TDP-43 subtypes shape transcriptomic signatures in Alzheimer's disease

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• TDP-43 pathology often co-occurs with Tau NFTs and amyloid plaques in Alzheimer's disease (AD), complicating understanding of its role.
• Distinguishing TDP-43's independent molecular programs from Tau-driven neurodegeneration is challenging due to overlapping pathologies.

Purpose of the Study:

• To delineate the distinct transcriptomic signatures associated with TDP-43 pathology in AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP).
• To investigate the influence of TDP-43 subtypes and regional differences on transcriptional landscapes in neurodegenerative diseases.

Main Methods:

• Generated regionally resolved transcriptomic profiles from control, AD, AD/LATE, and FTLD-TDP cohorts.
• Integrated transcriptomic data with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau).
• Stratified analyses by TDP-43 morphological subtypes (α, β for AD/LATE; A, B for FTLD-TDP).

Main Results:

• TDP-43 is associated with distinct transcriptomic programs in AD/LATE, independent of Tau burden and differing from FTLD-TDP.
• Transcriptomic alterations showed regional specificity, with amygdala changes common to both diseases and frontal cortex changes largely specific to FTLD-TDP.
• Stratification by TDP-43 subtype revealed specific biological trajectories, including immune activation and cellular vulnerabilities, not seen in unstratified groups.

Conclusions:

• TDP-43 pathology shapes autonomous, subtype-dependent transcriptional landscapes in AD and related disorders.
• The findings provide a framework for decoupling mixed proteinopathies and understanding TDP-43's specific contributions to neurodegeneration.
• Subtype and regional analyses are crucial for uncovering the full spectrum of TDP-43's molecular impact.