Abstract
Background
Cognitive trajectory varies widely and can distinguish people who develop dementia
from people who remain cognitively normal. Variation in cognitive trajectory is only
partially explained by traditional neuropathologies. We sought to identify novel genes
associated with cognitive trajectory using DNA methylation profiles from human postmortem
brain.
Methods
We performed a brain epigenome-wide association study of cognitive trajectory in 636
participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging
Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To
maximize our power to detect epigenetic associations, we used the recently developed
Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains
simultaneously.
Results
We found an epigenome-wide association for differential methylation of sites in the
CLDN5 locus and cognitive trajectory (p = 9.96 × 10−7) that was robust to adjustment for cell type proportions (p = 8.52 × 10−7). This association was primarily driven by association with declines in episodic
(p = 4.65 × 10−6) and working (p = 2.54 × 10−7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs
of amyloid-β and neurofibrillary tangle pathology.
Conclusions
Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated
with cognitive trajectory beyond traditional Alzheimer’s disease pathologies. The
association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early
role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer’s
disease.
Keywords
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Article Info
Publication History
Published online: February 03, 2021
Accepted:
January 27,
2021
Received in revised form:
January 6,
2021
Received:
June 25,
2020
Identification
Copyright
© 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
