Browsing by Author "Devine, Sherral A."

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    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 Medicine
    Background: 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.
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    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 Medicine
    Background: 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.
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    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 Medicine
    Background: 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.
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    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 Medicine
    Background: 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.