Brain iron as a surrogate biomarker of pathological TDP-43 identifies brain region-specific signatures in aging, and disease

Abstract Background TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in aging and disease are not well characterised. We investigated molecular TDP-43 dysregulation across aging, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology. Methods Molecular TDP-43 dysregulation was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40–80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology. Findings TDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from aging by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Brain regional ferritin strongly predicted TDP-43 burden: in ALS, amygdala and frontal cortex ferritin showed significant positive ferritin-TDP-43 associations, with age-associated ferritin–TDP-43 relationships observed in older healthy controls, particularly in the frontal cortex and hippocampus. Interpretation TDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As brain region-specific ferritin accumulation is detectable with iron-sensitive MRI sequences, our findings could represent a biomarker for identifying and stratifying TDP-43–related disease.