Browsing by Author "Dumitrescu, Logan C."
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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 Astrocyte Reactivity Polygenic Risk Score May Predict Cognitive Decline in Alzheimer’s Disease(World Scientific, 2025) Phillips, Jared M.; Schneider, Julie A.; Bennett, David A.; Crane, Paul K.; Risacher, Shannon L.; Saykin, Andrew J.; Dumitrescu, Logan C.; Hohman, Timothy J.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineAlzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration. Polygenic risk scores (PRS) aggregate the effects of multiple genetic loci to provide a single, continuous metric representing an individual's genetic risk for a specific phenotype. We hypothesized that an astrocyte activation PRS could aid in the early detection of faster clinical decline. Therefore, we constructed an astrocyte activation PRS and assessed its predictive value for cognitive decline and AD biomarkers (i.e., cerebrospinal fluid [CSF] levels of Aβ1-42, total tau, and p-tau181) in a cohort of 791 elderly individuals. The astrocyte activation PRS showed significant main effects on cross-sectional memory (β = -0.07, p = 0.03) and longitudinal executive function (β = -0.01, p = 0.03). Additionally, the PRS interacted with amyloid positivity (p.intx = 0.02), whereby indicating that amyloid burden modifies the association between the PRS and annual rate of language decline. Furthermore, the PRS was negatively associated with CSF Aβ1-42 levels (β = -3.4, p = 0.07) and interacted with amyloid status, such that amyloid burden modifies the association between the PRS and CSF phosphorylated tau levels (p.intx = 0.08). These findings suggest that an astrocyte activation PRS could be a valuable tool for early disease risk prediction, potentially enabling intervention during the interval between pathogenic amyloid and tau accumulation.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 Genetic and Sex Associations with Earlier Estimated Onset of Amyloid Positivity from over 4000 Harmonized Positron Emission Tomography Images(Wiley, 2025-01-09) Castellano, Tonnar; Wang, Ting Chen; Nolan, Emma; Archer, Derek B.; Cody, Karly; Harrison, Theresa M.; Wu, Yiyang; Durant, Alaina; Janve, Vaibhav A.; Engelman, Corinne D.; Jagust, William J.; Albert, Marilyn S.; Johnson, Sterling C.; Resnick, Susan M.; Sperling, Reisa A.; Bilgel, Murat; Saykin, Andrew J.; Vardarajan, Badri N.; Mayeux, Richard; Betthauser, Tobey J.; Dumitrescu, Logan C.; Mormino, Elizabeth; Hohman, Timothy J.; Koran, Mary Ellen I.; Radiology and Imaging Sciences, School of MedicineBackground: New techniques have been developed to estimate the age when someone converted to amyloid positivity (EAOA) from PET, oftentimes offering information about a participant decades before they joined a research study. EAOA is variable across populations but we do not know the causes for these differences. This study aims to validate APOE associations with EAOA and explore genetic and sex‐based factors with EAOA. Methods: Data from six cohorts were analyzed. Our analysis included 4220 non‐Hispanic white people (57.6% women; 86.7% cognitively unimpaired at baseline scan). Amyloid PET data were harmonized using gaussian mixture models. EAOA was calculated using the sampled iterative local approximation (SILA) algorithm. Sex differences in EAOA were compared using t‐tests amongst amyloid positive individuals. A genome‐wide association study of EAOA was performed. Gene analyses were conducted using MAGMA. Results: Average EAOA was 81.1 years across all individuals regardless of amyloid status. APOE e2 homozygotes had slightly later EAOA than e3/e3 homozygotes. APOE e4 homozygotes converted to amyloid positivity 8.2 years before e3/e4 heterozygotes and over two decades earlier than e3 homozygotes. APOE e2/e4 converted to positivity roughly three years later than e3/e4 and nearly ten years earlier than e3 homozygotes. APOE genotype differences in EAOA described were statistically significant (p < .01). There were significant sex differences between men and women when examining amyloid positivity. Men converted to amyloid positivity over 2 years later than women (65.3 vs 63.2 years, p=3.23x10‐5). The rs12981369 polymorphism in ABCA7 was associated with EAOA (β = 2.14, p=9.27×10−9). Brain eQTL databases indicate associations between rs12981369 and gene expression of ABCA7. Gene‐level analyses revealed significant associations for ABCA7, HMHA1, and KIF13B. Conclusion: This study further describes the role of APOE and reveals roles for ABCA7 and KIF13B on amyloid onset. We identified a novel variant on chromosome 19 correlating with later amyloid onset conversion and highlight important differences between sexes. These findings highlight EAOA as a powerful endophenotype of AD and offer insights into potential drug‐targetable mechanisms for early AD intervention.Item Novel rare variant associations with late‐life cognitive performance(Wiley, 2025-01-09) Regelson, Alexandra N.; Archer, Derek B.; Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse; Bush, William S.; Kuzma, Amanda B.; Cuccaro, Michael L.; Cruchaga, Carlos; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Mayeux, Richard; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Johnson, Sterling C.; Engelman, Corinne D.; Bennett, David A.; Barnes, Lisa L.; Larson, Eric B.; Nho, Kwangsik; Goate, Alison M.; Renton, Alan E.; Marcora, Edoardo; Fulton-Howard, Brian; Patel, Tulsi; Risacher, Shannon L.; DeStefano, Anita L.; Schneider, Julie A.; Habes, Mohamad; Seshadri, Sudha; Satizabal, Claudia L.; Maillard, Pauline; Toga, Arthur W.; Crawford, Karen; Tosun, Duygu; Vance, Jeffery M.; Mormino, Elizabeth; DeCarli, Charles S.; Montine, Thomas J.; Beecham, Gary; Biber, Sarah A.; De Jager, Philip L.; Vardarajan, Badri N.; Lee, Annie J.; Brickman, Adam M.; Reitz, Christiane; Manly, Jennifer J.; Lu, Qiongshi; Rentería, Miguel Arce; Deming, Yuetiva; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan C.; Medical and Molecular Genetics, School of MedicineBackground: Despite evidence that Alzheimer’s disease (AD) is highly heritable, there remains substantial “missing” heritability, likely due in part to the effect of rare variants and to the past reliance on case‐control analysis. Here, we leverage powerful endophenotypes of AD (cognitive performance across multiple cognitive domains) in a rare variant analysis to identify novel genetic drivers of cognition in aging and disease. Method: We leveraged 8 cohorts of cognitive aging with whole genome sequencing data from the AD Sequencing Project to conduct rare variant analyses of multiple domains of cognition (N = 9,317; mean age = 73; 56% female; 52% cognitively unimpaired). Harmonized scores for memory, executive function, and language were derived using confirmatory factor analysis models. Participants genetically similar to the 1000Genomes EUR reference panel were included in analysis. Variants included in the analysis had a minor allele frequency < 0.01, a minor allele count of ≥ 10, and were annotated as a high or moderate impact SNP using VEP. Associations of baseline scores in each cognitive domain were performed using SKAT‐O, including 92,905 rare variants among 16,243 genes. All tests were adjusted for sex, baseline age, sequencing center and platform, and genetic principal components. Correction for multiple comparisons was completed using the Benjamini‐Hochberg false discovery rate (FDR) procedure. Result: APOE was associated with baseline memory, language, and executive function, though only memory survived multiple‐test correction (p.FDR = 0.001). Outside of APOE, ITPKB was associated with baseline executive function (p.FDR = 0.048). AKTIP, SHCBP1L, and CCNF showed nominal associations with multiple domains of cognition that did not survive correction for multiple comparisons (p.FDRs<0.07). Conclusion: These results highlight novel rare variants associated with cognition. IPTKB is an AGORA nominated gene target for potential AD treatment. It is important in the regulation of immune cells and displays higher expression in the cortex of AD patients compared to controls. CCNF and AKTIP are brain eQTLs and have differential RNA expression in AD brains. Previously, variants in AKTIP have been associated with educational attainment, intelligence, and memory, while variants in CCNF have been associated with neuritic plaques and neurofibrillary tangles. Future analyses will incorporate longitudinal cognition and expand into additional populations.Item Occupational complexity and cognitive resilience in the Framingham Heart Study(Wiley, 2025-01-09) Hwang, Phillip H.; Feng, Irena; Durape, Shruti; 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.; Saykin, Andrew J.; Crane, Paul K.; Au, Rhoda; Farrer, Lindsay A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineBackground: Greater occupational complexity may be protective against dementia in later life, but it is unclear if it contributes to cognitive resilience and whether different aspects of occupational complexity are associated with resilience. We examined relationships between occupational complexity related to data, people, and things, and cognitive resilience to neurodegeneration. Method: 1,699 participants from the Framingham Heart Study Offspring cohort who were aged ≥60 years, had a plasma total tau (t‐tau) measure (a marker of neurodegeneration), and a neuropsychological (NP) exam visit within five years of the plasma t‐tau measurement were included. Plasma t‐tau was measured using the Simoa assay (Quanterix) on samples collected at Exam 8 (2005‐2008). NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. Occupational data were collected at the NP exam, from which occupational complexity was disaggregated into data complexity, people complexity, and things complexity according to the 1970 US Census Dictionary of Occupational Titles. Cognitive resilience was operationalized using a residual approach by regressing each NP factor score on the plasma t‐tau measure, adjusting for age, sex, education, time from blood draw, and APOE ε4 status. The adjusted residuals were then regressed on each type of occupational complexity, dichotomized into higher complexity versus lower complexity. Result: The sample was, on average, 70 years of age, 53% female, and had 15 years of education. Higher data (β = 0.20, 95% confidence interval (CI) = 0.15‐0.25, p<0.001), people (β = 0.11, 95% CI = 0.07‐0.15, p<0.001), and things (β = 0.05, 95% CI = 0.01‐0.09, p = 0.015) occupational complexity were most strongly associated with resilience in executive function. Higher data (β = 0.10, 95% CI = 0.05‐0.15, p<0.001) and people (β = 0.07, 95% CI = 0.03‐0.11, p = 0.001) occupational complexity were associated with resilience in memory. Higher data (β = 0.07, 95% CI = 0.01‐0.12, p = 0.014) occupational complexity was associated with resilience in language. Conclusion: Specific types of occupational complexity contribute to resilience to neurodegeneration in specific cognitive domains differently. Occupational complexity may offer the most resilience in executive function and occupations with high data complexity may offer the most cognitive resilience.Item Sex, racial/ethnic, and APOE‐ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging(Wiley, 2025-01-09) Peterson, Amalia Jo; Sathe, Aditi; Yang, Yisu; Durant, Alaina; Shashikumar, Niranjana; Pechman, Kimberly R.; Dumitrescu, Logan C.; Gifford, Katherine A.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Schilling, Kurt; Landman, Bennett A.; Schneider, Julie A.; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of MedicineBackground: There is growing recognition that white matter microstructural integrity is affected in Alzheimer’s disease. The goal of this study was to characterize sex, racial/ethnic, and apolipoprotein (APOE)‐ε4 allele differences in white matter integrity. Methods: This study included participants from ADNI, BLSA, ROS/MAP/MARS, and VMAP, all longitudinal cohorts of aging. This combined dataset included 6,837 imaging sessions from 2,619 participants age 50+ with diffusion MRI (dMRI) and demographic and clinical data (60% female, 31.4% APOE‐ε4 carriers, 78.9% White). dMRI was preprocessed using the PreQual pipeline. Free‐water (FW) correction was used to generate FW and FW‐corrected intracellular metrics including fractional anisotropy (FAFWcorr), mean diffusivity (MDFWcorr), axial diffusivity (AxDFWcorr), and radial diffusivity (RDFWcorr). Conventional and FW‐corrected metrics were harmonized using the Longitudinal ComBat package. Linear mixed‐effects models related sex, race/ethnicity, and APOE‐ε4 allele status to longitudinal diffusion metrics in 48 white matter tracts, adjusting for age at baseline, sex, education, race/ethnicity, APOE‐ε4 carrier status, cognitive status at baseline, and converter status. All models were corrected for multiple comparisons using the FDR approach. Result: Sex differences in white matter were most notable in projection tracts (Figure 1A) and were primarily in FW‐corrected metrics. Females had lower FAFWcorr and higher RDFWcorr, indicative of worse microstructure, but lower AxDFWcorr. This sex difference was most pronounced for FAFWcorr in the ventral premotor projection tract (p=1.53x10‐62). There were global differences in white matter integrity by race/ethnicity (Figure 1B). Non‐Hispanic White participants tended to have higher conventional FA, FAFWcorr and AxDFWcorr and lower RDFWcorr. There was no association between APOE‐ε4 status and white matter integrity and no significant sex x race/ethnicity, sex x APOE‐ε4, or race/ethnicity x APOE‐ε4 interactions for conventional or FW‐corrected metrics when corrected for multiple comparisons. Conclusion: There were striking sex and racial/ethnic (but not APOE‐ε4) differences in white matter tract integrity in a large cohort of aging adults. Female participants tended to have measures reflective of worse white matter integrity, and non‐Hispanic White participants tended to have measures reflective of greater integrity. Additional research exploring the etiology of these differences will be important to better understand disparities in Alzheimer’s disease.Item Traumatic brain injury and cognitive resilience in the Framingham Heart Study(Wiley, 2025-01-09) Hwang, Phillip H.; Durape, Shruti; Price, Eden; 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.; Saykin, Andrew J.; Crane, Paul K.; Tripodis, Yorghos; Alosco, Michael L.; Katz, Douglas I.; Dams-O'Connor, Kristen; Au, Rhoda; Farrer, Lindsay A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineBackground: Some evidence supports an association between traumatic brain injury (TBI) and greater risk of dementia, but the role of cognitive resilience in this association is poorly understood. Method: 2,050 participants from the Framingham Heart Study Offspring cohort who were aged ≥60 year and had a plasma total tau (t‐tau) measure at Exam 8 (2005‐2008), and a neuropsychological (NP) exam visit within five years were included. Plasma t‐tau was measured using the Simoa assay (Quanterix). NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. Information on TBIs was collected by comprehensive review of medical records, health history updates, exams, and self‐report. TBI occurrence and severity were operationalized using modified ACRM & VA/DoD criteria, respectively. Cognitive resilience was operationalized using a residual approach by regressing each NP factor score on the plasma t‐tau measure, adjusting for age at Exam 8, sex, education, time from blood draw, and APOE ε4 genotype. The adjusted residuals were then regressed on history of TBI (yes versus no), and severity of TBI (moderate‐to‐severe versus mild versus none). Result: The sample was, on average, 67 years of age at Exam 8, 54% female, and college educated. No differences were observed in plasma t‐tau levels between those with and without TBI. Having a history of TBI was significantly associated with a reduction in resilience in executive function (β: ‐0.110; 95% CI: ‐0.175, ‐0.044; p: 0.001) as compared to not having a history of TBI. No significant associations were observed between history of TBI and resilience in memory or language. Greater TBI severity was significantly associated with worse resilience in executive function in a dose‐response manner (Ptrend: <0.001), with the association being strongest in the moderate‐to‐severe TBI group (β: ‐0.209; 95% CI: ‐0.340, ‐0.078; p: 0.002) followed by the mild TBI group (β: ‐0.082; 95% CI: ‐0.155, ‐0.010; p: 0.026). Conclusion: Having a TBI was associated with worse resilience to neurodegeneration in executive function, and most strongly among individuals with moderate‐to‐severe TBI. These results suggest that having a TBI may increase vulnerability to late‐life executive dysfunction after accounting for a primary neurodegenerative disease process.Item Uncovering the role of white matter microstructure in longitudinal memory and executive function decline: insights from a multi‐site study of 2,220 participants across 4,918 paired imaging‐cognition sessions(Wiley, 2025-01-09) Archer, Derek B.; Peter, Chris; Sathe, Aditi; Yang, Yisu; Durant, Alaina; Shashikumar, Niranjana; Pechman, Kimberly R.; Dumitrescu, Logan C.; Gifford, Katherine A.; Mukherjee, Shubhabrata; Klinedinst, Brandon S.; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Schilling, Kurt; Landman, Bennett A.; Schneider, Julie A.; Barnes, Lisa L.; Bennett, David A.; Crane, Paul K.; Kukull, Walter A.; Johnson, Sterling C.; Albert, Marilyn S.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of MedicineBackground: Recent research emphasizes the significance of white matter tracts and the free‐water (FW) component in understanding cognitive decline. The goal of this study is to conduct a large‐scale assessment on the role of white matter microstructure on longitudinal cognitive decline. Method: This study used a cohort collated from seven longitudinal cohorts of aging (ADNI, BIOCARD, BLSA, NACC, ROS/MAP/MARS, VMAP, and WRAP). In total, this dataset included 2,220 participants aged 50+ who had both diffusion MRI and harmonized composites of memory performance and executive function. This dataset included a total of 4,918 imaging sessions with corresponding cognitive data (mean number of visits per participant: 1.69 ± 1.67, interval range: 1‐10 years). Diffusion MRI was preprocessed using the PreQual pipeline and FW correction was used to create FW and FW‐corrected intracellular metrics. Conventional and FW‐corrected measures were harmonized using the Longitudinal ComBat package. Linear mixed effects regression was used for longitudinal analysis, in which we covaried for age, age squared, education, sex, race/ethnicity, diagnosis at baseline, APOE‐ε4 status, and APOE‐ε2 status. All models were corrected for multiple comparisons using the FDR approach. Result: For longitudinal memory performance, we found global associations with conventional diffusion MRI metrics, in which abnormalities were associated with lower memory performance. Following FW correction, we found that the FW metric itself was strongly associated with memory performance, in which higher FW was associated with lower memory performance and exacerbated decline. Interestingly, following FW‐correction the intracellular contributions were largely mitigated. As illustrated in Figure 1A, the most significant effects were found in the limbic tracts, with the most significant associations found for cingulum bundle FW (p=5.80x10‐45). Figure 1B illustrates the association between cingulum FW and longitudinal memory performance. Findings for longitudinal executive function performance are shown in Figure 2. Conclusion: To date, this is the largest study combining FW‐corrected diffusion MRI data and harmonized cognitive composites to understand cognitive trajectories in aging. Future studies evaluating how white matter microstructure may be incorporated into models of AD may further our knowledge into the neurodegenerative cascade of AD.