Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has both genetic and environmental risk factors. Gene-environment interaction may help explain some missing heritability. There is strong evidence for cigarette smoking as a risk factor for AD.

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: 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: "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: 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: There is growing evidence that epigenetic age acceleration may predict late life cognitive decline and dementia, but it is unknown whether this is due to accelerated neurodegeneration or reduction in cognitive resilience. We examined the relationship between epigenetic clocks and domain specific neuropsychological (NP) factor scores, mild cognitive impairment (MCI), Alzheimer's Disease (AD), and all-cause dementia, before and after accounting for plasma total tau (t-tau), a marker of neurodegeneration.

Method: DNA methylation and plasma t-tau (Simoa assay; Quanterix) data from 2091 Framingham Heart Study Offspring cohort participants were generated from blood at the same Exam 8 visit (2005-2008).

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: 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: Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. The Puerto Rican (PR) population, a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We performed a genome-wide association study (GWAS) in the PR population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.

Basic Science and Pathogenesis.

Background: Alzheimer disease (AD) is a progressive dementia with high heritability. While genome-wide association studies have identified common variation associated with AD, most of these loci have effects too small to explain the segregation of disease within multiplex families. As such, these multiplex families likely harbor novel genetic variants with strong effects, and thus still play an important role in assessing the genetic etiology of AD.

Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.

Basic Science and Pathogenesis.

Background: We previously identified a 44-base pair deletion in (ATP-binding cassette sub-family A member 7) (ABCA7) that is significantly associated with Alzheimer's disease (AD) in African Americans (AA), producing a frameshift mutation resulting in a truncated protein (p.Arg578Alafs). ABCA7 is a lipid transporter across cellular membranes.

Basic Science and Pathogenesis.

Background: Dysregulation of endolysosomal trafficking is a major pathogenic mechanism in Alzheimer's disease (AD). From the family of AD-linked endosomal pathway genes, SORL1 stands out as one of the highest risk factors. SORL1 encodes an endocytic sorting receptor that mediates endosomal trafficking and processing of key AD-associated molecules, including pathogenic forms of amyloid-β (e.

Basic Science and Pathogenesis.

Background: 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.

Basic Science and Pathogenesis.

Background: While Alzheimer's disease and dementia prevalence increase with age, some older adults retain cognitive performance equal to those in mid-life. One group, referred to as SuperAgers (SA), are ≥ 80 years old and demonstrate episodic memory function at or above the level expected for a middle-aged adult. Genetic studies of SA may reveal heritable factors that promote superior cognition in older adults.

Basic Science and Pathogenesis.

Background: Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer's disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.

Clinical Manifestations.

Background: The utility of neuropsychological measures commonly used to diagnose individuals with suspected MCI or AD was recently explored in European cohorts, however their utility in Caribbean Hispanic (CH) populations is not well understood.

Method: Our sample consisted of 507 CH individuals from ongoing studies of Puerto Rican and Cuban American older adults (74%% Female, mean age = 74.1, mean education = 12.

Clinical Manifestations.

Background: Over 13,000 individuals from both domestic and African sites will be collected for the READD-ADSP study. Adjudicating this number of individuals is challenging, so we evaluated knowledge-based decision tree algorithms to predict clinical diagnoses using nationally representative norms and standard cut-offs. Additional models were constructed using culturally adjusted cut-offs, domain average cut-offs, and exclusion of the Trail Making Test (TMT) which performed poorly.

Examination of MGMT as a risk gene for dementia in the Amish.

Introduction: Recently, the O-6-methylguanine-DNA methyltransferase (MGMT) locus was proposed as influencing the risk of Alzheimer's disease (AD) in women who did not carry the apolipoprotein E ε4 allele. We examined an Amish founder population for any influence of genetic variation in and around the MGMT locus on the risk for dementia.

Methods: Genetic association was performed for single nucleotide polymorphisms (SNPs) surrounding the MGMT locus.

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 ).

Alzheimer's Disease Sequencing Project Release 4 Whole Genome Sequencing Dataset.

The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.