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AD-causing variants that affect PSEN1 transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains

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dc.contributor.author Schultz, Stephanie A.
dc.contributor.author Allegri, Ricardo Francisco
dc.contributor.author Schultz, Aaron P.
dc.contributor.author Goate, Alison M.
dc.contributor.author Levey, Allan I.
dc.contributor.author Fagan, Anne M.
dc.contributor.author Hanseeuw, Bernard J.
dc.contributor.author Koeppe, Robert A.
dc.contributor.author Gordon, Brian A.
dc.contributor.author Cruchaga, Carlos
dc.contributor.author Karch, Celeste M.
dc.contributor.author Chen, Charles D.
dc.contributor.author Xiong, Chengjie
dc.contributor.author Jack Jr, Clifford R.
dc.contributor.author Fitzpatrick, Colleen D.
dc.contributor.author McDade, Eric
dc.contributor.author Chui, Helena C.
dc.contributor.author Mori, Hiroshi
dc.contributor.author Lee, Jae-Hong
dc.contributor.author Noble, James M.
dc.date.accessioned 2023-12-11T14:30:52Z
dc.date.available 2023-12-11T14:30:52Z
dc.date.issued 2022-12
dc.identifier.citation Schultz, S.A., Allegri, R.F., Schultz, A.P., Goate, A.M., Levey, A.I., Fagan, A.M., Hanseeuw, B.J., Koeppe, R.A., Gordon, B.A., Cruchaga, C., Karch, C.M., Chen, C.D., Xiong, C., Jack Jr, C.R., Fitzpatrick, C.D., McDade, E., Chui, H.C., Mori, H., Lee, J.-H., Noble, J.M., Hassenstab, J.J., Levin, J., Morris, J.C., Johnson, K.A., Liu, L., Farlow, M.R., Jucker, M., Farrell, M.E., Graff-Radford, N.R., Joseph-Mathurin, N., Fox, N.C., Schofield, P.R., Martins, R.N., Sanchez-Valle, R., Perrin, R.J., Berman, S., Salloway, S.P., Shirzadi, Z., Rosa-Neto, P., Benzinger, T.L.S., Bateman, R.J., Sperling, R.A., Chhatwal, J.P. AD-causing variants that affect PSEN1 transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains. Alzheimer’s & Dementia 2022; 18, e067186. es_ES
dc.identifier.uri https://doi.org/10.1002/alz.067186
dc.identifier.uri https://repositorio.fleni.org.ar/xmlui/handle/123456789/901
dc.description.abstract Background Rates of cognitive and biomarker change in Autosomal Dominant Alzheimer disease (ADAD) vary substantially across individuals. Prior cross-sectional work suggests that the location of the pathogenic variant within PSEN1, specifically whether the underlying variant affects transmembrane (TM) or cytoplasmic (CY) domains in PSEN1, may be a key determinant in these differential rates of progression. Here we use longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN-Obs) to examine whether variants affecting TM versus CY domains in PSEN1 have differential rates of change in key cognitive and neurodegenerative markers, and whether these differences are relevant to ADAD clinical trials. Methods Using longitudinal clinical, cognitive, and MRI data from PSEN1 pathogenic variant carriers [TM group N=76 and CY group N=44; Table 1], we assessed rates of change in Mini-Mental State Exam (MMSE), Clinical Dementia Rating® Sum of Boxes (CDR®-SOB), and hippocampal volume (HV) using linear mixed effects models accounting for disease stage (estimated years to symptom onset [EYO]). We further assessed how PSEN1 mutation location (TM versus CY) impacts sample size and detectable effect size in a potential ADAD clinical trial (modeled as a 4-year trial with annual assessments; 80% power; α = 0.05). Results PSEN1 TM and PSEN1 CY groups did not differ on baseline age, EYO, or CDR®. The PSEN1 TM group had significantly greater rates of change on MMSE (B[SE] = -0.42[0.1], p=0.002), CDR®-SOB (B[SE] = 0.23[0.1], p=0.001), and HV atrophy (B[SE] = -58.93[14.3], p=0.0006 compared to the PSEN1 CY group (Fig.1). Consistent with these differential rates of change, power analyses indicated the required sample size to detect a 30% treatment effect on MMSE or HV would be reduced by 59.6% for MMSE and 91.0% for HV for a trial population comprised of PSEN1 TM versus CY carriers (Fig.2). Conclusions Individuals who had a variant affecting the transmembrane domains of PSEN1 had greater rates of cognitive decline and neurodegeneration compared to those with variants affecting cytoplasmic domains. In addition to having implications for ADAD pathophysiology, these results suggest that incorporating information regarding the location of PSEN1 variants may be beneficial in analyzing and designing stratification approaches for ADAD trials. es_ES
dc.publisher Wiley es_ES
dc.subject Enfermedad de Alzheimer es_ES
dc.subject Alzheimer Disease es_ES
dc.title AD-causing variants that affect PSEN1 transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.description.fil Fil: Allegri, Ricardo Francisco. Fleni. Departamento de Neurología. Servicio de Neurología Cognitiva, Neuropsicología y Neuropsiquiatría; Argentina.
dc.description.fil Fil: Schultz, Stephanie A. Massachusetts General Hospital; Estados Unidos.
dc.description.fil Fil: Schultz, Aaron P. Massachusetts General Hospital; Estados Unidos.
dc.description.fil Fil: Goate, Alison M. Icahn School of Medicine at Mount Sinai; Estados Unidos.
dc.description.fil Fil: Levey, Allan I. Emory Goizueta Alzheimer’s Disease Research Center; Estados Unidos.
dc.description.fil Fil: Fagan, Anne M. Washington University in St.Louis; Estados Unidos.
dc.description.fil Fil: Hanseeuw, Bernard J. Massachussets General Hospital; Estados Unidos.
dc.description.fil Fil: Koeppe, Robert A. University of Michigan; Estados Unidos.
dc.description.fil Fil: Gordon, Brian A. Knight Alzheimer Disease Research Center; Estados Unidos.
dc.description.fil Fil: Cruchaga, Carlos. Knight Alzheimer Disease Research Center; Estados Unidos.
dc.description.fil Fil: Karch, Celeste M. Washington University in St. Louis School of Medicine; Estados Unidos.
dc.description.fil Fil: Chen, Charles D. Washington University in St. Louis; Estados Unidos.
dc.description.fil Fil: Xiong, Chengjie. Washington University in St. Louis; Estados Unidos.
dc.description.fil Fil: Jack Jr, Clifford R. Mayo Clinic; Estados Unidos.
dc.description.fil Fil: Fitzpatrick, Colleen D. Massachusetts General Hospital; Estados Unidos.
dc.description.fil Fil: McDade, Eric. Washington University School of Medicine St.Louis; Estados Unidos.
dc.description.fil Fil: Chui, Helena C. USC; Estados Unidos.
dc.description.fil Fil: Mori, Hiroshi. Osaka City University Medical School; Japón.
dc.description.fil Fil: Lee, Jae-Hong. University of Ulsan College of Medicine; Corea.
dc.description.fil Fil: Noble, James M. Columbia University; Estados Unidos.
dc.relation.ispartofVOLUME 18
dc.relation.ispartofNUMBER S4 Supplement: Basic Science and Pathogenesis – Part 2
dc.relation.ispartofPAGINATION e067186
dc.relation.ispartofCOUNTRY Estados Unidos
dc.relation.ispartofCITY Hoboken
dc.relation.ispartofTITLE Alzheimer's & dementia : the journal of the Alzheimer's Association
dc.relation.ispartofISSN 1552-5279
dc.type.snrd info:ar-repo/semantics/artículo es_ES


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