African ancestry APOE e4 non-carriers with higher educational attainment are resilient to Alzheimer disease pathology-specific blood biomarker pTau181

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 studies have shown that higher levels of education are associated with reduced cognitive impairments among those with ADP. However, it remains unclear whether higher levels of education are associated with functional impairments among those with ADP. We studied 410 AA individuals with advanced levels of pTau181 (a biomarker for ADP; individuals as those having log 10 (pTau181) level greater than one standard deviation above the mean) to determine whether EA (categorized as low EA for individuals with ≤ 8 years of education and high EA for those with >8 years) promotes functional resilience and whether this effect varies between APOE ε4 carriers and non-carriers. We used the four non-memory components of the Clinical Dementia Rating (CDR) to create a composite score (CDR-FUNC) to evaluate functional difficulties (scored from 0=no impairment to 12=severe). We employed the non-parametric Mann-Whitney U test to assess the relationship between EA and CDR-FUNC in advanced levels of pTau181 individuals. The results showed that EA promotes resilience to functional problems in AA individuals with advanced levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W=730.5, p=0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ε4 non-carriers compared to ε4 carriers (W=555.5, p=0.022). This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ε4. The results highlight the intricate interplay of genetic and non-genetic factors in AD progression, suggesting a need for more personalized strategies to manage functional decline in AD

Does higher educational attainment influence functional capabilities among African Americans with Alzheimer’s disease?

Background 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 compensate clinically for the neurodegenerative processes of AD. If true, then EA should also be associated with other aspects of AD, including functional impairment, often measured using the Clinical Dementia Rating scale (CDR). The aim of this study is to test the hypothesis that higher EA is associated with decreased functional impairment in AA. Methods Participants consisted of 158 AA AD cases with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories:12 years. We used a regression model to test the association between years of education and functional impairment (composite score) with the age at onset and sex as covariates. Using the non‐memory components of the CDR: Judgment and Problem solving, Home and Hobbies, Community Involvement, and Personal Care, we formulated a composite score of 12 totaling the individual score of the 4 components. A composite score of 0 is no functional impairment and 12 equals severe functional impairment. Results The dataset was 77.2% female with a mean age of exam of 78.8 years and a mean CDR functional composite score of 1.97 and a mean educational attainment of 11.3 years. Our results showed a significant association between education and the composite score ( ). An increase in the years of education was negatively correlated with functional impairment. Conclusion Our data support the hypothesis that higher educational attainment is associated with reduced functional impairment. These results extend and support the concept that EA is a measure of CR in AA, extending the role of CR and EA to functional abilities. Further studies on the mechanism by which EA is protective is needed. In addition, our results suggest that EA should be considered when evaluating functional abilities in individuals thought to have AD

Education and its effect on risk and age at onset in Alzheimer disease (AD) in African Americans

Background 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 similarly correlated with risk of AD in the AA population. We also examined the relationship of education and age at onset (AAO) of AD in AA. Method Participants consisted of 132 AA AD cases and 428 AA cognitively intact (CI) individuals with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories: 12 years. We used logistic regression to determine the effect of age, sex, education level and APOE4 status between cases versus controls. Additionally, using a linear model we examined the effect of education on AAO including sex and APOE4 status as covariates. Result Results showed that increasing years of education had a protective effect on AD risk. Initially including sex and age as covariates, both higher education categories were significant, with 9‐12 years (p = 0.02;OR = 0.461[0.23,0.9])) and >12 years (p = 1.30e0‐04;OR = 0.26[0.13,0.41]). Adding APOE4 dosage (0(Ref), 1,2 alleles) to the model (significant at p = 9.54e‐05; p = 5.27e‐07), the effect of education remained significant (p = 0.03;OR = 0.46[0.23,0.93]) and p = 4.84e‐05;OR = 0.22[0.10,0.46]) for 9‐12 and >12, respectively further supporting its role in AD risk. We examined the effect of education on AAO. Education (8‐12 years) trended in significance (p‐value = 0.07; β = ‐3.76[‐7.82,0.307]) with >12 years significant (p‐value = 1.63e‐04; β = ‐13.07,‐4.25]) supporting later AAO with higher education. The effect of APOE4 on AAO was not significant (p = 0.226). APOE4 added to the model as a covariate did not have a significant effect on AAO, however, education levels continued trending (8‐12; p = 0.07; β = ‐3.76[‐7.86,0.34]) and significant (>12; p = 3.71e‐04; β = ‐8.33[‐12.84,‐3.82]). Conclusion These data support the hypothesis that higher education results in a decreased risk of AD in AA regardless of APOE4 status. We also found a similar protective effect for a later AAO. Thus, the potential outcome of education on cognitive reserve appears across multiple racial backgrounds

African Ancestry Individuals with Higher Educational Attainment are Resilient to Alzheimer's Disease Measured by pTau181

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 and functional impairments are correlated, they are distinguishable in their manifestations. To investigate whether levels of education are associated with functional impairments among those with ADP. This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels. The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W = 730.5, p = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W = 555.5, p = 0.022). This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4

The Alzheimer's Disease Sequencing Project - Follow Up Study (ADSP-FUS): Increasing ethnic diversity in Alzheimer's genetics research with the addition of potential new cohorts

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 to expand the utility of new discoveries for individuals from all populations. Additional multi-ethnic cohorts are presently being recruited (e.g., Amerindian, Asian and Indian). The cohorts consist of participants from studies of AD, dementia, and aging-related conditions. Clinical classification (i.e., AD, dementia, and non-affected) is implemented using algorithms based on a minimal set of criteria derived from standard measures (e.g., global cognitive screeners, dementia rating scales, etc.) and clinical history. Data dictionaries are curated for each cohort by the FUS clinical staff. In total, the ADSP-FUS intends to sequence over 60,000 individuals. Biospecimens are processed and DNA is prepared and allocated through the National Centralized Repository for Alzheimer's (NCRAD). The DNA is delivered to the Uniformed Services University of the Health Sciences (USUHS) for whole genome sequencing (WGS). The resulting raw sequence data is conveyed to the Genome Center for Alzheimer's Disease (GCAD) for processing and harmonization followed QC analysis at University of Pennsylvania and University of Miami resulting in analysis-ready genotype data. Lastly, all clinical, genotype and sequence data are sent to the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), serving as the ASDP-FUS data storage, management and sharing center. Over 60,000 samples have been ascertained and are distributed by ancestry as follows: 7,686 African; 9,652 Hispanic; 40,575 non-Hispanic white (1,400 EOAD and 3,745 autopsy); 89 Amerindian; 4,003 Asian and 2,000 Indian. To date, we have sequenced 8,208 NHW; 5,528 African; 6,149 Hispanic & 89 Amerindian. The ADSP-FUS will enhance ongoing efforts to identify shared and novel genetic risk factors for LOAD among different populations. This project will expand our knowledge of potential genetic risk and protective variants for LOAD across all populations with the hope of developing new treatments that work for everyone

PRADI cohort case‐control study on related factors of Alzheimer’s disease

BackgroundAlzheimer’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 both island‐wide geographic distribution, as well as extensions to PR communities in the continental US. In this study we assessed the relationship between AD and cardiovascular risk factors of AD in the PR population.MethodWe assessed over 700 elderly PR individuals for dementia, as well as medical history. Affection status was assessed using standard AD clinical criteria (NINCDS‐ADRDA) or mild cognitive impairment. All medical history was obtained by a self‐report or informant report. Differences between affected and unaffected were initially tested using a chi‐square test (for sex, diabetes, hypercholesterolemia, heart disease, hypertension, and stroke) and a t‐test for the age of the exam. Follow‐up analyses on stroke were performed using logistic regression with age at exam and sex as covariates in the model.ResultThe analysis revealed no differences sex differences between AD and unaffected (p‐value > 0.05). Similarly, affected and unaffected showed similar levels of type 2 diabetes, hypercholesterolemia, heart disease, and hypertension (p‐value > 0.05). Affected individuals did however show an increase in stroke incidence (14.0% vs 5.2%; p‐value = 8.3e‐5). This difference persisted even when controlling for age of exam and sex. We did see a difference in age of exam between cases and controls, but this is likely due to ascertainment scheme.ConclusionThis analysis suggests that stroke may be a contributing factor to dementia in the PR population. However, given biases in the ascertainment scheme, additional assessments need to be performed. Additionally, work is ongoing to assess the role of ancestry and genetic factors in this association

The Alzheimer’s Disease Sequencing Project – Follow Up Study (ADSP‐FUS): APOE genotype status and demographic characteristics across datasets

Abstract 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) existing ethnically diverse and unique cohorts. The upcoming phase ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on inclusion of Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations. Methods ADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications are assigned based on standard criteria from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, genome‐wide array and APOE genotyping is acquired or performed for all ADSP‐FUS samples. Results The ADSP‐FUS currently consists of 38 cohorts comprised of ∼40,000 individuals, with plan to sequence >100,000 individuals from diverse ancestries. Genotyping, sequencing, and clinical adjudication has been performed on 23,428 participants (cases N = 6,961, median age = 73; controls N = 13,007, median age = 72; ADRD N = 3,460, median age = 77. More participants are female (62.3%) than male and are evenly distributed across cases (61.0%), controls (63.1%), and ADRD (61.8%). As expected, the most prevalent APOE genotype is APOE 3/3 (% by cases/controls for 2/2 = 0.2,0.4; 2/3 = 4.3, 8.2; 2/4 = 2.2, 1.8; 3/3 = 43.8, 64.4; 3/4 = 39.5, 23.0; 4/4 = 10.1, 2.2). These proportions vary greatly between ethnicities, with the highest for APOE 4/4 observed in Asian participants (8.8%) and the lowest in Hispanic participants (2.5%), for example. Mean Braak stage for AD cases is higher (5.1+1.2) than controls (2.6+1.3) and ADRD participants (3.5+1.6). Conclusion The results provide an overview of features of ADSP‐FUS cohorts. As the ADSP‐FUS expands in size and diversity, this genomic resource, available via NIAGADS, will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP‐FUS will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective

The Alzheimer’s Disease Sequencing Project Follow Up Study (ADSP‐FUS): increasing ethnic diversity in Alzheimer’s disease (AD) genetics research

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 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 existing ethnically diverse and unique cohorts. The upcoming phase for ADSP‐FUS, ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations (e.g., the Asian cohort for Alzheimer’s disease). The ADSP‐FUS enables the utility of new discoveries for individuals from all populations. Method ADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications (AD, dementia, and cognitively intact) are assigned based on standard criteria and derived from clinical measures and history. Data dictionaries are curated for each cohort by the FUS clinical staff. The ADSP‐FUS initiatives intend to sequence over 100,000 individuals from diverse ancestries. Biospecimens are processed and DNA is prepared and allocated for whole genome sequencing (WGS) at designated NIA sequencing centers. All raw sequence data is transferred to the Genome Center for Alzheimer’s Disease (GCAD) for processing and harmonization following QC analysis at the University of Pennsylvania and University of Miami, resulting in analysis‐ready genotype and sequence data. All clinical, genotype and sequence data are housed at the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), which stores, manages, and distributes ASDP‐FUS data to AD researchers. Results Over 50,152 samples have been ascertained with ancestry groupings as follows: 10,166 NHB‐AA; 10,531 HL; 22,002 NHW‐EA (including 1,400 EOAD and 3,745 autopsy); 89 Amerindian; and 7,364 Asian (Korean and Indian) individuals. Currently, we have sequenced up to a total of 31,990 individuals. Conclusion The ADSP‐FUS continues to identify shared and novel genetic risk factors for AD among diverse populations. This genomic resource is crucial to expanding our knowledge of potential genetic risk and protective variants for AD across all populations with the hope of developing new treatments for everyone