Browsing by Author "Biber, Sarah A."

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    Assessment of Interest and Resources Needed for the Development of Scalable Healthcare Professionals Facilitated Strategies to Diversify Alzheimer’s Disease Research Participation
    (Wiley, 2025-01-09) Parker, Monica W.; Glover, Crystal M.; Johnson, David K.; Arce Rentería, Miguel; Biber, Sarah A.; Wang, Sophia; Psychiatry, School of Medicine
    Background: Increasing underrepresented racial and ethnic minority group (URG) participation in early‐stage Alzheimer’s disease and related dementias (ADRD) research is critical to inclusive characterization of underlying pathology and testing of disease‐modifying treatments. One promising recruitment strategy to accelerate URG participation is for healthcare professionals (HCPs) to facilitate referrals. The use of HCP‐facilitated recruitment strategies across the Alzheimer’s Disease Research Center (ADRC) network, a major referral source for ADRD multisite observational and clinical trials, has not been examined. We hypothesized that there would be interest in the development of scalable HCP‐facilitated recruitment strategies to accelerate URG participation across the ADRC network. Methods: We emailed Outreach, Recruitment and Engagement (ORE) Cores within the NIA‐funded ADRC network to complete a web‐based REDCap™ survey on their current HCP‐facilitated recruitment strategies for URG participants, resources enhancing use of these strategies, and their interest in strategy development. We conducted descriptive statistics using SPSS 29.0. Results: Out of 37 ADRCs, 27 (73.0%) completed the survey. Although the majority of ADRCs (66.7%, N = 18) reported HCPs referring URG participants (Table 1), they mostly relied on HCP faculty based at the ADRC (48.1%, N = 13) or the ADRC affiliated academic medical center (51.9%, N = 14) (Table 2). Nearly all (92.5%, N = 25) ORE Cores expressed interest in participating in or learning more about future efforts to develop HCP‐facilitated recruitment strategies for increasing URG participation. Resources which would increase use of HCP‐facilitated strategies for URG referrals included guidance on outreach and engagement strategies (70.4%, N = 19), culturally tailored resources for HCPs to refer participants (59.3%, N = 16), technology and informatic recruitment strategies (63.0%, N = 17), and staff effort (63.0%, N = 17) (Table 3). Conclusions: Our survey identified key opportunities to develop novel scalable HCP‐facilitated recruitment strategies to accelerate URG participation. Although most ORE Cores expressed interest in expanding their HCP‐facilitated recruitment strategies to have more inclusive research participation, there is need for both higher‐level strategic guidance and ready‐to‐use resources to implement these strategies. Future studies will need to develop and test scalable HCP‐facilitated strategies and resources to systematically accelerate URG research participation.
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    Differences in referral source across racial and ethnic groups at Alzheimer’s Disease Research Centers
    (Wiley, 2025-01-09) Chan, Carol; Lane, Kathleen A.; Gao, Sujuan; Adeoye-Olatunde, Omolola A.; Biber, Sarah A.; Risacher, Shannon L.; Saykin, Andrew J.; Wang, Sophia; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Background: Despite recognition of the need to increase underrepresented groups (URG) engagement in Alzheimer’s disease and related dementias (ADRD) studies, enrollment remains low. As a first step in examining these disparities, these analyses aimed to compare referral sources for Alzheimer’s Disease Research Centers (ADRC) enrollment of URG participants. Method: These analyses included data from 48,330 participants across 46 ADRCs, obtained through the National Alzheimer’s Coordinating Center Uniform Data Set. Generalized logistic regression models with generalized estimating equations were used to examine the association of racial/ethnic group and professional vs non‐professional referral source. The ‘professional’ category included referrals made by healthcare professionals or ADRC staff, while the ‘non‐professional’ category included referrals made by self, family or friends. This association was examined across the entire sample, and then individuals who had completed magnetic resonance imaging (MRI). The analyses were adjusted for age, gender, education, visit year, and categorical CDR with random site effect to adjust for study site. Result: Descriptive statistics are shown in Table 1. Non‐Hispanic Black and Asian participants were less likely to have completed an MRI. Across the entire sample, Non‐Hispanic Black and Non‐Hispanic Asian participants were less likely to be referred by a professional contact than Non‐Hispanic White participants (Table 2). In those who had completed an MRI, there were no significant differences across the racial groups, although we note that the sample sizes for those with MRI were much smaller (Table 3). Results for both analyses were similar when only participants who had a diagnosis of MCI or dementia and a global CDR of 0.5 or 1 at baseline were included. Conclusion: One major factor leading to lower rates of URG participation in ADRD research is disproportionately fewer healthcare professional referrals. To develop and optimize ADRC recruitment strategies, future studies are needed to explore reasons for differences in URG referrals by healthcare professionals and non‐professionals.
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    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 Medicine
    Background: 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.
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    Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease
    (Wiley, 2025) Peterson, Amalia; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Deters, Kacie D.; Shashikumar, Niranjana; Pechman, Kimberly R.; Kim, Michael E.; Gao, Chenyu; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Gifford, Katherine A.; Wilson, Jo Ellen; Cambronero, Francis E.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Habes, Mohamad; Wang, Di; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. Methods: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. Results: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. Discussion: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. Highlights: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.
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    Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer’s disease
    (bioRxiv, 2024-06-12) Peterson, Amalia; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Deters, Kacie D.; Shashikumar, Niranjana; Pechman, Kimberly R.; Kim, Michael E.; Gao, Chenyu; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Gifford, Katherine A.; Wilson, Jo Ellen; Cambronero, Francis; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Alzheimer’s Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer’s Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. Methods: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. Results: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. Discussion: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.
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    The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI)
    (Wiley, 2025) Mormino, Elizabeth C.; Biber, Sarah A.; Rahman-Filipiak, Annalise; Arfanakis, Konstantinos; Clark, Lindsay; Dage, Jeffrey L.; Detre, John A.; Dickerson, Bradford C.; Donohue, Michael C.; Kecskemeti, Steven; Hohman, Timothy J.; Jagust, William J.; Keene, Dirk C.; Kukull, Walter; Levendovszky, Swati R.; Rosen, Howie; Thompson, Paul M.; Villemagne, Victor L.; Wolk, David A.; Okonkwo, Ozioma C.; Rabinvovici, Gil D.; Rivera-Mindt, Monica; Foroud, Tatiana; Johnson, Sterling C.; Neurology, School of Medicine
    The presence of multiple pathologies is the largest predictor of dementia. A major gap in the field is the in vivo detection of mixed pathologies and their antecedents. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address this gap. The ADRCs longitudinally follow ≈ 17,000 participants, ranging from cognitively unimpaired to dementia, arising from Alzheimer's disease (AD) and related dementias (ADRD; e.g., AD, Lewy body disorders, vascular). Motivated by the Alzheimer's Disease Neuroimaging Initiative's (ADNI) impact, the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) was formed. Leveraging existing ADRC infrastructure, CLARiTI will integrate standardized imaging and plasma collection to characterize mixed pathologies and use community-engaged research methods to ensure that ≥ 25% of the sample is from underrepresented populations (e.g., ethnoculturally minoritized, low education). The resulting ADRD profiles, within a more diverse sample, will provide key resources for ADRCs and an unprecedented, more generalizable publicly available imaging-plasma dataset. HIGHLIGHTS: In vivo detection of mixed pathologies is critical for Alzheimer's disease and related dementias research. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address gaps related to mixed pathologies. The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will enhance this national program by adding standardized imaging and plasma collection to existing ADRC infrastructure. This effort will provide key resources for ADRCs and an unprecedented publicly available imaging-plasma-neuropath dataset.
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    The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
    (Wiley, 2025) Lorenz, Anna; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Kim, Michael E.; Gao, Chenyu; Newlin, Nancy R.; Ramadass, Karthik; Kanakaraj, Praitayini; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Shashikumar, Niranjana; Pechman, Kimberly R.; Jackson, Trevor Bryan; Workmeister, Abigail W.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Habes, Mohamad; Wang, Di; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI)The BIOCARD Study Team; The Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Bendlin, Barbara; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences. Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status. Results: AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure. Discussion: These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults. Highlights: AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.
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    White Matter Abnormalities and Cognition in Aging and Alzheimer Disease
    (American Medical Association, 2025-06-09) Peter, Christopher; Sathe, Aditi; Shashikumar, Niranjana; Pechman, Kimberly R.; Workmeister, Abigail W.; Jackson, T. Bryan; Huo, Yuankai; Mukherjee, Shubhabrata; Mez, Jesse; Dumitrescu, Logan C.; Gifford, Katherine A.; Bolton, Corey J.; Gaynor, Leslie S.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun-Turgut, Duygu; Habes, Mohamad; Wang, Di; Toga, Arthur W.; Thompson, Paul M.; Zhang, Panpan; Schilling, Kurt G.; Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Bendlin, Barbara B.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Crane, Paul K.; Cuccaro, Michael L.; Hohman, Timothy J.; Archer, Derek B.; Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) Analyst Team; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Biomarkers of Cognitive Decline Among Normal Adults (BIOCARD) Study Team; Alzheimer’s Disease Sequencing Project (ADSP); Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Kanakaraj, Praitayini; Kim, Michael E.; Gao, Chenyu; Newlin, Nancy R.; Ramadass, Karthik; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Choi, Seo-Eun; Klinedinst, Brandon; Lee, Michael L.; Scollard, Phoebe; Trittschuh, Emily H.; Sanders, Elizabeth A.; Radiology and Imaging Sciences, School of Medicine
    Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD). Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment. Design, setting, and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were aged 50 years or older, and passed neuroimaging quality control. Demographic and clinical covariates included age, sex, education, race and ethnicity, APOE haplotype status (ε2, ε3, ε4), and clinical status. The present study was conducted from June 2024 to February 2025. Exposures: White matter microstructure and cognitive performance and decline. Main outcomes and measures: Clinical diagnosis, imaging measures (dMRI, T1-weighted MRI, and amyloid and tau positron emission tomography), and cognitive tests. Results: Of 4467 participants who underwent 9208 longitudinal cognitive sessions, 2698 (60.4%) were female, and the mean age (SD) was 74.3 (9.2) years; 3213 were cognitively unimpaired, 972 had mild cognitive impairment, and 282 had AD dementia. White matter free water (FW) showed the strongest associations with cross-sectional cognitive performance and longitudinal cognitive decline across all domains, particularly memory. FW in limbic tracts, such as the cingulum, presented the strongest associations with both memory performance (cingulum: β = -0.718; P < .001; fornix: β = -1.069; P < .001) and decline (cingulum: β = -0.115; P < .001; fornix: β = -0.153; P < .001). White matter FW measures interacted with baseline diagnosis, gray matter atrophy, APOE ε4 status, and amyloid positivity to predict poorer cognitive performance and accelerated cognitive decline. Noteworthy interactions include fornix FW and hippocampal volume (β = 10.598; P < .001), cingulum FW and SPARE-AD index (β = -0.532; P < .001), and inferior temporal gyrus transcallosal tract FW and baseline diagnosis (β = -0.537; P < .001), all predicting poorer memory performance. Conclusions and relevance: White matter microstructural changes, particularly FW, play a critical role in cognitive decline in aging and AD-related cognitive impairment. These findings highlight the importance of FW correction in dMRI studies and highlight the limbic system, especially the cingulum and fornix, as key regions associated with cognitive decline; the interaction models highlight that integrating FW-corrected metrics with other AD biomarkers may further elucidate the biological mechanisms of neurodegeneration in aging.