Mike Cuccaro

Mike Cuccaro
University of Miami Miller School of Medicine | UM · Department of Human Genetics (Dr. John T. Macdonald Foundation)

PhD

About

321
Publications
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Introduction
Skills and Expertise

Publications

Publications (321)
Article
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 Ru...
Article
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...
Article
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...
Article
Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI. Methods: A total of 1522 individuals screened for CI were genotyped. The outcome studied was...
Article
Most Alzheimer disease (ad) associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the post-transcriptional modification of RNA bases, is a regulatory feature that is altered in ad patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are...
Article
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 ris...
Article
Full-text available
Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 ris...
Article
Full-text available
Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated...
Article
Introduction: Alzheimer disease (AD) and related dementias are characterized by damage caused by neuropathological lesions in the brain. These include AD lesions (plaques and tangles) and non-AD lesions such as vascular injury or Lewy bodies. We report here an assessment of lesion association to dementia in a large clinic-based population. Method...
Preprint
Full-text available
Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation c...
Article
Recruiting African Americans in AD studies remains a challenge, particularly during a pandemic, where major health disparities in this population are illuminated. The recruitment literature suggests myriad factors that contribute to the underrepresentation of AAs, including, but not limited to “mistrust” in researchers and their institutions. Maint...
Article
The COVID‐19 pandemic has placed a demand on researchers to limit in‐person contact with participants, greatly impacting Alzheimer Disease (AD) research. To address this problem, we describe here an approach to using digital technology to continue nationwide clinical recruitment and ascertainment of biological samples while adhering to COVID‐19 gui...
Article
The ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to discovering ancestry‐specific genetic factors in Alzheimer's disease. As part of the Puerto Rican Alzheimer Disease Initiative (PRADI), we ascertained 80+ multigenerational families with multiple AD family members and reported linkage...
Article
Plasma proteins as biomarkers for the differential diagnosis of AD from other similar neurodegenerative disorders, as well as the identification of preclinical AD, has recently been well supported across several large AD cohorts. However, these are composed primarily of individuals of non‐Hispanic European ancestry. Few studies have been performed...
Article
Among older Peruvians (over 65‐years) the prevalence of dementia is 7%, with 56% meeting clinical criteria for Alzheimer Disease (AD). Peruvians, are an admixed population with approximately 80% Amerindian ancestral background. We have ascertained a cohort of Alzheimer Disease (AD) cases and cognitively intact controls for genetic studies. All part...
Article
A recent study of educational attainment (EA) in African Americans (AA) demonstrated that it is associated with a decreased risk of AD, as previously described in the Non‐Hispanic White population. Several studies have also suggested that EA is a proxy for the concept of cognitive reserve (CR) or the capacity of the brains of some individuals to co...
Article
Background: Alzheimer's disease (AD) is a progressive neurological disease that leads to atrophy of the brain and cognitive decline. There are many factors that play a role in the risk of AD, such as age, smoking, gender, and genetics. the genetic influence on AD is strong, with heritability estimates between 40-60%. Identifying genetic factors th...
Article
Background: The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) is collaborating with the Alzheimer's Disease Sequencing Project (ADSP) to ensure that subjects with sequencing have available biospecimens. The latest phase of the ADSP, the Follow-Up Study (ADSP-FUS), is generating sequencing on additional subje...
Article
Background: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively normal (CN; unaffected after age 75) individuals. We hypothesize that these CN individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genetic...
Article
Background: Recently we demonstrated that local genomic ancestry (LA) drives the difference in AD risk between European (EU) and African (AF) carriers of APOEε4/4. As a follow-up study using single-nuclei RNAseq, we found that AD APOEε4 homozygotes with EU Local Ancestry (LA) had a significantly increased APOEε4 expression compared to AD APOEε4/4...
Article
Background: We recently published a genome-wide association study (GWAS) for Alzheimer disease (AD) in African Americans (AA; 2,784 cases, 5,222 cognitively normal individuals) (Kunkle et al. JAMA Neurol. 2021). We now present a GWAS meta-analysis of this AA data stratified by APOEε4-genotype. Method: All datasets were imputed to the African Gen...
Article
Background: While studying cognition in the Amish, we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuoconstructive memory in this population. Here, we investigate this by comparing...
Article
Background: Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer's disease (AD) neuropathology at autopsy. Studying these "resilient" individuals may lead to the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of A...
Article
Background: The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late-onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial-ethnic diversity. The ADSP-FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data t...
Article
Background: There are notable sex differences in the clinical manifestation of Alzheimer's disease (AD), including differences in baseline and longitudinal changes in memory performance. However, sex-stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex-specific g...
Article
Background: Local ancestry (LA) surrounding the APOE4 allele is associated with an increased risk for Alzheimer Disease (AD) in European (EU) LA compared to African (AF) LA. We recently demonstrated that APOE4 has significantly higher expression in astrocytes in brain from EU compared to AF APOE4 LA carriers, but the specific molecular mechanism l...
Article
Background: Generalization of Alzheimer disease (AD) genetic findings to ancestrally admixed populations, such as African Americans (AA) and Caribbean Hispanics from Puerto Rico (PR), is challenging as they are underrepresented in most studies. There is evidence of differing underlying genetic architecture of AD in these groups, but identification...
Article
Background: Disorders of cognition are important from both personal and public health perspectives. The Modified Mini-Mental State (3MS) examination is a brief mental status test designed to detect cognitive impairment and widely used as a screening test for dementia including Alzheimer's disease (AD). The Old Order Amish have a homogeneous lifest...
Article
Background: Early-onset Alzheimer disease (EOAD) is a highly genetic dementia typically defined as Alzheimer disease dementia with an age of onset of 65 years or younger. While known mutations in genes such as APP, PSEN1, and PSEN2 account for a small portion of EOAD, approximately 90% of all EOAD cases lack these known mutations. Since little is...
Article
Background: Previous studies have identified genetic risk factors for Alzheimer Disease (AD). In the Amish community, many individuals maintain normal cognitive function at older ages, despite having relatively high genetic risk of AD. These individuals may carry protective alleles that buffer the genetic risk. To find such loci, we utilized the A...
Article
Background: Greater than 20 genetic loci have been consistently associated with Alzheimer disease (AD). Accumulating evidence has implicated the endolysosomal pathway in disease pathology. The sortilin-related receptor 1 (SORL1) gene has been associated with AD through multiple studies and has been suggested to function as a guide for amyloid prec...
Article
Background: Alzheimer's disease is the most prevalent type dementia and has a strong genetic component. Much of AD genomic research has focused on identifying risk variants, primarily in European ancestry populations. After immigration to the United States, the Amish experienced a genetic bottleneck, making it likely that their underlying genetic...
Preprint
Background: While studying cognition in the Old Order Amish (OOA), we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuospatial memory in this population. Here, we investigate this by...
Preprint
Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained...
Preprint
Background: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively unimpaired (CU; unaffected after age 75) individuals. We hypothesize that these CU individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genet...
Article
Full-text available
The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed f...
Article
Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade, which along with their genetic homogeneity, makes it an interesting population to study the e...
Article
Most genetic studies on Alzheimer’s disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development of AD and to...
Article
Addressing the disparity Late Onset Alzheimer’s disease (LOAD) prevalence among African Americans (AA) requires deliberate inclusion of this population in Alzheimer’s disease (AD) studies. Recruiting AA for research studies remains a significant challenge for AD genetic studies. Recruiting and retaining AA males (AAMs) is an even greater challenge,...
Article
There is limited study of the effect of genetically determined ancestral background and diabetic risk on cognitive status in admixed populations. Puerto Ricans are an admixed population with European (EU), African (AF), and Amerindian (AI) backgrounds. We analyzed the impact of ancestry and diabetes on cognitive status in older Puerto Ricans. The d...
Article
Genetic risk factors for Alzheimer disease (AD) demonstrate distinct effects across diverse ancestral populations. The ancestral heterogeneity (admixture) of Caribbean Hispanics from Puerto Rico (PR), makes studies of the PR population important in the discovery of ancestry‐specific factors in AD. To expand ongoing genomic investigations of AD in P...
Article
The APOE ε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among non‐Hispanic White (NHW) populations APOE shows the strongest effect in Northern European (NEu) (rs429358: OR = 3.32, CI:3.20‐3.45) and has a relatively lower effect in Southern European (SEu; i.e., Iberia, Italy, etc) populations (rs429358:...
Article
The ApoEε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among the populations ApoE shows the strongest effect in East Asians (EA) (ε3/ε4 odds ratio OR: 3.1–5.6; ε4/ε4 OR: 11.8–33.1) and has a relatively lower effect in non‐Hispanic Whites (NHW) (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9). The effect of ApoEε4 in pop...
Article
The ATP‐binding cassette, sub‐family A (ABC1), member 7 (ABCA7) gene has been implicated as a risk factor in Alzheimer’s disease (AD) across populations. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associated with dis...
Article
With over 5.1 million individuals, the Puerto Rican population makes up over 1.5% of the US population and is the 2nd largest Hispanic/Latino population in the continental US. There are an estimated of 60,000 cases of AD on the island. The Puerto Rico Alzheimer's and Related Dementias Initiatives (PRADI) cohort will both leverage and complement exi...
Article
The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A major concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing both ethnically diverse and unique cohorts with extensive clinica...
Article
Over 20 genetic loci have been consistently associated with Alzheimer disease (AD) with accumulating evidence pointing to alterations of the endolysosomal pathway as playing key roles. The sortilin‐related receptor 1 (SORL1) gene has been associated with AD through multiple genetic studies and has been suggested to function by guiding APP to the en...
Article
Increased years of education have been previously associated with a decreased risk of developing Alzheimer disease (AD) with cognitive reserve suggested as the source of the protective effect in Non‐Hispanic Whites (NHW). African Americans (AA) are twice as likely to develop AD compared to NHW. We investigated the hypothesis that education was simi...
Article
The Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐Western Amish...
Article
Alzheimer’s disease (AD) has become a burden of social and economic importance, affecting millions of families and society at large. The Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) cohort was developed to investigate AD and genetics factors of AD in the Puerto Rican population. PRADI recruitment was a snowball sampling, with bot...
Article
Most studies on Alzheimer Disease (AD) have focused on the identification of variants associated with increased risk. The Amish is a genetically homogeneous population ideal to investigate susceptibility genes for complex traits such as AD. This study aims to use family‐based linkage and association approaches to identify genetic variants that prot...
Article
Understanding the effects of genetic factors that drive Alzheimer’s Disease (AD) pathogenesis, including genetic differences across diverse ancestral populations, will drive discovery of novel pharmacological targets. Weighted gene co‐expression network analysis (WGCNA) is a powerful method for finding gene clusters (modules) with correlated expres...
Article
Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White (NHW) populations and has a relatively lower effect...
Article
Autism features occur frequently among individuals with eating disorders (ED). This co‐occurrence is not well understood but there is speculation that select traits (e.g., rigidity) are common to both autism and ED. To explore the co‐occurrence of autistic traits and ED features, we used the Simons Simplex Collection (SSC; N = 2,623 families) to te...
Poster
Full-text available
There is limited study of the effect of genetically determined ancestral background and diabetic risk on cognitive status in admixed populations. Puerto Ricans are an admixed population with European (EU), African (AF), and Amerindian (AI) backgrounds. We analyzed the impact of ancestry and diabetes on cognitive status in older Puerto Ricans.
Article
Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer's disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional...
Article
Full-text available
Objective Here, we re-examine TOMM40 -523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E ( APOE) ε 4 haplotypes. Methods The TOMM40 -523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε 3 and APOE ε 4...
Article
Full-text available
This study examined reasons for participation in a genetic study of risk for multiple sclerosis (MS). Our sample consisted of 101 patients diagnosed with MS who were approached about enrolling in the Multiple Sclerosis Genetic Susceptibility Study. Participants were predominantly Hispanic (80%), female (80%), and well educated (71%), having at leas...
Preprint
Full-text available
Background The ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing...
Preprint
Full-text available
Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populatio...
Article
Whole exome sequencing and copy‐number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop‐gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This va...
Article
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...
Article
Full-text available
Involvement of participants from different racial and ethnic groups in genomic research is vital to reducing health disparities in the precision medicine era. Racial and ethnically diverse populations are underrepresented in current genomic research, creating bias in result interpretation. Limited information is available to support motivations or...
Article
Full-text available
Introduction: Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as par...