Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach
Abstract Background The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEA...
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2025-02-01
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| author | Deepti Putcha Yuta Katsumi Alexandra Touroutoglou Ani Eloyan Alexander Taurone Maryanne Thangarajah Paul Aisen Jeffrey L. Dage Tatiana Foroud Clifford R. Jack Joel H. Kramer Kelly N. H. Nudelman Rema Raman Prashanthi Vemuri Alireza Atri Gregory S. Day Ranjan Duara Neill R. Graff-Radford Ian M. Grant Lawrence S. Honig Erik C. B. Johnson David T. Jones Joseph C. Masdeu Mario F. Mendez Erik Musiek Chiadi U. Onyike Meghan Riddle Emily Rogalski Stephen Salloway Sharon Sha R. Scott Turner Thomas S. Wingo David A. Wolk Kyle Womack Maria C. Carrillo Gil D. Rabinovici Bradford C. Dickerson Liana G. Apostolova Dustin B. Hammers the LEADS Consortium |
| author_facet | Deepti Putcha Yuta Katsumi Alexandra Touroutoglou Ani Eloyan Alexander Taurone Maryanne Thangarajah Paul Aisen Jeffrey L. Dage Tatiana Foroud Clifford R. Jack Joel H. Kramer Kelly N. H. Nudelman Rema Raman Prashanthi Vemuri Alireza Atri Gregory S. Day Ranjan Duara Neill R. Graff-Radford Ian M. Grant Lawrence S. Honig Erik C. B. Johnson David T. Jones Joseph C. Masdeu Mario F. Mendez Erik Musiek Chiadi U. Onyike Meghan Riddle Emily Rogalski Stephen Salloway Sharon Sha R. Scott Turner Thomas S. Wingo David A. Wolk Kyle Womack Maria C. Carrillo Gil D. Rabinovici Bradford C. Dickerson Liana G. Apostolova Dustin B. Hammers the LEADS Consortium |
| author_sort | Deepti Putcha |
| collection | DOAJ |
| description | Abstract Background The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort. Methods Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes. Results We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia. Conclusion A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations. |
| format | Article |
| id | doaj-art-0403ed0217d849d0886e1fd7562bc594 |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-0403ed0217d849d0886e1fd7562bc5942025-02-09T12:16:13ZengBMCAlzheimer’s Research & Therapy1758-91932025-02-0117111510.1186/s13195-025-01689-8Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approachDeepti Putcha0Yuta Katsumi1Alexandra Touroutoglou2Ani Eloyan3Alexander Taurone4Maryanne Thangarajah5Paul Aisen6Jeffrey L. Dage7Tatiana Foroud8Clifford R. Jack9Joel H. Kramer10Kelly N. H. Nudelman11Rema Raman12Prashanthi Vemuri13Alireza Atri14Gregory S. Day15Ranjan Duara16Neill R. Graff-Radford17Ian M. Grant18Lawrence S. Honig19Erik C. B. Johnson20David T. Jones21Joseph C. Masdeu22Mario F. Mendez23Erik Musiek24Chiadi U. Onyike25Meghan Riddle26Emily Rogalski27Stephen Salloway28Sharon Sha29R. Scott Turner30Thomas S. Wingo31David A. Wolk32Kyle Womack33Maria C. Carrillo34Gil D. Rabinovici35Bradford C. Dickerson36Liana G. Apostolova37Dustin B. Hammers38the LEADS ConsortiumFrontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical SchoolFrontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical SchoolFrontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Biostatistics, Center for Statistical Sciences, Brown UniversityDepartment of Biostatistics, Center for Statistical Sciences, Brown UniversityDepartment of Biostatistics, Center for Statistical Sciences, Brown UniversityAlzheimer’s Therapeutic Research Institute, University of Southern CaliforniaDepartment of Neurology, Indiana University School of MedicineDepartment of Medical and Molecular Genetics, Indiana University School of MedicineDepartment of Radiology, Mayo ClinicDepartment of Neurology, University of CA – San FranciscoDepartment of Medical and Molecular Genetics, Indiana University School of MedicineAlzheimer’s Therapeutic Research Institute, University of Southern CaliforniaDepartment of Radiology, Mayo ClinicBanner Sun Health Research InstituteDepartment of Neurology, Mayo Clinic in FloridaWien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical CenterDepartment of Neurology, Mayo Clinic in FloridaDepartment of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern UniversityTaub Institute and Department of Neurology, Columbia University Irving Medical CenterDepartment of Neurology, Emory University School of MedicineDepartment of Radiology, Mayo ClinicNantz National Alzheimer Center, Houston Methodist and Weill Cornell MedicineDepartment of Neurology, David Geffen School of Medicine at UCLADepartment of Neurology, Washington University in St. LouisDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of MedicineDepartment of Neurology, Alpert Medical School, Brown UniversityDepartment of Neurology, University of ChicagoDepartment of Neurology, Alpert Medical School, Brown UniversityDepartment of Neurology & Neurological Sciences, Stanford UniversityDepartment of Neurology, Georgetown UniversityDepartment of Neurology and Human Genetics, Emory University School of MedicineDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Washington University in St. LouisMedical & Scientific Relations Division, Alzheimer’s AssociationDepartment of Neurology, University of CA – San FranciscoFrontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Indiana University School of MedicineDepartment of Neurology, Indiana University School of MedicineAbstract Background The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort. Methods Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes. Results We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia. Conclusion A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.https://doi.org/10.1186/s13195-025-01689-8Alzheimer’s diseaseEarly-onsetNeuropsychologyPhenotypesVariantsCognition |
| spellingShingle | Deepti Putcha Yuta Katsumi Alexandra Touroutoglou Ani Eloyan Alexander Taurone Maryanne Thangarajah Paul Aisen Jeffrey L. Dage Tatiana Foroud Clifford R. Jack Joel H. Kramer Kelly N. H. Nudelman Rema Raman Prashanthi Vemuri Alireza Atri Gregory S. Day Ranjan Duara Neill R. Graff-Radford Ian M. Grant Lawrence S. Honig Erik C. B. Johnson David T. Jones Joseph C. Masdeu Mario F. Mendez Erik Musiek Chiadi U. Onyike Meghan Riddle Emily Rogalski Stephen Salloway Sharon Sha R. Scott Turner Thomas S. Wingo David A. Wolk Kyle Womack Maria C. Carrillo Gil D. Rabinovici Bradford C. Dickerson Liana G. Apostolova Dustin B. Hammers the LEADS Consortium Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach Alzheimer’s Research & Therapy Alzheimer’s disease Early-onset Neuropsychology Phenotypes Variants Cognition |
| title | Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach |
| title_full | Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach |
| title_fullStr | Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach |
| title_full_unstemmed | Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach |
| title_short | Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach |
| title_sort | heterogeneous clinical phenotypes of sporadic early onset alzheimer s disease a neuropsychological data driven approach |
| topic | Alzheimer’s disease Early-onset Neuropsychology Phenotypes Variants Cognition |
| url | https://doi.org/10.1186/s13195-025-01689-8 |
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