Browsing by Author "Strittmatter, Stephen M."

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    Alzheimer’s Disease Plasma Biomarker Results from across 14 Alzheimer’s Disease Research Centers
    (Wiley, 2025-01-09) Russ, Kristen A.; Asthana, Sanjay; Johnson, Sterling C.; Wilson, Rachael E.; Craft, Suzanne; Register, Thomas C.; Lockhart, Samuel N.; Nairn, Angus C.; Strittmatter, Stephen M.; van Dyck, Christopher H.; Foroud, Tatiana M.; Dage, Jeffrey L.; Neurology, School of Medicine
    Background: The Alzheimer’s Disease Center Fluid Biomarker (ADCFB) Initiative samples are analyzed centrally at NCRAD for AD plasma biomarkers. When combining NACC accessible data from across centers, biofluid biomarker data must be evaluated carefully. This will become more critical with the implementation of disease modifying therapies. Methods: Beta amyloid 1‐42 (Aβ42) and beta amyloid 1‐40 (Aβ40) were analyzed utilizing the Neurology 4‐Plex E kits on a Quanterix Simoa HD‐X. All assays were performed according to manufacturer’s instructions. NACC data from participants 65 or older was combined with biomarker results into one data set. Samples with PET results from the same visit as the blood collection were utilized for this analysis (n=114). Results: Data for amyloid and tau PET was used along with Aβ42/40 ratios to assess the area under the curve (AUC) for this data set (Figure 1). Amyloid PET and Tau PET by Aβ42/40 ROC analysis including age and APOE4 carrier status showed lower than expected AUCs (both 0.72). A subset of data (n=90) was analyzed using participants that were not on any FDA‐approved drugs for AD. This had no effect on AUCs for amyloid or tau PET by Aβ42/40 ratios. Distribution of Aβ42/40 ratios across sites showed a single site had a subset of very high Aβ42/40 ratios (n=8) in comparison to other sites. After removal of the Aβ42/40 outliers from the specific site from the data set, diagnostic accuracies of Aβ42/40 for both Amyloid PET (AUC=0.77) and Tau PET (AUC=0.76) were increased. More investigation into the exact cause of the outliers is necessary, but Aβ42/40 elevations independent from other biomarkers have been seen in clinical trials of Solanezumab and some other Aβ targeting antibodies. Conclusion: To avoid errors in data analysis when using shared data, it is important to track clinical trial co‐enrollment and drug type within ADCs at NACC. As FDA‐approved treatments become available or co‐enrollment of AD drug trials at centers occurs, it is critical to carefully track participant variables and review biofluid biomarker data when it is being combined across centers or studies.
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    Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel
    (American Medical Association, 2021-01-01) Kunkle, Brian W.; Schmidt, Michael; Klein, Hans-Ulrich; Naj, Adam C.; Hamilton-Nelson, Kara L.; Larson, Eric B.; Evans, Denis A.; De Jager, Phil L.; Crane, Paul K.; Buxbaum, Joe D.; Ertekin-Taner, Nilufer; Go, Rodney C.P.; Obisesan, Thomas O.; Kamboh, Ilyas; Bennett, David A.; Hall, Kathleen S.; Goate, Alison M.; Foroud, Tatiana M.; Martin, Eden R.; Wang, Li-Sao; Byrd, Goldie S.; Farrer, Lindsay A.; Haines, Jonathan L.; Schellenberg, Gerard D.; Mayeux, Richard; Pericak-Vance, Margaret A.; Reitz, Christiane; Graff-Radford, Neill R.; Martinez, Izri; Ayodele, Temitope; Logue, Mark W.; Cantwell, Laura B.; Jean-Francois, Melissa; Kuzma, Amanda B.; Adams, L.D.; Vance, Jeffery M.; Cuccaro, Michael L.; Chung, Jaeyoon; Mez, Jesse; Lunetta, Kathryn L.; Jun, Gyungah R.; Lopez, Oscar L.; Hendrie, Hugh C.; Reiman, Eric M.; Kowall, Neil W.; Leverenz, James B.; Small, Scott A.; Levey, Allan I.; Golde, Todd E.; Saykin, Andrew J.; Starks, Takiyah D.; Albert, Marilyn S.; Hyman, Bradley T.; Petersen, Ronald C.; Sano, Mary; Wisniewski, Thomas; Vassar, Robert; Kaye, Jeffrey A.; Henderson, Victor W.; DeCarli, Charles; LaFerla, Frank M.; Brewer, James B.; Miller, Bruce L.; Swerdlow, Russell H.; Van Eldik, Linda J.; Paulson, Henry L.; Trojanowski, John Q.; Chui, Helena C.; Rosenberg, Roger N.; Craft, Suzanne; Grabowski, Thomas J.; Asthana, Sanjay; Morris, John C.; Strittmatter, Stephen M.; Kukull, Walter A.; Psychiatry, School of Medicine
    Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, setting, and participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main outcomes and measures: Diagnosis of Alzheimer disease. Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.