Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA-binding Protein 43

Area of Science:

• Neuroscience
• Neuropathology
• Geriatric Medicine

Background:

• Age-related dementias often involve multiple pathologies, complicating diagnosis.
• Alzheimer's disease (AD) can co-occur with transactive response DNA-binding protein 43 (TDP-43) pathology, forming AD/TDP.
• Distinguishing these complex pathologies is crucial for understanding dementia syndromes.

Purpose of the Study:

• To investigate neuronal integrity and the burden of TDP-43 and tau in the hippocampal trisynaptic circuit.
• To compare these markers in amnestic dementia due to AD/TDP, AD alone, and non-amnestic dementia due to frontotemporal lobar degeneration with TDP-43 (FTLD-TDP).

Main Methods:

• Analyzed 48 characterized cases (14 AD, 16 AD/TDP, 18 FTLD-TDP).
• Utilized digital HALO software to quantify TDP-43 and tau burden and neuronal loss.
• Focused analysis on the dentate gyrus (DG), CA3, and CA1 hippocampal subregions.

Main Results:

• TDP-43 was greatest in the DG for both AD/TDP and FTLD-TDP.
• Tau levels were significantly higher in DG and CA3 in AD/TDP compared to AD.
• Lower neuronal counts were observed in AD and AD/TDP groups versus FTLD-TDP, correlating with amnestic symptoms.

Conclusions:

• AD/TDP is distinguishable from AD and FTLD-TDP by unique hippocampal tau and TDP-43 regional distributions.
• Findings suggest TDP-43 pathology may potentiate tau aggregation in the context of AD/TDP.
• Differential neuropathological burden in hippocampal circuits underlies distinct dementia phenotypes.