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Publications (413)
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 cer...
APOEε4 is the strongest genetic risk factor for Alzheimer′s disease (AD) with approximately 50% of AD patients carrying at least one APOEε4 allele. Our group identified a protective interaction between APOEε4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOEε4 homozygotes by approximately 75%. The protective...
INTRODUCTION
Alzheimer's 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 in...
Introduction
Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. Puerto Ricans (PR), a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We aimed to conduct a genome-wide association study (GWAS) and comprehensive analyses to identify...
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...
INTRODUCTION
Despite a two‐fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts.
METHODS
Genome‐wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within‐dataset results were meta‐analyzed, followed by functional genomics analyses.
RESULTS
A novel...
Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic...
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 (Afri...
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. While cognitive an...
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. As med...
The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer’s Disease Sequencing Project. The joi...
Background
Apolipoprotein E4 (APOE4) is common in the population yet is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Here, we sought to identify genetic effects that differ by APOE4 genotype leveraging stratified and APOE interaction analyses. We hypothesized that we could identify novel genetic associations with longi...
Background
A recently recognized subset of older individuals are an anomaly of cognitive decline; the “SuperAgers”, unsurprisingly named, achieve cognitive scores equivalent to much younger cognitively normal (CN) middle‐aged adults. Using longitudinal cognitive data harmonized across eight cohorts of aging and Alzheimer’s Dementia (AD), we investi...
Background
The APOE4 genotype is the main contributor to the risk of developing Late Onset Alzheimer’s Disease (LOAD), while the APOE3 genotype has no effect on LOAD risk. Previously our group has shown that Local Ancestry (LA) surrounding APOE4 regulates APOE expression in adult individuals. As LOAD pathology has been shown to develop decades befo...
Background
Alzheimer’s Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to...
Background
Although African Americans are twice as likely to develop Alzheimer’s Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified s...
Background
Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic arc...
Background
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI an...
Background
The COVID‐19 pandemic has profoundly affected people’s lives worldwide. Stress and social restriction have a negative physical and psychological effect on people with dementia and their caregivers. Peru was one of the countries that experienced social restrictions and high rates of COVID‐19 morbidity and mortality.
Methods
We assessed t...
Background
Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have...
Background
More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes.
Method
We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐cal...
Background
The ATP Binding Cassette Subfamily A Member 7 (ABCA7) gene is a risk factor for Alzheimer’s disease (AD). While ABCA7 has been implicated as a genetic determinant of AD across populations, the risk effect is the strongest in African Americans (AAs). We previously identified a common 44 base pair deletion in ABCA7 (p.Arg578Alafs) that is...
Background
A shift in focus from risk to resilience for Alzheimer’s disease (AD) encourages efforts to uncover novel AD biological mechanisms. Rare variants identified through whole genome sequencing (WGS) may represent an important and understudied component of complex trait genetics. While population‐based studies are powered to discover associat...
Background
Alzheimer disease (AD) presents with two primary pathologies: neurofibrillary tangles (NFT) and neuritic plaques (NP). However, these hallmark pathologies typically co‐occur with pathologies from AD‐related dementias like cerebral amyloid angiopathy (CAA) [Godrich, 2022; PMID: 35142102]. While CAA is known to impact cognitive impairment,...
Background
Memory performance can serve as a strong endophenotype for Alzheimer’s disease (AD) that changes early and continues to decline with disease progression. Yet, the genetic architecture of memory is not well characterized in older adults. Here, we build on existing memory GWAS studies by performing predicted gene expression analysis (Predi...
Background
The variant G206A in Presenilin‐1 ( PSEN1 ) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants...
Background
Cerebral amyloid angiopathy (CAA) commonly co‐occurs with Alzheimer’s disease (AD) pathologies, leading to an increased risk and severity of cognitive decline. While CAA is known to impact cognitive impairment, the genetics of CAA are not well understood, and most previous sample sizes have been small. To address this gap, we conducted a...
Background
The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS)...
Background
African Americans (AAs) are twice as likely to have Alzheimer’s disease (AD) as their White counterparts; yet, this population is largely missing from brain donation research. According to the National Alzheimer’s Coordinating Center, merely 2% of brain donations are obtained from AAs. Medical mistrust among AAs has been well‐documented...
Background
Alzheimer disease (AD) is the fourth leading cause of death in Puerto Rico. The Puerto Rican (PR) population has a high proportion of older adults (18%, over > 65), with 12.5% of them suffering from ADThese statistics highlight the need to investigate the genetic risk factors underlying AD in the PR population, as it could lead to the de...
Background
Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Ab42/Ab40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, measurement of these biomarkers is mostly from individuals of non‐Hispanic, European ancestry. Given differences in...
Background
Patterns of cognitive performance associated with different stages of dementia have been primarily studied in Non‐Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical...
Background
Puerto Ricans, the second largest US Latino group, are underrepresented in genomic studies of Alzheimer disease (AD). We describe a multi‐source ascertainment approach, networking with community and governmental stakeholders, as part of the Puerto Rico (PR) Alzheimer Disease Initiative (PRADI) whose goal is to increase recruitment and re...
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 int...
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We...
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 (Nmales = 11,942; Nfemales = 15,641). Le...
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 l...
Importance
Apolipoprotein E ( APOE )*2 and APOE *4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and eth...
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. However, the impact of these NPS on AD in di...
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. Using this information, polygenic risk scores (PRSs) can be calculated to quant...
INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimers Disease (AD) genomics efforts.
METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis...
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 Amis...
Importance:
Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele.
Objective:
To investigate whether sex and race modify APOE ε4 a...
Background
KBASE is a prospective cohort study launched at Seoul National University (SNU), South Korea, in 2014 using similar design and methods as the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). The KBASE cohort consists of well‐characterized participants (420 cognitively normal, 140 mild cognitive impairment, and 90 AD dem...
Cognitive and functional abilities in individuals with Alzheimer disease (AD) pathology (ADP) show greater than expected variability. While most individuals show substantial impairments in these abilities, a considerable number show little or no impairments. Factors contributing to this variability are not well understood. For instance, multiple st...
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loc...
A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRI...
Introduction:
Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology.
Methods:
Whole-genome sequenc...
Background
More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes.
Methods
We conducted genome-wide scans for cognitive domain performance using harmonized and co-ca...
Unlabelled:
A missense variant in the tetratricopeptide repeat domain 3 ( TTC3 ) gene (rs377155188, p.S1038C, NM_003316.4:c.3113C>G) was found to segregate with disease in a multigenerational family with late onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individ...
Introduction:
The underrepresentation of African Americans (AAs) in Alzheimer's disease (AD) research may limit potential benefits from translational applications. This article describes an approach to recruit AA families into an AD genomic study and characteristics of seeds (family connectors) used to overcome recruitment barriers of AA families...
Objective:
Memory and cognitive problems are central to the diagnosis of Alzheimer's disease (AD). Psychometric approaches to defining phenotypes can aid in identify genetic variants associated with AD. However, these approaches have mostly been limited to affected individuals. Defining phenotypes of both affected and unaffected individuals may he...
We previously reported strong linkage on chromosome 9p21 in multiplex Alzheimer disease (AD) families from Puerto Rico. Nine families had the highest linkage contribution. 3/9 families shared seven coding variants with displayed evidence for AD association in similar ancestral. Although these variants reside in genes with neuronal expression and fu...
Plasma proteins, including phosphorylated threonine‐181 of Tau (pTau181) are used as biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, observation and measurement of these biomarkers are mostly from individuals of non‐Hispanic, European ancestry. Given differences in AD risk, generalizability of the...
Peru is one of the five largest countries in Latin America and harboring a high Amerindian ancestry component in this population. The Latin American population, including Peruvians, are underrepresented in research studies of Alzheimer disease (AD).We have developed an international collaborative research initiative to ascertain a Peruvian cohort f...
As plasma biomarker assays have become more widely available, they are increasingly being used to characterize AD and related dementias. The Old Order Amish are a cultural and genetic isolate in the US that have participated in genetic studies for decades. This study investigated plasma phosphorylated tau at threonine‐181 (pTau181) in an Old Order...
The hallmark lesions of Alzheimer Disease (AD) include tangles and plaques; however, these seldom appear alone. Lesions of AD‐related dementias such as vascular dementias and Lewy body dementias often co‐occur with AD. These co‐occurring lesions and total lesion burden are associated with a higher likelihood of dementia and severe cognitive impairm...
Mitochondrial dysfunction is an important feature of Alzheimer’s Disease (AD) pathogenesis. Reduced glucose utilization and increased oxidative stress are intermediates through which impaired mitochondria may promote AD‐associated brain changes. Association between groups of variants (“haplogroups”) in the mitochondrial genome and AD have been repo...
Alzheimer’s Disease (AD) is the most common form of dementia and has limited treatments. While AD risk has a large genetic component, under 50% of the genetic risk has been identified. By focusing on identifying genetic variants that delay or prevent the onset of AD, our goal is to identify new associated genes and variants. To detect such loci, we...
The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP Discovery and Discovery Extension cohorts beyond non‐Hispanic Whites of European Ancestry (NHW‐EA). Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to sequence...
Depression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is...
Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner. Data were obtained from 38,386 parti...
Polygenic risk scores (PRS) may be a useful approach to predict the risk of the complex disease and to be an important clinical tool for early intervention. PRS studies in Alzheimer Disease (AD) have focused on individuals of European Ancestry resulting in a >75% prediction accuracy. PRS generated from genome wide data in one population often provi...
Recent analyses of rare variants using whole exome sequencing have found an enrichment of SORL1 loss‐of‐function (LoF) variants in early onset Alzheimer’s disease (EOAD). This makes SORL1 one of the highest risk factors for AD, along with other candidate EOAD genes such as APP, PS1, and PS2. SORL1 encodes an endocytic receptor involved in the traff...
Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic eti...
Native American populations are substantially underrepresented in Alzheimer disease (AD) genetic studies. The Peruvian (PE) population with up to ∼80 of Amerindian ancestry (AI) provides a unique opportunity to assess the role of AI ancestry in AD. We performed whole‐genome sequencing in PE case‐control study to assess the effect of the known AD lo...
The vast majority of biomedical data currently available for any disease is derived from studies in non‐Hispanic white (NHW) populations. Specifically, clinical information, genetic factors as well as biomarkers for frontotemporal dementia (FTD) have been studied predominantly in those NHW populations. To increase representation in biomedical resea...
We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype. Leveraging 15,933 non‐Hispanic white participants across four longit...
Variants in the presenilin‐1 gene (PSEN1) are known to be pathogenic for Alzheimer disease (AD). The change of glycine at amino acid 206 to alanine (G206A) in PSEN1 has been identified in AD Caribbean Hispanic families from Puerto Rico with variable ages of onset and incomplete segregation (Athan et.al., 2001). Here we set out to confirm the role o...
Background:
This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.
Methods:
We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping an...
Current genetic studies for AD and other dementias are making efforts to incorporate underrepresented populations including admixed Latinos. Peruvian population is characterized by admixed ancestry with a significant Amerindian component, which varies according to specific regions across Peru. The Peruvian Alzheimer Disease initiative (PeADI) was d...
Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY as a risk factor for AD in the Mid‐Western Amish, a founder population with homogeneous lifestyle,...
Alzheimer’s disease (AD), the most common type of dementia, has a complex etiology with a strong genetic component. Many genetic risk variants for AD have been identified including APOE, the largest known genetic risk factor. However, most of this research has examined only broad populations of individuals with European ancestry and there is mounti...
The Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) patient cohort was developed to investigate AD and the associated genetics factors in the Puerto Rican population. PRADI recruitment was a snowball sampling, with both island‐wide geographic distribution, and extensions of the PR communities in the continental US. A prior analysis...
As part of the Research in African American Alzheimer Disease Initiative (REAAADI) and Late‐Onset AD Family Study (LOAD), genotyping array and whole genome sequencing (WGS) data were generated for 51 families (160 affected and 318 unaffected). Multipoint linkage analyses identified a peak LOD score on chr5q35 (HLOD=3.20). Additionally, a suggestive...
Identifying the genes and biological pathways involved in Alzheimer disease (AD) is critical in the effort to develop effective therapies. Significant work has identified genetic variants conferring risk and protection for AD in individuals of diverse ancestries, but identification of downstream functional effects including modulation of gene regul...
African Americans (AA) are underrepresented in Alzheimer’s disease (AD) brain donation research, making up approximately 2% of brain donations to the National Alzheimer’s Coordinating Center (NACC). The objective of this study is to gain insights into the attitudes of Black∖AA individuals toward brain donation and perceptions of medical research th...
Objective: Studies use different instruments to measure cognitirating cognitive tests permit direct comparisons of individuals across studies and pooling data for joint analyses. Method: We began our legacy item bank with data from the Adult Changes in Thought study (n = 5,546), the Alzheimer’s Disease Neuroimaging Initiative (n = 3,016), the Rush...
Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated...
African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to...
Approximately 30% of elderly adults are cognitively unimpaired at time of death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of AD neuropathology may uncover novel therapeutic targets to treat AD. It is well-established that there are sex differences in...