Biomarkers.

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is implicated in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Immunohistochemically stained TDP-43 is linked to faster rates of hippocampal atrophy (HA) in AD. However, it is unclear whether phosphorylated TDP-43 (pTDP-43) measured using an immunoassay is also associated with HA. We explored associations between pTDP-43 levels, TDP-43 immunohistochemistry, and annual rate of HA in AD. We hypothesized that higher pTDP-43 levels would be associated with positive TDP-43 immunohistochemistry, and faster rates of HA.

Method: Thirty-seven cognitively impaired participants from the Mayo Clinic Alzheimer's Disease Research Center underwent serial brain MRIs and brain autopsy. Hippocampal TDP-43 was detected histochemically, and pTDP-43 was quantified using biochemical assay. Hippocampal volumes were measured using the longitudinal pipeline in FreeSurfer-7 and annualized HA rates were calculated. Linear regression analyzed the relationship between HA and pTDP-43 biochemical assay levels. pTDP-43 was categorized as positive (≥400) or negative (<400), and logistic regression tested the association of these levels with HA rates. The correlation between TDP-43 immunohistochemistry status and biochemical assay levels was evaluated using descriptive statistics. All analyses were adjusted for potential confounders.

Results: The mean age at death was 83.5 (±9.9) years with 49% females. Median scan interval was 3-years. A negative relationship was observed between age at death and annual HA rate (β=-3.1; 95% CI [-5.3,-0.9]; p=0.007), and a positive relationship was observed between pTDP-43 level and annual HA rate (β=0.02; 95% CI [0.003,0.03]; p=0.015). A one-unit increase in HA rate was associated with a 3% increase in the odds of being pTDP-43 positive (≥400) (odds ratio=1.03; CI [1.007,1.05]; p=0.014). Cases that tested positive for Immunohistochemistry TDP-43 had significantly higher mean pTDP-43 immunoassay levels (1508 ± 2072 vs. 202 ± 131; p=0.008). More cases with positive IHC TDP-43 surpassed the pTDP-43 immunoassay cut-off level of 400 vs the negative participants (p=0.003).

Conclusion: Higher pTDP-43 levels in the hippocampus are linked to faster HA in AD and correlated with immunohistochemistry TDP-43 positivity. These findings underscore the role of TDP-43 in AD neurodegeneration. The biological and clinical implications of these observations necessitate further exploration in subsequent studies.