Browsing by Author "Au, Rhoda"
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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 APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response(Springer Nature, 2024-02-29) Panitch, Rebecca; Sahelijo, Nathan; Hu, Junming; Nho, Kwangsik; Bennett, David A.; Lunetta, Kathryn L.; Au, Rhoda; Stein, Thor D.; Farrer, Lindsay A.; Jun, Gyungah R.; Radiology and Imaging Sciences, School of MedicineThe joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in the APOE region containing TOMM40, APOE, and APOC1 genes with P < 5 × 10-8 between APOE ε4 carriers and non-carriers in brain or blood. In brain, the most significant CpG site hypomethylated in ε4 carriers compared to non-carriers was from the TOMM40 in the total sample, while most of the evidence was derived from AD cases. However, the CpG site was not significantly modulating expression of these three genes in brain. Three CpG sites from the APOE were hypermethylated in APOE ε4 carriers in brain or blood compared in ε4 non-carriers and nominally significant with APOE expression in brain. Three CpG sites from the APOC1 were hypermethylated in blood, which one of the 3 CpG sites significantly lowered APOC1 expression in blood using all subjects or ε4 non-carriers. Co-methylation network analysis in blood and brain detected eight methylation networks associated with AD and APOE ε4 status. Five of the eight networks included genes containing network CpGs that were significantly enriched for estradiol perturbation, where four of the five networks were enriched for the estrogen response pathway. Our findings provide further evidence of the role of APOE genotype on methylation levels associated with AD, especially linked to estrogen response pathway.Item Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians(Wiley, 2024) Ho, Pei-Chuan; Yu, Wai Haung; Tee, Boon Lead; Lee, Wan-Ping; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Choi, Yun-Beom; Yang, Hyun-Sik; Vardarajan, Badri N.; Tzuang, Marian; Lieu, Kevin; Lu, Anna; Faber, Kelley M.; Potter, Zoë D.; Revta, Carolyn; Kirsch, Maureen; McCallum, Jake; Mei, Diana; Booth, Briana; Cantwell, Laura B.; Chen, Fangcong; Chou, Sephera; Clark, Dewi; Deng, Michelle; Hong, Ting Hei; Hwang, Ling-Jen; Jiang, Lilly; Joo, Yoonmee; Kang, Younhee; Kim, Ellen S.; Kim, Hoowon; Kim, Kyungmin; Kuzma, Amanda B.; Lam, Eleanor; Lanata, Serggio C.; Lee, Kunho; Li, Donghe; Li, Mingyao; Li, Xiang; Liu, Chia-Lun; Liu, Collin; Liu, Linghsi; Lupo, Jody-Lynn; Nguyen, Khai; Pfleuger, Shannon E.; Qian, James; Qian, Winnie; Ramirez, Veronica; Russ, Kristen A.; Seo, Eun Hyun; Song, Yeunjoo E.; Tartaglia, Maria Carmela; Tian, Lu; Torres, Mina; Vo, Namkhue; Wong, Ellen C.; Xie, Yuan; Yau, Eugene B.; Yi, Isabelle; Yu, Victoria; Zeng, Xiaoyi; St. George-Hyslop, Peter; Au, Rhoda; Schellenberg, Gerard D.; Dage, Jeffrey L.; Varma, Rohit; Hsiung, Ging-Yuek R.; Rosen, Howard; Henderson, Victor W.; Foroud, Tatiana; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Feldman, Howard H.; Mayeux, Richard; Chui, Helena; Jun, Gyungah R.; Ta Park, Van M.; Chow, Tiffany W.; Wang, Li-San; Medical and Molecular Genetics, School of MedicineIntroduction: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. Methods: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. Results: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. Discussion: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. Highlights: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.Item Designing the next-generation clinical care pathway for Alzheimer’s disease(Springer Nature, 2022) Hampel, Harald; Au, Rhoda; Mattke, Soeren; van der Flier, Wiesje M.; Aisen, Paul; Apostolova, Liana; Chen, Christopher; Cho, Min; De Santi, Susan; Gao, Peng; Iwata, Atsushi; Kurzman, Ricky; Saykin, Andrew J.; Teipel, Stefan; Vellas, Bruno; Vergallo, Andrea; Wang, Huali; Cummings, Jeffrey; Neurology, School of MedicineThe reconceptualization of Alzheimer's disease (AD) as a clinical and biological construct has facilitated the development of biomarker-guided, pathway-based targeted therapies, many of which have reached late-stage development with the near-term potential to enter global clinical practice. These medical advances mark an unprecedented paradigm shift and requires an optimized global framework for clinical care pathways for AD. In this Perspective, we describe the blueprint for transitioning from the current, clinical symptom-focused and inherently late-stage diagnosis and management of AD to the next-generation pathway that incorporates biomarker-guided and digitally facilitated decision-making algorithms for risk stratification, early detection, timely diagnosis, and preventative or therapeutic interventions. We address critical and high-priority challenges, propose evidence-based strategic solutions, and emphasize that the perspectives of affected individuals and care partners need to be considered and integrated.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 Implementing a biomarker‐enabled care pathway to accelerate identification of early‐stage Alzheimer’s disease in primary care(Wiley, 2025-01-09) Borson, Soo; Au, Rhoda; Chodos, Anna H.; Gandy, Sam E.; Jain, Holly; Kerwin, Diana R.; Mintzer, Jacobo; Monroe, Stephanie; Robinson, Delecia; Wilcock, Donna M.; Mielke, Michelle M.; Neurology, School of MedicineBackground: New blood‐based and digital biomarkers for Alzheimer’s disease (AD) make early detection possible at stages when novel, disease‐specific therapies are likely to be most effective. These approaches may offer less invasive, more cost‐effective alternatives to traditional methods such as cerebrospinal fluid (CSF) collection or positron emission tomography (PET) imaging for diagnosing and staging AD. Building care pathways leveraging blood‐based and digital biomarkers starts with understanding the current biomarker landscape and considering opportunities for widespread implementation in primary care clinical practice. Methods: A multidisciplinary team representing neurology, neuropsychology, geriatrics, primary care, epidemiology, laboratory programs, and patient advocacy was convened to review a summary of current biomarker research findings and discuss barriers and opportunities to implement biomarkers as part of an AD consensus‐driven clinical care pathway. Results: The emergence of biomarkers has shifted diagnosis from primarily clinical to a biological definition of AD. However, there is currently no consensus on where biomarkers fit within an AD care pathway and when they should be utilized in primary care or dementia specialist care settings. We found a relative paucity of published data on biomarker test accuracy in diagnosis outside tightly controlled research settings, limiting guidance around how results should be interpreted and managed in real‐world care settings. Evidence gaps are especially pressing for heterogeneous, diverse populations under‐represented in AD research. New biomedical therapies specific to the pathobiology of AD are driving research on blood and digital biomarkers to inform optimal ways to accelerate identification. As most individuals with AD are not evaluated by specialists, accurate and usable information about the place of biomarkers in the diagnosis and treatment of cognitive impairment must reach primary care Conclusions: With growing interest in the promise of non‐invasive biomarkers to improve detection, differentiation, and diagnosis of AD, new research is needed to generate real‐world evidence about their performance across populations, how to interpret results, and how best to use them in patient management. Effective educational strategies are needed to disseminate high‐quality evidence that engages primary care and healthcare delivery systems in implementing optimal clinical pathways. More detailed learnings for successful care pathway implementation will be shared.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 Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease(Wiley, 2022-11) Jun, Gyungah R.; You, Yang; Zhu, Congcong; Meng, Gaoyuan; Chung, Jaeyoon; Panitch, Rebecca; Hu, Junming; Xia, Weiming; The Alzheimer's Disease Genetics Consortium; Bennett, David A.; Foroud, Tatiana M.; Wang, Li-San; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Au, Rhoda; Lunetta, Kathryn L.; Ikezu, Tsuneya; Stein, Thor D.; Farrer, Lindsay A.; Medical and Molecular Genetics, School of MedicineIntroduction The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. Methods We conducted a genome‐wide association study for AD among 2096 ɛ2 carriers. The potential role of the top‐ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele‐specific induced pluripotent stem cell (iPSC)–derived neurons and astrocytes and in 224 neuropathologically examined human brains. Results PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10−7) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10−27). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10−4) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10−7). Discussion PP2A may be linked to classical complement activation leading to AD‐related tau pathology.Item Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease(Wiley, 2022) Jun, Gyungah R.; You, Yang; Zhu, Congcong; Meng, Gaoyuan; Chung, Jaeyoon; Panitch, Rebecca; Hu, Junming; Xia, Weiming; The Alzheimer’s Disease Genetics Consortium; Bennett, David A.; Foroud, Tatiana M.; Wang, Li-San; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Au, Rhoda; Lunetta, Kathryn L.; Ikezu, Tsuneya; Stein, Thor D.; Farrer, Lindsay A.; Medical and Molecular Genetics, School of MedicineIntroduction: The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. Methods: We conducted a genome-wide association study for AD among 2096 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. Results: PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10-7 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10-27 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10-4 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10-7 ). Discussion: PP2A may be linked to classical complement activation leading to AD-related tau pathology.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.