Slow-Coagulation Transscleral Cyclophotocoagulation in Pseudoexfoliation Glaucoma.

Purpose: To evaluate the outcomes of slow-coagulation transscleral cyclophotocoagulation (SC-TSCPC) in pseudoexfoliation glaucoma (PXG).

Methods: A single-center, retrospective non-comparative study including consecutive patients with medically uncontrolled PXG who underwent SC-TSCPC (1250-milliwatt power and 4-second duration). The primary outcome measure was surgical success (defined as intraocular pressure (IOP) between 6 - 21 mmHg with ≥20% reduction compared to baseline and no need for further glaucoma surgeries or development of vision-threatening complications).

Basic Science and Pathogenesis.

Background: Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method: Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer's Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome-wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: Common and rare variants in SORL1 have been associated with increased risk of Alzheimer's disease (AD). Since 2019, we have run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer's disease and other related dementias for genetic studies (PeADI).

Method: A Peruvian family (4 AD cases and two mild cognitive impairment (MCI) cases) was recruited through the PeADI study.

Basic Science and Pathogenesis.

Background: In this introductory talk, we embark on a journey of through the genomic frontiers of Alzheimer's research via the revolutionary Alzheimer's Disease Sequencing Project (ADSP).

Method: ADSP integrates together various components that collectively unravel the intricate genetic landscape of Alzheimer's disease with the ultimate goal of advancing precision medicine for the millions affected globally by this devastating disease. With a goal of sequencing and analyzing up to 150,000 complete genomes and associated clinical and functional data in the next five years, ADSP has amassed an unprecedented wealth of genomic data from diverse populations, providing a comprehensive and holistic understanding of the genetic underpinnings of Alzheimer's disease.

Basic Science and Pathogenesis.

Background: Neuropsychiatric Symptoms (NPS) (e.g., aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with accelerated decline, out-of-home placement, increased costs, and greatly increased suffering of patients and families.

Basic Science and Pathogenesis.

Background: Annotation of target genes of non-coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry-specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi-C analysis in frontal cortex of African American (AA) and Non-Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer-promoter (EP) interactions.

Basic Science and Pathogenesis.

Background: Age is the largest risk factor for late-onset Alzheimer's Disease (LOAD). Although >80 genetic loci have been associated with LOAD, little is known about the age dependencies of these associations except the APOE region.

Method: We performed cross-ancestry and ancestry-specific genome-wide gene-age interaction and age-stratified association study using TOPMed-imputed genome-wide association study (GWAS) data from Alzheimer's Disease Genetics Consortium (ADGC) including 34,833 non-Hispanic Whites (NHW), 7,264 African Americans (AA), 3,232 East Asians (EA), and 2,024 Caribbean Hispanics (CH) aged 60 years and older.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: Prior studies have shown differences in the genetic etiology and clinical presentation of Alzheimer's Disease across populations. For example, for multiple genetic loci associated with AD, effect sizes can vary drastically between individuals of different ancestral backgrounds. Few investigations into differences in epigenetic features like DNA methylation have been conducted in AD, particularly in diverse individuals.

Basic Science and Pathogenesis.

Background: Neuropsychiatric Symptoms (NPS) including aggression, psychosis, anxiety, apathy and depression are highly prevalent in Alzheimer's Disease patients and are associated with accelerated decline and a detrimental impact on suffering and quality of life of both patients and caregivers. There are no effective pharmaceutical interventions targeting these symptoms, making a better understanding of the etiologic mechanisms underlying NPS in AD critical to develop improved treatments.

Method: To facilitate identification of genetic loci and mechanistic pathways underlying NPS in AD, we have initiated an effort (NIH: U01AG079850) to collate and harmonize all available NPS data in over 70 cohorts (>80,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), and analyze these data to identify genetic loci and mechanistic pathways associated with NPS in AD.

Basic Science and Pathogenesis.

Background: Recent advances in Alzheimer's Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African-descent individuals have an almost doubled risk of developing AD compared to European-descent individuals. Transcriptome-wide association studies (TWAS) have advanced the analysis of non-coding variants by integrating gene expression with GWAS data.

Basic Science and Pathogenesis.

Background: Polygenic Risk Scores (PRS) are important in predicting disease risk and are usually rely on markers selected by thresholding p-values from genome-wide association studies (GWAS). In traditional approaches, one single model is built to calculate risk scores, employing effect size to determine additive risk. However, this traditional method overlooks potential interactions between genetic loci resulting in reduced prediction power.

Basic Science and Pathogenesis.

Background: The Apoliproprotein E (APOE) e4 allele is the most significant genetic risk factor for late-onset Alzheimer disease (AD). However, the risk associated with the APOE e4 allele differs across populations with individuals of African ancestry having a reduced risk than individuals of European (EU) ancestry. Further, single-nuclei RNAseq analysis in autopsy samples from AD APOEε4 homozygotes with EU Local Ancestry (LA) had a significantly increased APOEε4 expression compared to those with African LA, particularly in astrocytes.

Basic Science and Pathogenesis.

Background: The effect size of APOE4 varies across genetic ancestries with African (AFR) local ancestry conferring a lower risk when compared to other ancestries. Recently, we identified a strong effect of the A allele of rs10423769 (with a minor allele frequency of 0.12 in AFR and 0.

Basic Science and Pathogenesis.

Background: We identified the missense variant Ser1038Cys (rs377155188) in the tetratricopeptide repeat domain 3 (TTC3) gene that segregate in a non-Hispanic white late onset Alzheimer disease (LOAD) family. This variant is predicted to be deleterious and extremely rare (MAF<0.01%).

Basic Science and Pathogenesis.

Background: Cerebrovascular disease (CVD) is a major cause of mortality in females, while two-thirds of Alzheimer's disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well-established; it is unclear if associations between APOE and CVD are sex-specific.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) and Age-Related Macular Degeneration (AMD) are two age related neurodegenerative diseases that share multiple characteristics, including deposition of amyloid beta. In AD, amyloid plaque accumulation contributes to neurological dysfunction, while in AMD amyloid is a component of the hallmark retinal drusen complexes that lead to degeneration of central vision. Both diseases have significant and opposite risk due to the APOE e4 and e2 alleles.

Basic Science and Pathogenesis.

Background: In the US, African Americans (admixed with African and European) followed by Hispanics (admixed with Amerindian, African, and European) are the most affected groups compared to non-Hispanic Whites (NHW). While genetic diversity and admixture play crucial roles in disease risk, the ancestry-specific mechanisms remain poorly understood with most AD-related studies focusing on NHW. Despite the recent field efforts to include genetically admixed populations, there continues to be a lack of functional studies in AD across the different cell types in these populations.

Basic Science and Pathogenesis.

Background: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.

Method: We investigated the protein expression, morphological differences of Ng and correlated Ng to hyperphosphorylated tau in the postmortem brains of 17 AD cases and 17 age and sex-matched controls.

Basic Science and Pathogenesis.

Background: Previous studies have reported that non-Hispanic white (NHW) females carrying the APOE ε4 allele differ in risk of developing Alzheimer's disease (AD) when compared to men. Recent studies suggest the association between APOE ε4 and AD risk may be modified by age and its local ancestry in admixed populations. However, there is still scant evidence on how sex could interact with these factors.

Basic Science and Pathogenesis.

Background: The Genome Center for Alzheimer's Disease (GCAD) coordinates the integration and meta-analysis of all available Alzheimer's disease (AD) relevant whole genome sequencing (WGS) data to facilitate the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated via the collaboration of scientists from the Alzheimer's Disease Sequencing Project (ADSP) and GCAD. To minimize data heterogeneity introduced by different sequencing protocols and machines, GCAD processes all samples using identical pipelines.

Basic Science and Pathogenesis.

Background: Despite its high heritability, the genetic mechanisms influencing Alzheimer's Disease (AD), particularly in health disparity populations like African Americans (AA) and Hispanics (HI), are not fully understood. The lack of ancestral diversity in genetic datasets, notably in eQTL studies that associate genetic variation with gene expression, exacerbates these disparities. Our study seeks to address this gap by comparing the AD interactions of racially and ethnically diverse expression Quantitative Trait Loci (eQTL) effects to investigate the genetic influence on AD in underrepresented populations.

Basic Science and Pathogenesis.

Background: Late-onset Alzheimer Disease (LOAD) risk and prevalence differ by ancestral group. Furthermore, the frequency of APOE-4 and its effect size on LOAD risk also differ by ancestry group. If these patterns are a function of evolutionary history, we may find ancestry group-specific evidence of recent selection at the APOE locus or APOE eQTLs.