Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Alzheimer Disease Research

Background:

• TAR DNA-binding protein 43 (TDP-43) is a key protein in frontotemporal lobar degeneration.
• Abnormal TDP-43 (abTDP-43) is found in approximately 25% of Alzheimer disease (AD) cases.
• The clinical, imaging, and pathological differences in AD with abTDP-43 are not well understood.

Purpose of the Study:

• To investigate distinct clinical, neuropsychological, imaging, and pathological features in pathologically confirmed AD with abTDP-43.
• To compare AD patients with and without abTDP-43 immunoreactivity.

Main Methods:

• Eighty-four subjects with pathologically confirmed AD underwent neuropsychometric testing and volumetric MRI.
• Immunohistochemistry identified abTDP-43 in 29 (34%) subjects.
• Voxel-based morphometry analyzed gray matter atrophy, comparing groups to controls.

Main Results:

• AD subjects with abTDP-43 were older at onset and death, with poorer performance on cognitive tests (CDR, MMSE, Boston Naming Test).
• Both groups showed medial temporal and temporoparietal gray matter loss, but abTDP-43 group had greater hippocampal atrophy.
• Hippocampal sclerosis was the sole pathological predictor of abTDP-43.

Conclusions:

• Abnormal TDP-43 immunoreactivity in AD is associated with a distinct clinicopathological and radiological phenotype.
• The findings highlight TDP-43's role in modifying AD presentation and progression.