Frontotemporal lobar degeneration complexity: atypical presentations and heterogeneous proteinopathies in five cases

Introduction: Frontotemporal lobar degeneration (FTLD) encompasses heterogeneous clinical syndrome within the frontotemporal spectrum, where clinicopathological associations may be misleading. This case series illustrates clinicopathological variability and mismatches. Methods: A retrospective case series was conducted within the brain donation program at the Golgi Cenci Foundation. Cases presenting at onset with a frontotemporal-spectrum phenotype, longitudinal clinical data, and post-mortem neuropathological characterization were included. Results: Five cases (mean age at onset 65.4 years) were clinically diagnosed with major neurocognitive disorder due to frontotemporal dementia (FTD). Neuropathological examination revealed clinicopathological heterogeneity: two cases showed FTLD-TDP-A associated with GRN mutations, including a classic case and one with posterior (parieto-occipital) involvement; one non-fluent variant primary progressive aphasia (nfvPPA) case demonstrated FTLD-TDP-A with multiple co-pathologies; one semantic-variant-like case was driven by high Alzheimer's disease neuropathological changes; and one behavioral variant FTD-like case corresponded to frontal-variant Alzheimer's disease (fvAD) with extensive mixed pathology, including Lewy body disease, LATE-NC, and vascular pathology. Discussion: Findings indicate that clinical phenotypes are more influenced by the anatomical distribution of pathology than by the specific molecular substrate. Frequent coexisting proteinopathies and asymmetric involvement contribute to phenotypic variability, reinforcing the role of neuropathological examination of both hemispheres for accurate clinicopathological correlations and definitive etiological diagnosis.