ArticleAlzheimer's research & therapy2025
Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach.
Article in Alzheimer's research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed.
- Cortical thickness signature of early-onset Alzheimer's disease across clinical stages and A/T1 biomarker profiles.Journal of neurology · 2026Article
- Atypical Alzheimer disease: a multi-axis framework toward defining heterogeneity.Nature reviews. Neurology · 2026Review
- Descriptive Analysis of Retrospective Observational Real-World Evidence of a Monoclonal Anti-Amyloid Therapy Program in a Wide Catchment Specialty Memory Clinic.Neurology and therapy · 2026Article
- Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Proteome-wide genetic study identified therapeutic targets for early-onset and late-onset Alzheimer's disease.International journal of surgery (London, England) · 2026Article
- Idiotypic-susceptible Alzheimer's disease: a clinically relevant, neurofibrillary tangle subtype.Acta neuropathologica · 2026Article
- Low Sensitivity of Neuropsychological Scales Hinder Detection of Potential Benefit of Treatments in Alzheimer's Disease: A Position Paper.European journal of neurology · 2026Review
- Tau topography subtypes account for clinical heterogeneity and longitudinal trajectories in early-onset Alzheimer's disease.Brain communications · 2026Article
- Alterations of the brain functional organization in young-onset Alzheimer's disease: Is it a matter of "time"?Journal of Alzheimer's disease : JAD · 2025Article
- Biological age acceleration in Alzheimer's disease modulates relative cortical to medial temporal lobe neurodegeneration.Neurobiology of aging · 2025Article
- Design and baseline findings of the NEODEM prospective cohort on early-onset neurodegenerative dementia.Alzheimer's & dementia (Amsterdam, Netherlands)Article
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Abstract
backgroundThe 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.
methodsNeuropsychological 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.
resultsWe 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.
conclusionA 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.
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