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Updated: Nov 9, 2025

The Detection of 5-Hydroxymethylcytosine in Neural Stem Cells and Brains of Mice

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Published on: September 19, 2019

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline.

Anke Hüls¹, Chloe Robins², Karen N Conneely³

¹Department of Human Genetics, Emory University, Atlanta, Georgia; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Biological Psychiatry

|April 11, 2021

Summary

Differential methylation of the CLDN5 gene is linked to cognitive trajectory, impacting memory decline even without significant Alzheimer's pathology. This suggests CLDN5 plays an early role in cognitive aging.

Keywords:

Cognition Cognitive trajectory Dementia Epigenetics Gene-based analysis Neuropathology

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Area of Science:

Neuroscience
Genetics
Epigenetics

Background:

Cognitive trajectory varies significantly, with factors beyond traditional neuropathologies influencing dementia risk.
Identifying novel genetic and epigenetic markers is crucial for understanding cognitive decline.

Purpose of the Study:

To identify novel genes associated with cognitive trajectory using DNA methylation profiles.
To investigate the relationship between epigenetic variations and cognitive decline in postmortem brain tissue.

Main Methods:

Performed a brain epigenome-wide association study on 636 participants from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP).
Analyzed DNA methylation profiles from the dorsolateral prefrontal cortex.
Utilized the Gene Association with Multiple Traits test to analyze five cognitive domains simultaneously.

Main Results:

Found a significant epigenome-wide association between differential methylation in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10⁻⁷).
This association remained robust after adjusting for cell type proportions (p = 8.52 × 10⁻⁷).
The association was primarily driven by declines in episodic and working memory, and was significant even in individuals with minimal amyloid-β and neurofibrillary tangle pathology.

Conclusions:

Differential methylation of CLDN5, a gene encoding a key blood-brain barrier protein, is associated with cognitive trajectory independently of traditional Alzheimer's disease pathologies.
CLDN5 methylation's association with cognitive trajectory in low-pathology individuals suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer's disease progression.