Polygenic risk scores for LATE-neuropathologic change: Implications for clinical utility
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Jung-Min Pyun1, Young Ho Park1, Lincoln M P Shade2
1Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea.
Introduction:
Limbic-predominant age-related TDP-43 encephalopathy (LATE) exhibits clinical features resembling Alzheimer's disease (AD) and frequently occurs as a co-pathology, yet there are fewer biomarkers for LATE relative to AD.
Methods:
We calculated polygenic risk scores for LATE-neuropathologic change (LATE-PRS) and performed association analysis with neuropathology (N = 99) and longitudinal cognitive change rates (N = 538) in Alzheimer's Disease Neuroimaging Initiative participants aged ≥ 75 years, stratified by amyloid positron emission tomography (PET) positivity status.
Results:
LATE-PRS was significantly associated with pathologically confirmed LATE (odds ratio = 2.292, P = 0.002), independent of AD pathology. In cognitively impaired individuals, LATE-PRS was associated with faster executive function decline in PET-negative individuals (β = -0.002, P = 0.041), and faster memory (β = -0.002, P < 0.001) and executive function (β = -0.001, P = 0.035) decline in PET-positive individuals. In the overall sample, associations were significant only in the PET-negative individuals.
Discussion:
LATE-PRS may serve as a potential biomarker for LATE risk and cognitive progression.