Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer’s Disease and Amyotrophic Lateral Sclerosis

Background

TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology.

Methods

Pathological TDP-43 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 ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43–81% of regional TDP-43 variance.

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 TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis.

Short Abstract

Here we show that pathological TDP-43 emerges during normal ageing from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after 60 years. In Alzheimer’s disease (AD), TDP-43 pathology was present in 90% of cases and distinguished from ageing by disproportionate amygdala involvement, while in amyotrophic lateral sclerosis (ALS) it was nearly ubiquitous across hippocampus, amygdala, and frontal cortex. Using sensitive detection tools, we demonstrate that region-specific ferritin strongly predicts TDP-43 burden: amygdala ferritin explained 87% of variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin levels in all three regions explained 43–81% of TDP-43 variance. As TDP-43 pathology confers a worse prognosis in AD, the ability of ferritin, quantifiable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its potential as a biomarker for disease stratification and prognostic assessment.

Graphical Abstract

Highlights

• TDP-43 brain pathology occurs in normal ageing from early in the fourth decade, characterised by a 4.5-fold increase in hippocampus pathology from the sixth decade.

• TDP-43 brain pathology is detectable in 90% of AD cases, with a disease-signature of increased amygdala pathology relative to age-matched controls.

• In ALS, TDP-43 is nearly ubiquitous in amygdala, hippocampus and frontal cortex.

• Hippocampus high brain ferritin distinguishes AD from and age-matched controls

• Brain ferritin is a brain region-specific marker of TDP-43 pathology in ageing and disease, with amygdala ferritin explaining 87% of the variance in amygdala TDP-43 pathology in ALS, and 66% of amygdala TDP-43 pathology in AD

• In AD, ferritin levels for all three brain regions explain between 43-81% of variance in their TDP-43 pathology levels