer’s Disease in individuals of admixed ancestry.

Background: While Alzheimer disease (AD) is the most common cause of dementia, it has long been recognized that cardiovascular and cerebrovascular health plays a major role in cognitive function. As such, the development of accessible biomarkers to assess vascular cognitive impairment and dementia (VCID) is a key step towards identifying effective prevention and treatment strategies. While a set of blood‐based VCID biomarkers has been under investigation, there is a critical paucity of data from genetically admixed individuals.

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.

Ancestral Genomic Functional Differences in Oligodendroglia: Implications for Alzheimer's Disease.

Background: This study aims to elucidate ancestry-specific changes to the genomic regulatory architecture in induced pluripotent stem cell (iPSC)-derived oligodendroglia, focusing on their implications for Alzheimer's disease (AD). This work addresses the lack of diversity in previous iPSC studies by including ancestries that contribute to African American (European/African) and Hispanic/Latino populations (Amerindian/African/European).

Methods: We generated 12 iPSC lines-four African, four Amerindian, and four European- from both AD patients and non-cognitively impaired individuals, with varying genotypes ( and ).

Cognitive dysfunction following brain trauma results from sex-specific reactivation of the developmental pruning processes.

Cognitive losses resulting from severe brain trauma have long been associated with the focal region of tissue damage, leading to devastating functional impairment. For decades, researchers have focused on the sequelae of cellular alterations that exist within the perilesional tissues; however, few clinical trials have been successful. Here, we employed a mouse brain injury model that resulted in expansive synaptic damage to regions outside the focal injury.

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.

Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer's Disease.

Introduction: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from -eQTL meta-analyses and the largest clinically-adjudicated Alzheimer's Disease (AD) GWAS.

Methods: We implemented the OTTERS TWAS pipeline, leveraging -eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684) to predict gene expression, then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944).

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.

Utilizing RNA sequencing to identify gene expression markers of stroke-causing thrombi origin: A pilot study.

Introduction: Stroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots.

Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications.

Both POLG and MGME1 are needed for mitochondrial DNA (mtDNA) maintenance in animal cells. POLG, the primary replicative polymerase of the mitochondria, has an exonuclease activity (3'→5') that corrects for the misincorporation of bases. MGME1 serves as an exonuclease (5'→3'), producing ligatable DNA ends.

mitoTALEN reduces the mutant mtDNA load in neurons.

Mutations within mtDNA frequently give rise to severe encephalopathies. Given that a majority of these mtDNA defects exist in a heteroplasmic state, we harnessed the precision of mitochondrial-targeted TALEN (mitoTALEN) to selectively eliminate mutant mtDNA within the CNS of a murine model harboring a heteroplasmic mutation in the mitochondrial tRNA alanine gene (m.5024C>T).

African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer's Disease Measured by pTau181.

Background: Cognitive and functional abilities in individuals with Alzheimer's disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP.

Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning.

GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity.

The intricate cellular ecosystem of human peripheral veins as revealed by single-cell transcriptomic analysis.

The venous system has been historically understudied despite its critical roles in blood distribution, heart function, and systemic immunity. This study dissects the microanatomy of upper arm veins at the single cell level, and how it relates to wall structure, remodeling processes, and inflammatory responses to injury. We applied single-cell RNA sequencing to 4 non-diseased human veins (3 basilic, 1 cephalic) obtained from organ donors, followed by bioinformatic and histological analyses.

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD.