Alzheimer’s disease (AD) is a devastating neurodegenerative condition characterized by declining cognitive function. Billions of dollars are put into research each year to understand the complexities of AD pathology. Historically, research focused on AD risk factors, but now there is a shift towards investigating protective factors. One key question surrounds the resilience of those who defy disease progression. Nearly a third of cognitively normal elderly possess substantial AD pathology. A recent study examined gene expression relating to metallothionein, a protein responsible for metal detoxification, and mitochondrial function, the energy producer in all cells. Other studies explored protective genes in those with a high genetic risk of AD, and gene expression in AD-resilient individuals versus those with symptoms to develop precision therapeutic interventions.
One notable finding concerns metallothionein gene expression. Resilient individuals exhibited higher expression of genes related to metallothionein, indicating a higher rate of heavy metal detoxification. They also play a role in antioxidant defense mechanisms to combat oxidative stress that occurs with mitochondrial dysfunction. Increased expression of metallothionein-related genes likely plays a protective role against neurodegeneration either through detoxification of harmful metals or mitigation of oxidative stress.
Heightened expression of genes stabilizing mitochondrial function was also observed in resilient individuals compared to symptomatic individuals. Mitochondrial dysfunction is associated with various neurodegenerative diseases including AD. Investigations are underway into therapeutic approaches such as mitochondrial replacement therapies and mitochondrial transfer techniques from donor cells. More research is needed to understand the potential benefits of these treatments for neurodegenerative diseases.
An interesting approach to studying protective genes involves identifying those with a known higher risk. Carriers of APOE-ε4 alleles face a significantly higher risk of developing AD symptoms; however, not all carriers become symptomatic. Conversely, carriers of the APOE-ε2 allele experience protection through enhanced clearance of Aβ. The protective allele is believed to improve the endocytosis of Aβ that leads to its removal from the brain.
For APOE-ε4 carriers, other genes may offer protection via their interaction with APOE-ε4. Genes involved in cellular trafficking, such as those regulating endocytosis and transport, help prevent the accumulation of Aβ and tau. These help to prevent the onset of AD pathology from occurring by maintaining homeostasis between the production and clearance of these two misfolded proteins. In animal models, expressing protective variants of these cellular trafficking genes enhances Aβ clearance through endocytic pathways. Lipid metabolism genes, which regulate cholesterol homeostasis and lipid bilayer stability, are also protective by maintaining neuronal membrane integrity and function. Disruptions in lipid metabolism lead to increased Aβ plaque formation and subsequent tau pathology. Endosomal and lysosomal systems which degrade and remove cellular waste, benefit from protective genes that enhance lysosomal enzyme activity and reduce Aβ and tau accumulation. Synaptic dysfunction and neuroinflammation are significant drivers of AD progression. Protective genes that support synaptic function, including synaptic vesicle recycling, neurotransmitter release, and synaptic plasticity, maintain neuronal connectivity. Additionally, other protective genes regulate microglial activation and modulate pro-inflammatory cytokine production to limit neuroinflammation. By focusing their attention on these protective mechanisms, researchers gain valuable insights into the multiple causes of AD and potential personalized treatments.
One surprising observation is the lack of changes in the unfolded protein response (UPR) between resilient individuals and symptomatic individuals. The UPR is a cellular stress response pathway activated in response to protein misfolding and aggregation, which is crucial in AD pathology.
Although many aspects of AD may seem beyond individual control, there are actions people can take to enhance their resilience against AD pathology. Large-scale gene expression analyses have identified potential interventions to slow AD progression. One key finding emphasizes the importance of exercise. Physical activity influences many genes involved in neuroprotection, cognitive function, and inflammation. Exercise can modulate gene expression related to neurogenesis, synaptic plasticity, and oxidative stress. It is a cost-effective and accessible strategy, complementing other therapeutic approaches.
These findings offer critical insights into genetic factors involved in AD resilience and raise important questions for the future. A deeper understanding of the interactions between genetic and environmental factors, such as diet and exercise, could lead to targeted therapies that replicate the protective mechanisms observed in resilient individuals.
Sources:
de Vries, L. E., Jongejan, A., Monteiro Fortes, J., Balesar, R., Rozemuller, A. J., Moerland, P. D., … & Verhaagen, J. (2024). Gene-expression profiling of individuals resilient to Alzheimer’s disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response. Acta Neuropathologica Communications, 12(1), 68.
Hill, M. A., & Gammie, S. C. (2022). Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment. Scientific reports, 12(1), 17189.
Ng, N., Newbery, M., Miles, N., & Ooi, L. (2025). Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging. Neural Regeneration Research, 20(3), 794-796.
Seto, M., Weiner, R. L., Dumitrescu, L., & Hohman, T. J. (2021). Protective genes and pathways in Alzheimer’s disease: moving towards precision interventions. Molecular neurodegeneration, 16(1), 29.