Evaluating the association of genotype and cognitive resilience in SuperAgers.

Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts.

Objective: To determine the frequency of genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases.

Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations.

Unlabelled: The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was formed, presenting here the largest sequencing study of ASD in Latin American individuals (n>15,000).

Alzheimer Disease Plasma Biomarkers in the Mid-Western Amish.

Introduction: Alzheimer disease (AD) plasma biomarkers are noninvasive measures of the key amyloid beta (Aβ) and tau pathologies. Validation and generalization studies are needed to fully understand their potential for AD prediction and diagnosis in the elderly population.

Methods: In 1,067 Amish individuals aged ≥ 65, we measured plasma Aβ and tau to assess their relationships with AD-related outcomes.

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.

Cerebral amyloid angiopathy impacts neurofibrillary tangle burden and cognition.

Cerebral amyloid angiopathy commonly co-occurs with amyloid β plaques and neurofibrillary degeneration and is proposed to contribute to cognitive impairment. However, the interplay among these pathologic changes of Alzheimer disease is not well understood. Here we replicate and extend findings of a recent study that suggested the association of cerebral amyloid angiopathy and cognitive impairment is mediated by neurofibrillary degeneration.

Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer's disease in the Alzheimer's Disease Sequencing Project: Study design and methodology.

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.

Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

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.

Generation of an induced pluripotent stem cell line (UMi043-A) from an African American patient with Alzheimer's disease carrying an ABCA7 deletion (p.Arg578Alafs).

The ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene is associated with Alzheimer's disease (AD) risk in populations of African, Asian, and European ancestry. Numerous ABCA7 mutations contributing to risk have been identified, including a 44 base pair deletion (rs142076058) specific to individuals of African ancestry and predicted to cause a frameshift mutation (p.Arg578Alafs) (Cukier et al.

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.

Attitudes and Perceptions about Brain Donation Among African Americans: Implications for Recruitment into Alzheimer's Disease Research.

The objective of this study was to investigate attitudes toward brain donation and perceptions of medical research that influence brain donation among African Americans. Cross-sectional surveys were administered to African American community members (n = 227). Findings indicate that only 27% of respondents were willing to donate their brain.

Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.

Introduction: Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.

Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.

Results: We found high heritability for two ancestry backgrounds.

Sex-specific genetic architecture of late-life memory performance.

Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear.

Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N  = 11,942; N  = 15,641).

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.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants.

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.

Neuropsychiatric features in a multi-ethnic population with Alzheimer disease and mild cognitive impairment.

Background: Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non-Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary by population in AD. This is likely the result of both sociocultural and genetic ancestral differences.

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

Background: Verbal and visuospatial memory impairments are common to Alzheimer disease and Related Dementias (ADRD), but the patterns of decline in these domains may reflect genetic and lifestyle influences. The latter may be pertinent to populations such as the Amish who have unique lifestyle experiences.

Methods: Our data set included 420 Amish and 401 CERAD individuals.