Multiple neuronal pathologies are common in young patients with pathologically proven Frontotemporal lobar degeneration.

Aims: The past decade has seen a surge in studies identifying mixed pathologies in elderly populations. Importantly however, few studies have focussed on mixed pathology in Frontotemporal Lobar Degeneration (FTLD), particularly in younger cases.

Methods: The present study examined concomitant pathological neuronal inclusions of TDP-43, hyperphosphorylated tau and α-synuclein protein in the anterior cingulate, hippocampus and entorhinal cortex in young (≤65 years at death) vs. elderly (≥80 years at death) cases with pathologically confirmed FTLD (n = 52) or Alzheimer's disease (AD) (n = 47).

Results: Our results demonstrate the presence of additional neuronal pathologies not associated with the primary pathological diagnosis in a similar proportion of young and elderly FTLD cases, indicating that disease drivers rather than age are the major risk factors for multiple neuronal pathologies in FTLD. When only sporadic FTLD cases were considered, the proportion of cases with multiple neuronal pathologies across FTLD age cohorts remained similar, indicating that multiple neuronal pathologies in young FTLD cases is not driven by known genetic mutations. In contrast to these findings in FTLD, a significantly greater proportion of elderly compared to young AD cases demonstrated multiple neuronal pathologies, corroborating literature.

Conclusions: In summary, the present study reports for the first time that age is not a major risk factor for multiple neuronal pathologies in FTLD. These findings have significant implications for the development of protein-specific biomarkers and treatments for FTLD, and underscore the need for further research to identify the disease factors involved in driving multiple neuronal pathologies in FTLD.