Concordance between domain-based neuropsychological profiles and clinical phenotypes in young-onset dementia

Objective: Young-onset dementia (YOD; onset < 65 years) frequently presents with phenotypes that involve specific cognitive domains whilst relatively sparing episodic memory, such as behavioral variant frontotemporal dementia (bvFTD), posterior cortical atrophy (PCA), and primary progressive aphasias (PPA). We hypothesized that standard neuropsychological batteries may fail to identify these phenotypes and tested their ability to pick up cognitive deficits for YOD phenotypes based on their clinical criteria. Methods: In this observational study, we included 2,056 consecutive YOD patients from the Amsterdam Dementia Cohort, who were seen at Alzheimer Center Amsterdam, Amsterdam UMC between 2010 and 2023. Domain scores were created based on a neuropsychological battery comprising tests in memory, executive, visuospatial, and language. Using three qualitative strategies-normative domain-based classification, alignment with simulated clinical reasoning, and intra-individual profiling-we categorized patients in cognitive domain groups based on either count, kind, or severity of domain impairments. Results: Across approaches, typical (i.e., amnestic) Alzheimer's disease, PCA, and semantic variant PPA (svPPA) were relatively well recognized, yet bvFTD, logopenic variant PPA (lvPPA), and nonfluent variant PPA (nfvPPA) remained poorly detected. Intra-individual profiling added some nuance by confirming memory, visuospatial, and semantic deficits in typical AD, PCA, and svPPA, respectively, but unexpectedly highlighted executive impairments in nfvPPA and to a lesser extent in lvPPA. Conclusions: Our standard neuropsychological battery reliably identified key impairments in typical AD, PCA, and svPPA, but underperformed for bvFTD, lvPPA, and nfvPPA. Our findings underscore the need to augment test batteries with targeted social cognition and language measures to aid differential diagnosis in YOD.