Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease

Autores
Llibre Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; McDade, Eric; Strom, Amelia; Gordon, Brian; Mundada, Nidhi; Schindler, Suzanne E.; Tsoy, Elena; Ma, Yinjiao; Lu, Ruijin; Fagan, Anne M.; Benzinger, Tammie L. S.; Soleimani Meigooni, David; Aschenbrenner, Andrew J.; Miller, Zachary; Wang, Guoqiao; Kramer, Joel H.; Hassenstab, Jason; Rosen, Howard J.; Morris, John C.; Miller, Bruce L.; Xiong, Chengjie; Perrin, Richard J.; Allegri, Ricardo Francisco; Chrem Mendez, Patricio Alexis; Surace, Ezequiel Ignacio; Berman, Sarah B.; Chhatwal, Jasmeer; Masters, Colin L.; Farlow, Martin R.; Jucker, Mathias; Levin, Johannes; Fox, Nick C.; Day, Gregory; Gorno Tempini, Maria Luisa; Boxer, Adam L.; La Joie, Renaud; Rabinovici, Gil D.; Bateman, Randall
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Approximately 5% of Alzheimer’s disease cases have an early age at onset (<65 years), with 5–10% of these cases attributed to dominantlyinherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onsetAlzheimer’s disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onsetAlzheimer’s disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included117 participants with dominantly inherited Alzheimer’s disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individualswith sporadic early-onset Alzheimer’s disease enrolled at the University of California San Francisco Alzheimer’s Disease ResearchCenter. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the ratesof decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer’s disease exhibited an earlierage-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001].Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively)and a higher frequency of APOE-ϵ4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestationswere higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P =0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P <0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the earlystages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by ClinicalDementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3)pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levelswere higher in the dominantly inherited Alzheimer’s disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences werefound for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer’s disease differed in baseline profiles; sporadic early onset isbest distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executiveperformance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potentialcommon therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.
Fil: Llibre Guerra, Jorge J.. Washington University in St. Louis; Estados Unidos
Fil: Iaccarino, Leonardo. University of California; Estados Unidos
Fil: Coble, Dean. Washington University in St. Louis; Estados Unidos
Fil: Edwards, Lauren. University of California; Estados Unidos
Fil: Li, Yan. Washington University in St. Louis; Estados Unidos
Fil: McDade, Eric. Washington University in St. Louis; Estados Unidos
Fil: Strom, Amelia. University of California; Estados Unidos
Fil: Gordon, Brian. Washington University in St. Louis; Estados Unidos
Fil: Mundada, Nidhi. University of California; Estados Unidos
Fil: Schindler, Suzanne E.. Washington University in St. Louis; Estados Unidos
Fil: Tsoy, Elena. University of California; Estados Unidos
Fil: Ma, Yinjiao. Washington University in St. Louis; Estados Unidos
Fil: Lu, Ruijin. Washington University in St. Louis; Estados Unidos
Fil: Fagan, Anne M.. Washington University in St. Louis; Estados Unidos
Fil: Benzinger, Tammie L. S.. Washington University in St. Louis; Estados Unidos
Fil: Soleimani Meigooni, David. University of California; Estados Unidos
Fil: Aschenbrenner, Andrew J.. Washington University in St. Louis; Estados Unidos
Fil: Miller, Zachary. University of California; Estados Unidos
Fil: Wang, Guoqiao. Washington University in St. Louis; Estados Unidos
Fil: Kramer, Joel H.. University of California; Estados Unidos
Fil: Hassenstab, Jason. Washington University in St. Louis; Estados Unidos
Fil: Rosen, Howard J.. University of California; Estados Unidos
Fil: Morris, John C.. Washington University in St. Louis; Estados Unidos
Fil: Miller, Bruce L.. University of California; Estados Unidos
Fil: Xiong, Chengjie. Washington University in St. Louis; Estados Unidos
Fil: Perrin, Richard J.. Washington University in St. Louis; Estados Unidos
Fil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina
Fil: Chrem Mendez, Patricio Alexis. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina
Fil: Surace, Ezequiel Ignacio. Fundacion P/la Lucha C/enferm.neurologicas Infancia. Instituto de Neurociencias. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Instituto de Neurociencias.; Argentina
Fil: Berman, Sarah B.. University of Pittsburgh; Estados Unidos
Fil: Chhatwal, Jasmeer. Harvard Medical School; Estados Unidos
Fil: Masters, Colin L.. University of Melbourne; Australia
Fil: Farlow, Martin R.. Indiana University School of Medicine at Indianapolis; Estados Unidos
Fil: Jucker, Mathias. Eberhard Karls Universität Tübingen; Alemania
Fil: Levin, Johannes. Ludwig Maximilians Universitat; Alemania
Fil: Fox, Nick C.. University College London; Estados Unidos
Fil: Day, Gregory. Mayo Clinic Florida; Estados Unidos
Fil: Gorno Tempini, Maria Luisa. University of California; Estados Unidos
Fil: Boxer, Adam L.. University of California; Estados Unidos
Fil: La Joie, Renaud. University of California; Estados Unidos
Fil: Rabinovici, Gil D.. University of California; Estados Unidos
Fil: Bateman, Randall. Washington University in St. Louis; Estados Unidos
Materia
EARLY-ONSET ALZHEIMER'S DISEASE
SPORADIC
DOMINANTLY INHERITED
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/256328
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/256328
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s diseaseLlibre Guerra, Jorge J.Iaccarino, LeonardoCoble, DeanEdwards, LaurenLi, YanMcDade, EricStrom, AmeliaGordon, BrianMundada, NidhiSchindler, Suzanne E.Tsoy, ElenaMa, YinjiaoLu, RuijinFagan, Anne M.Benzinger, Tammie L. S.Soleimani Meigooni, DavidAschenbrenner, Andrew J.Miller, ZacharyWang, GuoqiaoKramer, Joel H.Hassenstab, JasonRosen, Howard J.Morris, John C.Miller, Bruce L.Xiong, ChengjiePerrin, Richard J.Allegri, Ricardo FranciscoChrem Mendez, Patricio AlexisSurace, Ezequiel IgnacioBerman, Sarah B.Chhatwal, JasmeerMasters, Colin L.Farlow, Martin R.Jucker, MathiasLevin, JohannesFox, Nick C.Day, GregoryGorno Tempini, Maria LuisaBoxer, Adam L.La Joie, RenaudRabinovici, Gil D.Bateman, RandallEARLY-ONSET ALZHEIMER'S DISEASESPORADICDOMINANTLY INHERITEDhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Approximately 5% of Alzheimer’s disease cases have an early age at onset (<65 years), with 5–10% of these cases attributed to dominantlyinherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onsetAlzheimer’s disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onsetAlzheimer’s disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included117 participants with dominantly inherited Alzheimer’s disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individualswith sporadic early-onset Alzheimer’s disease enrolled at the University of California San Francisco Alzheimer’s Disease ResearchCenter. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the ratesof decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer’s disease exhibited an earlierage-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001].Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively)and a higher frequency of APOE-ϵ4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestationswere higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P =0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P <0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the earlystages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by ClinicalDementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3)pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levelswere higher in the dominantly inherited Alzheimer’s disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences werefound for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer’s disease differed in baseline profiles; sporadic early onset isbest distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executiveperformance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potentialcommon therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.Fil: Llibre Guerra, Jorge J.. Washington University in St. Louis; Estados UnidosFil: Iaccarino, Leonardo. University of California; Estados UnidosFil: Coble, Dean. Washington University in St. Louis; Estados UnidosFil: Edwards, Lauren. University of California; Estados UnidosFil: Li, Yan. Washington University in St. Louis; Estados UnidosFil: McDade, Eric. Washington University in St. Louis; Estados UnidosFil: Strom, Amelia. University of California; Estados UnidosFil: Gordon, Brian. Washington University in St. Louis; Estados UnidosFil: Mundada, Nidhi. University of California; Estados UnidosFil: Schindler, Suzanne E.. Washington University in St. Louis; Estados UnidosFil: Tsoy, Elena. University of California; Estados UnidosFil: Ma, Yinjiao. Washington University in St. Louis; Estados UnidosFil: Lu, Ruijin. Washington University in St. Louis; Estados UnidosFil: Fagan, Anne M.. Washington University in St. Louis; Estados UnidosFil: Benzinger, Tammie L. S.. Washington University in St. Louis; Estados UnidosFil: Soleimani Meigooni, David. University of California; Estados UnidosFil: Aschenbrenner, Andrew J.. Washington University in St. Louis; Estados UnidosFil: Miller, Zachary. University of California; Estados UnidosFil: Wang, Guoqiao. Washington University in St. Louis; Estados UnidosFil: Kramer, Joel H.. University of California; Estados UnidosFil: Hassenstab, Jason. Washington University in St. Louis; Estados UnidosFil: Rosen, Howard J.. University of California; Estados UnidosFil: Morris, John C.. Washington University in St. Louis; Estados UnidosFil: Miller, Bruce L.. University of California; Estados UnidosFil: Xiong, Chengjie. Washington University in St. Louis; Estados UnidosFil: Perrin, Richard J.. Washington University in St. Louis; Estados UnidosFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; ArgentinaFil: Chrem Mendez, Patricio Alexis. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; ArgentinaFil: Surace, Ezequiel Ignacio. Fundacion P/la Lucha C/enferm.neurologicas Infancia. Instituto de Neurociencias. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Instituto de Neurociencias.; ArgentinaFil: Berman, Sarah B.. University of Pittsburgh; Estados UnidosFil: Chhatwal, Jasmeer. Harvard Medical School; Estados UnidosFil: Masters, Colin L.. University of Melbourne; AustraliaFil: Farlow, Martin R.. Indiana University School of Medicine at Indianapolis; Estados UnidosFil: Jucker, Mathias. Eberhard Karls Universität Tübingen; AlemaniaFil: Levin, Johannes. Ludwig Maximilians Universitat; AlemaniaFil: Fox, Nick C.. University College London; Estados UnidosFil: Day, Gregory. Mayo Clinic Florida; Estados UnidosFil: Gorno Tempini, Maria Luisa. University of California; Estados UnidosFil: Boxer, Adam L.. University of California; Estados UnidosFil: La Joie, Renaud. University of California; Estados UnidosFil: Rabinovici, Gil D.. University of California; Estados UnidosFil: Bateman, Randall. Washington University in St. Louis; Estados UnidosOxford University Press2023-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/256328Llibre Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; et al.; Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease; Oxford University Press; Brain Communications; 5; 6; 10-2023; 1-152632-1297CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/braincomms/article/doi/10.1093/braincomms/fcad280/7321528info:eu-repo/semantics/altIdentifier/doi/10.1093/braincomms/fcad280info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/37942088/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:35:14Zoai:ri.conicet.gov.ar:11336/256328instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:35:14.376CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
title Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
spellingShingle Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
Llibre Guerra, Jorge J.
EARLY-ONSET ALZHEIMER'S DISEASE
SPORADIC
DOMINANTLY INHERITED
title_short Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
title_full Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
title_fullStr Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
title_full_unstemmed Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
title_sort Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease
dc.creator.none.fl_str_mv Llibre Guerra, Jorge J.
Iaccarino, Leonardo
Coble, Dean
Edwards, Lauren
Li, Yan
McDade, Eric
Strom, Amelia
Gordon, Brian
Mundada, Nidhi
Schindler, Suzanne E.
Tsoy, Elena
Ma, Yinjiao
Lu, Ruijin
Fagan, Anne M.
Benzinger, Tammie L. S.
Soleimani Meigooni, David
Aschenbrenner, Andrew J.
Miller, Zachary
Wang, Guoqiao
Kramer, Joel H.
Hassenstab, Jason
Rosen, Howard J.
Morris, John C.
Miller, Bruce L.
Xiong, Chengjie
Perrin, Richard J.
Allegri, Ricardo Francisco
Chrem Mendez, Patricio Alexis
Surace, Ezequiel Ignacio
Berman, Sarah B.
Chhatwal, Jasmeer
Masters, Colin L.
Farlow, Martin R.
Jucker, Mathias
Levin, Johannes
Fox, Nick C.
Day, Gregory
Gorno Tempini, Maria Luisa
Boxer, Adam L.
La Joie, Renaud
Rabinovici, Gil D.
Bateman, Randall
author Llibre Guerra, Jorge J.
author_facet Llibre Guerra, Jorge J.
Iaccarino, Leonardo
Coble, Dean
Edwards, Lauren
Li, Yan
McDade, Eric
Strom, Amelia
Gordon, Brian
Mundada, Nidhi
Schindler, Suzanne E.
Tsoy, Elena
Ma, Yinjiao
Lu, Ruijin
Fagan, Anne M.
Benzinger, Tammie L. S.
Soleimani Meigooni, David
Aschenbrenner, Andrew J.
Miller, Zachary
Wang, Guoqiao
Kramer, Joel H.
Hassenstab, Jason
Rosen, Howard J.
Morris, John C.
Miller, Bruce L.
Xiong, Chengjie
Perrin, Richard J.
Allegri, Ricardo Francisco
Chrem Mendez, Patricio Alexis
Surace, Ezequiel Ignacio
Berman, Sarah B.
Chhatwal, Jasmeer
Masters, Colin L.
Farlow, Martin R.
Jucker, Mathias
Levin, Johannes
Fox, Nick C.
Day, Gregory
Gorno Tempini, Maria Luisa
Boxer, Adam L.
La Joie, Renaud
Rabinovici, Gil D.
Bateman, Randall
author_role author
author2 Iaccarino, Leonardo
Coble, Dean
Edwards, Lauren
Li, Yan
McDade, Eric
Strom, Amelia
Gordon, Brian
Mundada, Nidhi
Schindler, Suzanne E.
Tsoy, Elena
Ma, Yinjiao
Lu, Ruijin
Fagan, Anne M.
Benzinger, Tammie L. S.
Soleimani Meigooni, David
Aschenbrenner, Andrew J.
Miller, Zachary
Wang, Guoqiao
Kramer, Joel H.
Hassenstab, Jason
Rosen, Howard J.
Morris, John C.
Miller, Bruce L.
Xiong, Chengjie
Perrin, Richard J.
Allegri, Ricardo Francisco
Chrem Mendez, Patricio Alexis
Surace, Ezequiel Ignacio
Berman, Sarah B.
Chhatwal, Jasmeer
Masters, Colin L.
Farlow, Martin R.
Jucker, Mathias
Levin, Johannes
Fox, Nick C.
Day, Gregory
Gorno Tempini, Maria Luisa
Boxer, Adam L.
La Joie, Renaud
Rabinovici, Gil D.
Bateman, Randall
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EARLY-ONSET ALZHEIMER'S DISEASE
SPORADIC
DOMINANTLY INHERITED
topic EARLY-ONSET ALZHEIMER'S DISEASE
SPORADIC
DOMINANTLY INHERITED
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Approximately 5% of Alzheimer’s disease cases have an early age at onset (<65 years), with 5–10% of these cases attributed to dominantlyinherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onsetAlzheimer’s disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onsetAlzheimer’s disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included117 participants with dominantly inherited Alzheimer’s disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individualswith sporadic early-onset Alzheimer’s disease enrolled at the University of California San Francisco Alzheimer’s Disease ResearchCenter. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the ratesof decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer’s disease exhibited an earlierage-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001].Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively)and a higher frequency of APOE-ϵ4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestationswere higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P =0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P <0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the earlystages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by ClinicalDementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3)pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levelswere higher in the dominantly inherited Alzheimer’s disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences werefound for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer’s disease differed in baseline profiles; sporadic early onset isbest distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executiveperformance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potentialcommon therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.
Fil: Llibre Guerra, Jorge J.. Washington University in St. Louis; Estados Unidos
Fil: Iaccarino, Leonardo. University of California; Estados Unidos
Fil: Coble, Dean. Washington University in St. Louis; Estados Unidos
Fil: Edwards, Lauren. University of California; Estados Unidos
Fil: Li, Yan. Washington University in St. Louis; Estados Unidos
Fil: McDade, Eric. Washington University in St. Louis; Estados Unidos
Fil: Strom, Amelia. University of California; Estados Unidos
Fil: Gordon, Brian. Washington University in St. Louis; Estados Unidos
Fil: Mundada, Nidhi. University of California; Estados Unidos
Fil: Schindler, Suzanne E.. Washington University in St. Louis; Estados Unidos
Fil: Tsoy, Elena. University of California; Estados Unidos
Fil: Ma, Yinjiao. Washington University in St. Louis; Estados Unidos
Fil: Lu, Ruijin. Washington University in St. Louis; Estados Unidos
Fil: Fagan, Anne M.. Washington University in St. Louis; Estados Unidos
Fil: Benzinger, Tammie L. S.. Washington University in St. Louis; Estados Unidos
Fil: Soleimani Meigooni, David. University of California; Estados Unidos
Fil: Aschenbrenner, Andrew J.. Washington University in St. Louis; Estados Unidos
Fil: Miller, Zachary. University of California; Estados Unidos
Fil: Wang, Guoqiao. Washington University in St. Louis; Estados Unidos
Fil: Kramer, Joel H.. University of California; Estados Unidos
Fil: Hassenstab, Jason. Washington University in St. Louis; Estados Unidos
Fil: Rosen, Howard J.. University of California; Estados Unidos
Fil: Morris, John C.. Washington University in St. Louis; Estados Unidos
Fil: Miller, Bruce L.. University of California; Estados Unidos
Fil: Xiong, Chengjie. Washington University in St. Louis; Estados Unidos
Fil: Perrin, Richard J.. Washington University in St. Louis; Estados Unidos
Fil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina
Fil: Chrem Mendez, Patricio Alexis. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina
Fil: Surace, Ezequiel Ignacio. Fundacion P/la Lucha C/enferm.neurologicas Infancia. Instituto de Neurociencias. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Instituto de Neurociencias.; Argentina
Fil: Berman, Sarah B.. University of Pittsburgh; Estados Unidos
Fil: Chhatwal, Jasmeer. Harvard Medical School; Estados Unidos
Fil: Masters, Colin L.. University of Melbourne; Australia
Fil: Farlow, Martin R.. Indiana University School of Medicine at Indianapolis; Estados Unidos
Fil: Jucker, Mathias. Eberhard Karls Universität Tübingen; Alemania
Fil: Levin, Johannes. Ludwig Maximilians Universitat; Alemania
Fil: Fox, Nick C.. University College London; Estados Unidos
Fil: Day, Gregory. Mayo Clinic Florida; Estados Unidos
Fil: Gorno Tempini, Maria Luisa. University of California; Estados Unidos
Fil: Boxer, Adam L.. University of California; Estados Unidos
Fil: La Joie, Renaud. University of California; Estados Unidos
Fil: Rabinovici, Gil D.. University of California; Estados Unidos
Fil: Bateman, Randall. Washington University in St. Louis; Estados Unidos
description Approximately 5% of Alzheimer’s disease cases have an early age at onset (<65 years), with 5–10% of these cases attributed to dominantlyinherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onsetAlzheimer’s disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onsetAlzheimer’s disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included117 participants with dominantly inherited Alzheimer’s disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individualswith sporadic early-onset Alzheimer’s disease enrolled at the University of California San Francisco Alzheimer’s Disease ResearchCenter. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the ratesof decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer’s disease exhibited an earlierage-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001].Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively)and a higher frequency of APOE-ϵ4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestationswere higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P =0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P <0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the earlystages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by ClinicalDementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3)pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levelswere higher in the dominantly inherited Alzheimer’s disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences werefound for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer’s disease differed in baseline profiles; sporadic early onset isbest distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executiveperformance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potentialcommon therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.
publishDate 2023
dc.date.none.fl_str_mv 2023-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/256328
Llibre Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; et al.; Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease; Oxford University Press; Brain Communications; 5; 6; 10-2023; 1-15
2632-1297
CONICET Digital
CONICET
url http://hdl.handle.net/11336/256328
identifier_str_mv Llibre Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; et al.; Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer’s disease; Oxford University Press; Brain Communications; 5; 6; 10-2023; 1-15
2632-1297
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/braincomms/article/doi/10.1093/braincomms/fcad280/7321528
info:eu-repo/semantics/altIdentifier/doi/10.1093/braincomms/fcad280
info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/37942088/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613096218296320
score 13.070432

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