Browsing by Author "Choi, Seo-Eun"
Now showing 1 - 10 of 18
Results Per Page
Sort Options
Item A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores(BMC, 2023-06-22) Kang, Moonil; Ang, Ting Fang Alvin; Devine, Sherral A.; Sherva, Richard; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Gibbons, Laura E.; Scollard, Phoebe; Lee, Michael; Choi, Seo-Eun; Klinedinst, Brandon; Nakano, Connie; Dumitrescu, Logan C.; Durant, Alaina; Hohman, Timothy J.; Cuccaro, Michael L.; Saykin, Andrew J.; Kukull, Walter A.; Bennett, David A.; Wang, Li-San; Mayeux, Richard P.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Crane, Paul K.; Au, Rhoda; Lunetta, Kathryn L.; Mez, Jesse B.; Farrer, Lindsay A.; Radiology and Imaging Sciences, School of MedicineBackground: 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-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10-9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10-8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10-8). GRN (rs5848, P = 4.21 × 10-8) and PURG (rs117523305, P = 1.73 × 10-8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10-8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10-9) and PTPRD (rs145989094, P = 8.34 × 10-9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10-8) and PTPRD (rs145989094, P = 3.85 × 10-8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.Item Association of amyloid and cardiovascular risk with cognition: Findings from KBASE(Wiley, 2024) Chaudhuri, Soumilee; Dempsey, Desarae A.; Huang, Yen-Ning; Park, Tamina; Cao, Sha; Chumin, Evgeny J.; Craft, Hannah; Crane, Paul K.; Mukherjee, Shubhabrata; Choi, Seo-Eun; Scollard, Phoebe; Lee, Michael; Nakano, Connie; Mez, Jesse; Trittschuh, Emily H.; Klinedinst, Brandon S.; Hohman, Timothy J.; Lee, Jun-Young; Kang, Koung Mi; Sohn, Chul-Ho; Kim, Yu Kyeong; Yi, Dahyun; Byun, Min Soo; Risacher, Shannon L.; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of MedicineBackground: Limited research has explored the effect of cardiovascular risk and amyloid interplay on cognitive decline in East Asians. Methods: Vascular burden was quantified using Framingham's General Cardiovascular Risk Score (FRS) in 526 Korean Brain Aging Study (KBASE) participants. Cognitive differences in groups stratified by FRS and amyloid positivity were assessed at baseline and longitudinally. Results: Baseline analyses revealed that amyloid-negative (Aβ-) cognitively normal (CN) individuals with high FRS had lower cognition compared to Aβ- CN individuals with low FRS (p < 0.0001). Longitudinally, amyloid pathology predominantly drove cognitive decline, while FRS alone had negligible effects on cognition in CN and mild cognitive impairment (MCI) groups. Conclusion: Our findings indicate that managing vascular risk may be crucial in preserving cognition in Aβ- individuals early on and before the clinical manifestation of dementia. Within the CN and MCI groups, irrespective of FRS status, amyloid-positive individuals had worse cognitive performance than Aβ- individuals. Highlights: Vascular risk significantly affects cognition in amyloid-negative older Koreans. Amyloid-negative CN older adults with high vascular risk had lower baseline cognition. Amyloid pathology drives cognitive decline in CN and MCI, regardless of vascular risk. The study underscores the impact of vascular health on the AD disease spectrum.Item Associations between Amyloid, Cardiovascular Risk, and Cognitive Function in Korean Older Adults: Insights from the KBASE Cohort(Wiley, 2025-01-09) Chaudhuri, Soumilee; Dempsey, Desarae A.; Huang, Yen-Ning; Cao, Sha; Chumin, Evgeny J.; Craft, Hannah; Crane, Paul K.; Mukherjee, Shubhabrata; Choi, Seo-Eun; Lee, Michael L.; Scollard, Phoebe; Mez, Jesse; Trittschuh, Emily H.; Klinedinst, Brandon S.; Nakano, Connie; Hohman, Timothy J.; Yi, Dahyun; Byun, Min Soo; Risacher, Shannon L.; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE); Radiology and Imaging Sciences, School of MedicineBackground: Understanding the relationship between cardiovascular burden, amyloid, and cognition in Alzheimer’s disease (AD) is essential for targeted interventions, especially in ethnically diverse populations where research remains limited. This study aimed to investigate these relationships in a cohort of Korean older adults along the AD spectrum. Method: 526 participants from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort were included in this study. Vascular burden was quantified using Framingham Risk Score (FRS) and participants were categorized into four groups based on combinations of FRS (FRS High or FRS Low with a median split) and amyloid status (Aβ+ or Aβ‐ based on a cut‐off of 1.2373). Cognitive function was evaluated using standardized neuropsychological tests processed with structural equation models to produce domain scores for memory, executive functioning, language, and visuospatial. ANOVA was employed at baseline to analyze cognitive differences among these groups and within each clinical diagnosis. Longitudinal mixed effects models spanning a period of four years from the initial visit captured cognitive changes over time within these groups (Figure 1). Result: Significant group and pairwise differences were observed among the four groups in all cognitive domains (p < 0.0001). Stratified analysis within each clinical diagnoses group revealed that CN individuals in FRS high Aβ‐ demonstrated significantly lower memory scores compared to those with FRS low Aβ‐ (p < 0.0001), this trend was absent from MCI and AD groups (Figure 2). Longitudinally, FRS high Aβ+ and FRS low Aβ+ groups consistently demonstrated lower memory scores compared to the FRS low Aβ‐ group. Interestingly, no significant difference in cognition was observed between FRS high Aβ‐ and FRS low Aβ‐ groups over time. However, the most pronounced divergence in longitudinal cognition of the four FRS and Amyloid groups was observed within the MCI diagnosis group (Figure 3). Conclusion: This study highlights the differential impact of cardiovascular risk on cognition depending on amyloid status and clinical diagnosis group. This underscores the importance of considering both cardiovascular risk factors and amyloid pathology early‐on in understanding clinical manifestation and cognitive decline in the AD spectrum, particularly in ethnically diverse populations.Item Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults(American Medical Association, 2023) Walters, Skylar; Contreras, Alex G.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Peterson, Amalia; Gifford, Katherine A.; Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Genetics Consortium; Alzheimer’s Disease Sequencing Project; Radiology and Imaging Sciences, School of MedicineImportance: 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 and ε2 associations with cognition. Design, setting, and participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main outcomes and measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.Item Characterization of Language Profiles in Cognitively‐Defined Subgroups of Alzheimer’s Disease(Wiley, 2025-01-03) Gallée, Jeanne; Gibbons, Laura E.; Mukherjee, Shubhabrata; Scollard, Phoebe; Choi, Seo-Eun; James, Bryan D.; Klinedinst, Brandon S.; Lee, Michael L.; Mez, Jesse; Trittschuh, Emily H.; Saykin, Andrew J.; Crane, Paul K.; Medical and Molecular Genetics, School of MedicineBackground: The relationship between Alzheimer’s disease (AD) pathology and the associated clinical syndrome a patient presents with remains indeterminate. Cognitively‐defined subgroups of AD have revealed distinctions based on relative cognitive impairments, including AD‐Language, where challenges in language are substantial, and AD‐No Domain, where no relative asymmetries across cognitive domains occur. Pathological features of AD have been associated as the primary neuropathology of the logopenic variant of primary progressive aphasia (lvPPA). Hallmark clinical features of lvPPA include relatively spared comprehension in the face of decline in naming and repetition abilities. This work aimed to test the hypothesis that the lvPPA language profile was overrepresented in AD‐Language when compared to AD‐No Domain. Method: Measures of verbal comprehension, confrontation naming, and phrase‐level repetition were obtained from all participants from the Religious Orders Study (ROS), the RUSH Memory and Aging Project (MAP) and the Minority Aging Research Study (MARS) using confirmatory factor analyses. We subsetted the data to include participants belonging to the AD‐Language and AD‐No Domain groups at their initial AD diagnosis visit. We compared patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition. Pearson’s Chi‐squared tests with Yates continuity correction was used to test if the language patterns were statistically different between the two AD subgroups. Results: We analyzed language performance in 642 participants across AD‐Language (31.8%) and AD‐No Domain (68.2%) groups (Table 1). Thresholds were based on AD‐No Domain and set as the median for each subdomain (comprehension = ‐.101, naming = ‐.957, repetition = .233) to establish whether a score represented a relative strength or weakness in the language profile. Eight patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition were formed (Figure 1). The distribution of language patterns differed significantly between AD‐Language and AD‐No Domain (χ2 = 97.6, p <.001). Furthermore, the lvPPA pattern was found more frequently in AD‐Language (χ2 = 28.1, p <.001). Conclusion: Heterogeneity within the AD‐Language spectrum includes a significant proportion that is consistent with the language profile of lvPPA. Relative performance in domains of verbal comprehension, confrontation naming, and phrase‐level repetition varied by AD subgroup.Item Cognitively defined Alzheimer's dementia subgroups have distinct atrophy patterns(Wiley, 2024) Crane, Paul K.; Groot, Colin; Ossenkoppele, Rik; Mukherjee, Shubhabrata; Choi, Seo-Eun; Lee, Michael; Scollard, Phoebe; Gibbons, Laura E.; Sanders, R. Elizabeth; Trittschuh, Emily; Saykin, Andrew J.; Mez, Jesse; Nakano, Connie; Mac Donald, Christine; Sohi, Harkirat; Alzheimer’s Disease Neuroimaging Initiative; Risacher, Shannon; Medicine, School of MedicineIntroduction: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups. Methods: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory. Results: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10-10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group. Discussion: MRI findings differ across cognitively defined AD subgroups.Item Epigenetic age acceleration and cognitive resilience in the Framingham Heart Study(Wiley, 2025-01-03) Dacey, Ryan; Durape, Shruti; Wang, Mengyao; Hwang, Phillip H.; Gurnani, Ashita S.; Ang, Ting Fang Alvin; Devine, Sherral A.; Choi, Seo-Eun; Lee, Michael L.; Scollard, Phoebe; Gibbons, Laura E.; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Sherva, Richard; Dumitrescu, Logan C.; Hohman, Timothy J.; Cuccaro, Michael L.; Saykin, Andrew J.; Crane, Paul K.; Li, Yi; Levy, Daniel; Ma, Jiantao; Liu, Chunyu; Lunetta, Kathryn L.; Au, Rhoda; Farrer, Lindsay A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineBackground: 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). Three epigenetic clock measures: DunedinPACE, PC PhenoAge, and PC GrimAge were estimated from the DNA methylation data. Longitudinal NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. We tested the association of epigenetic age acceleration with cognitive trajectories using linear mixed effects models and with time to MCI, all‐cause dementia and AD using Cox‐proportional hazard models. Models were run with and without adjustment for plasma t‐tau. All models included APOE ε4‐carrier status, education, smoking, age, and sex as covariates. Epigenetic measures were standardized in all models. Result: At Exam 8, the sample was, on average, 66.3 (SD = 9.0) years of age, 54.8% female, and had 16.4 (SD = 2.7) years of education. DundeinPACE was significantly associated with faster decline in executive function (βtimeXepi_age = ‐0.005, 95% CI:[‐0.009,‐0.002], p = 0.0020), but not with baseline executive function. Older PhenoAge (βepi_age = ‐0.041, 95% CI:[‐0.067,‐0.014], p = 0.0028) and GrimAge (βepi_age = ‐0.042, 95% CI:[‐0.073,‐0.011], p = 0.0084) were significantly associated with worse baseline executive function, but not with rate of decline. Older PhenoAge also was significantly associated with worse baseline memory (βepi_age = ‐0.037, 95% CI:[‐0.061,‐0.012], p = 0.0036). DunedinPACE was significantly associated with time to MCI (HR = 1.20, 95% CI:[1.06,1.35], p = 0.0034), AD (HR = 1.30, 95% CI:[1.07,1.57], p = 0.0068) and all‐cause dementia (HR = 1.30, 95% CI:[1.10,1.53], p = 0.0017). Results remained similar after adjustment for plasma t‐tau. Conclusion: Epigenetic age acceleration may be a marker of cognitive resilience, particularly in executive function. Of the three epigenetic clocks examined, DundedinPACE showed the most robust associations with cognitive resilience, with lower DunedinPACE associated with greater cognitive resilience.Item Evaluating the association between APOE genotypes and cognitive resilience in SuperAgers(Wiley, 2025-01-03) Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; Cuccaro, Michael L.; Cruchaga, Carlos; Hassenstab, Jason J.; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Albert, Marilyn S.; Johnson, Sterling C.; Engelman, Corinne D.; Mayeux, Richard; Vardarajan, Badri N.; Crane, Paul K.; Dumitrescu, Logan C.; Hohman, Timothy J.; Gaynor, Leslie S.; The Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); The Alzheimer’s Disease Sequencing Project (ADSP); Medical and Molecular Genetics, School of MedicineBackground: “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. Method: Harmonized, longitudinal memory, executive function, and language scores in Non‐Hispanic White (NHW) and Non‐Hispanic Black (NHB) participants were obtained from the ADSP Phenotype Harmonization Consortium. Scores were age‐ and sex‐adjusted. SuperAgers (NHW = 1,625; NHB = 106) included individuals 80+ years of age with a memory score equal to or exceeding individuals aged 50‐64 and language and executive function domain scores within normal limits who remain cognitively normal across visits. SuperAgers were compared to Alzheimer’s disease (AD) cases (NHW = 8,400; NHB = 925) and cognitively normal controls (NHW = 7,355; NHB = 1,305), as well as age‐defined subgroups (Young = ages 50‐64, Older = ages 65‐79, Oldest‐Old = age 80+). We performed binary logistic regression analyses comparing APOE‐ε2 and APOE‐ε4 alleles (0 = none, 1 = 1+ alleles present) among SuperAgers and their counterparts, covarying for sex and education. We corrected for multiple comparisons using the Benjamini‐Hochberg procedure. Results: Across racial groups, SuperAgers had significantly higher proportions with APOE‐ε2 alleles and lower proportions with APOE‐ε4 alleles compared to cases (Table 1, Figure 1). Similar differences were observed between SuperAgers and Young and Old Controls, although differences were restricted to APOE‐ε4 in NHB comparisons. NHW SuperAgers had lower proportions with APOE‐ε4 alleles compared to Oldest‐Old Controls; APOE‐ε2 proportions did not differ. Conclusion: Within our large, harmonized cohort, larger proportions of SuperAgers had APOE‐ε2 alleles and smaller proportions had APOE‐ε4 alleles than AD cases across both NHW and NHB participants. Crucially, higher proportions of NHW SuperAgers had APOE‐ε2 alleles than younger controls (ages<80) and lower proportions had APOE‐ε4 alleles than all controls including age‐matched controls (ages 80+). This work provides the strongest evidence to date that APOE is associated with SuperAging. APOE‐ε2 did not differentiate NHB SuperAgers from controls nor APOE‐ε4 from other oldest‐old adults in present analyses. Future work will extend to whole genome analysis to identify novel genomic drivers of SuperAging.Item Evaluating the association of APOE genotype and cognitive resilience in SuperAgers(medRxiv, 2025-01-07) Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Klinedinst, Brandon S.; Trittschuh, Emily H.; Mez, Jesse; Farrer, Lindsay A.; Gifford, Katherine A.; Cruchaga, Carlos; Hassenstab, Jason; Naj, Adam C.; Wang, Li-San; Johnson, Sterling C.; Engelman, Corinne D.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Cuccaro, Michael L.; Kunkle, Brian W.; Pericak-Vance, Margaret A.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Bush, William S.; Haines, Jonathan L.; Mayeux, Richard; Vardarajan, Badri N.; Albert, Marilyn S.; Thompson, Paul M.; Jefferson, Angela L.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); The Alzheimer’s Disease Sequencing Project (ADSP); Crane, Paul K.; Dumitrescu, Logan; Archer, Derek B.; Hohman, Timothy J.; Gaynor, Leslie S.; Radiology and Imaging Sciences, School of MedicineImportance: "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 APOE 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. Design: This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD. Setting: Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples. Participants: Inclusion in our analyses required APOE genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints. Main outcomes and measures: Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old). Results: Across racialized groups, SuperAgers had significantly higher proportions of APOE-ε2 alleles and lower proportions of APOE-ε4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of APOE-ε4 alleles and significantly higher proportions of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE-ε4 alleles compared to cases and younger controls, and significantly higher proportions of APOE-ε2 alleles compared only to cases. Conclusions and relevance: In the largest study to date, we demonstrated strong evidence that the frequency of APOE-ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.Item Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease(Wiley, 2024) Archer, Derek B.; Eissman, Jaclyn M.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); Alzheimer's Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Mayeux, Richard P.; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Dumitrescu, Logan; Hohman, Timothy J.; Radiology and Imaging Sciences, School of MedicineIntroduction: 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. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.