Epigenetic Modulation of Cognitive Function in Neurodegenerative Diseases

Epigenetic mechanisms—such as DNA methylation, histone modifications and non-coding RNA activity—regulate gene expression without altering the underlying DNA sequence. In the healthy brain, these processes underpin synaptic plasticity, learning and memory by orchestrating patterns of chromatin accessibility in neurons and glia. In neurodegenerative diseases, including Alzheimer’s and related dementias, aberrant epigenetic marks contribute to transcriptional repression of key synaptic and metabolic genes, exacerbate protein aggregation and disrupt neuronal resilience. Emerging evidence indicates that restoring epigenetic balance can rescue cognitive deficits: enhancing histone acetylation promotes expression of plasticity-related receptors, while targeted modulation of DNA repair enzymes preserves transcription of genes essential for neurotransmission. Non-coding RNAs, including microRNAs and long non-coding RNAs, further modulate network activity and inflammatory responses in aged and diseased tissue. Together, these insights point to a convergent model in which epigenetic dysregulation drives functional decline and in which precise pharmacological or genetic interventions hold promise for disease modification and cognitive restoration.

Research from Nature Portfolio

Studies have revealed that activation of class I histone deacetylase HDAC1 enhances repair of oxidative DNA lesions in ageing and Alzheimer’s models by stimulating the 8-oxoguanine glycosylase pathway, thereby safeguarding synaptic gene transcription and improving memory performance. Complementary in vivo imaging of histone deacetylase expression in humans has mapped age- and sex-dependent epigenetic signatures in white matter and limbic regions; these patterns correlate with microstructural integrity and emotion-memory functions, underscoring dynamic regulation of cognitive circuits by epigenetic enzymes across the adult lifespan.

Epigenetic Modulation of Cognitive Function in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in epigenetic modulation of cognitive function in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation: Addition of methyl groups to cytosine bases, often silencing gene transcription.

Histone acetylation: Attachment of acetyl groups to lysine residues on histone tails, loosening chromatin and promoting gene expression.

Histone deacetylase (HDAC): Enzyme that removes acetyl groups from histones, generally repressing transcription.

Chromatin remodelling: Dynamic repositioning or modification of nucleosomes to regulate DNA accessibility.

Synaptic plasticity: The ability of synapses to strengthen or weaken over time, essential for learning and memory.

References

1. ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease. Molecular Neurodegeneration (2023).
2. Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer’s disease mouse model by regulating the expression of APP secretases. Alzheimer's Research & Therapy (2024).
3. Reduction of class I histone deacetylases ameliorates ER‐mitochondria cross‐talk in Alzheimer's disease. Aging Cell (2023).
4. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nature Communications (2020).
5. Neuroepigenetic signatures of age and sex in the living human brain. Nature Communications (2019).