Alzheimer’s disease (AD) poses a significant global health challenge, impacting millions of individuals across the world with devastating consequences for cognition and quality of life. Understanding AD remains a considerable challenge. Epigenetic mechanisms altering gene expression without altering DNA sequence may provide insight into AD pathology.
AD is a neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau proteins, resulting in neuronal dysfunction and cognitive decline. Epigenetic modifications have emerged as one of the crucial players in AD pathology.
Epigenetic changes can be caused by environmental exposure and lifestyle choices, influencing health and aging. Epigenetic changes control gene expression patterns, altering aspects of cellular function and identity. In AD, epigenetic modifications change the expression of genes involved in Aβ production, tau phosphorylation, neuroinflammation, and synaptic function.
Diabetes, high blood pressure, and a sedentary lifestyle have negative influences on health and increase the risk of AD. Conversely, incorporating a healthy diet and exercise promotes positive epigenetic changes and decreases the risk for AD. Exercise increases blood flow to the brain and promotes gene expression for synaptic plasticity, increasing cognitive function potential. A healthy diet decreases neuroinflammation and oxidative stress creating neuroprotection against cognitive decline. The Mediterranean diet accomplishes this by being rich in antioxidant molecules and anti-inflammatory nutrients involved in pathways that alter amyloid-β and tau protein accumulation.
Epigenetic processes like histone modifications, DNA methylation patterns, and non-coding RNA molecules play critical roles in modulating gene expression associated with AD pathology. Alterations in histone acetylation and methylation impact the transcription of genes involved in Aβ metabolism and clearance pathways. Similarly, changes in DNA methylation patterns have been linked to abnormal tau phosphorylation and neuronal dysfunction in AD. Non-coding RNAs regulate through transcriptional or post-transcriptional mechanisms to promote synaptogenesis and may be able to silence genes that are involved in AD pathology.
Restoring normal epigenetic patterns may prove to be a beneficial therapeutic strategy in the treatment of AD. One promising approach employs small molecules that selectively modulate the activity of histone deacetylases (HDACs) or histone acetyltransferases (HATs), thereby influencing gene expression patterns relevant to AD pathology. HDAC inhibitors enhance memory and synaptic plasticity in AD animal models by decreasing histone acetylation, altering gene expression profiles. Histone acetylation allows for modifications of histone proteins which are involved in the activation of AD-related genes that promote Aβ. When these regions are deacetylated by HDAC inhibitors, accumulation of Aβ is slowed. These compounds also reduce Aβ levels and tau phosphorylation in animal models, suggesting multiple therapeutic benefits. More research is needed to elucidate their use in human AD pathology treatment.
Despite the promising findings, researchers still face several challenges in translating epigenetic-based therapies into clinical practice. One major hurdle is understanding the specific epigenetic changes that occur at different stages of AD progression and their implications for disease severity and variability among patients. Additionally, the development of safe and effective epigenetic drugs that can selectively target disease-relevant pathways without causing negative effects remains a priority. Furthermore, the optimal timing of administering these interventions and the duration of treatment needs to be evaluated to maximize efficacy while minimizing risks.
Targeting epigenetic dysregulation in AD pathology holds the potential for disease-modifying treatments that could prevent, slow, or halt disease progression. Continued research efforts are critical for advancing precision medicine and improving outcomes for affected individuals, offering hope for those affected by AD and their families.
Sources:
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Heerboth, S., Lapinska, K., Snyder, N., Leary, M., Rollinson, S., & Sarkar, S. (2014). Use of epigenetic drugs in disease: an overview. Genetics & Epigenetics, 6, 9-19.
Li, J. Z., Ramalingam, N., & Li, S. (2025). Targeting epigenetic mechanisms in amyloid-β–mediated Alzheimer’s pathophysiology: unveiling therapeutic potential. Neural Regeneration Research, 20(1), 54-66.
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