Browsing by Author "Patel, Tulsi"

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    Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction
    (Springer Nature, 2024-06-20) İş, Özkan; Wang, Xue; Reddy, Joseph S.; Min, Yuhao; Yilmaz, Elanur; Bhattarai, Prabesh; Patel, Tulsi; Bergman, Jeremiah; Quicksall, Zachary; Heckman, Michael G.; Tutor-New, Frederick Q.; Demirdogen, Birsen Can; White, Launia; Koga, Shunsuke; Krause, Vincent; Inoue, Yasuteru; Kanekiyo, Takahisa; Cosacak, Mehmet Ilyas; Nelson, Nastasia; Lee, Annie J.; Vardarajan, Badri; Mayeux, Richard; Kouri, Naomi; Deniz, Kaancan; Carnwath, Troy; Oatman, Stephanie R.; Lewis-Tuffin, Laura J.; Nguyen, Thuy; Alzheimer’s Disease Neuroimaging Initiative; Carrasquillo, Minerva M.; Graff-Radford, Jonathan; Petersen, Ronald C.; Jack, Clifford R., Jr.; Kantarci, Kejal; Murray, Melissa E.; Nho, Kwangsik; Saykin, Andrew J.; Dickson, Dennis W.; Kizil, Caghan; Allen, Mariet; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease.
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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.