By: Kate Leinenweber
Brain atrophy and differences in cells between a healthy brain and a brain with Alzheimer’s disease. Image created in BioRender.
The Mayo Clinic estimates that, after being diagnosed with Alzheimer’s disease, patients can live from 3-11 years, with some even living for 20. Although there are many possible reasons behind this variation – from how far the disease has progressed by the time of diagnosis, to the quality of care that the person with Alzheimer’s receives – one major factor in disease progression is biological. Every person’s body is primed differently to deal with Alzheimer’s disease due to their genetics, lifestyle, and age. However, in a scientific era where genomics have the spotlight, the cellular mechanisms behind Alzheimer’s and the genes that contribute to them are particularly under scrutiny. What biological factors make the disease progress at different speeds for different people, and what does that tell us about how we can go about treating it?
In recent studies, the immune system has been shown to play a role in Alzheimer’s disease, possibly slowing disease onset and progression (Pereira, 2022). A type of cell present in the brain, called microglia, are responsible for regulating the immune response in the central nervous system. Microglia are macrophages, meaning that they are immune cells which engulf (or, literally, eat) anything in the body that shouldn’t be there. Macrophages in the rest of our body get rid of pathogens like bacteria and viruses before they can infect us; microglia get rid of debris and monitor damaged neurons or synapses to keep our brains functioning at their best. In Alzheimer’s disease, dead neurons and debris that accumulate in the brain contribute to worsening disease symptoms. By preventing the accumulation of debris in the brain, microglia are able to prevent Alzheimer’s symptoms from progressing as quickly as they would otherwise.
Amyloid and Tau Protein in Alzheimer’s
Biologically, Alzheimer’s disease is characterized by the aggregation of misfolded proteins in the brain, called amyloid plaques and tau neurofibrillary tangles. The presence of these abnormal proteins is not just a possible indicator of the disease; it is what doctors have been actively using to diagnose Alzheimer’s in recent years (Jack, 2024). Amyloid and tau are widely accepted to be a part of Alzheimer’s disease, and PET scans of Alzheimer’s patients generally show that both of these proteins – especially their misfolded or otherwise abnormal versions – are present in much higher amounts compared to healthy patients. Recent research has also shown that certain molecules which indicate inflammation in the body are present in higher amounts for Alzheimer’s patients (Jack, 2024). In addition to this, certain genes associated with the inflammatory response, such as the TREM2 gene, have variants that are correlated with a higher likelihood of developing Alzheimer’s. In one study, a rare mutated version of TREM2 was associated with nearly 3 times the risk and 3 years earlier onset of Alzheimer’s, further indicating that the immune system is involved in the disease’s progression (Jonnson, 2013).
Neuroinflammation
The state of the immune system has been shown to change throughout the stages of Alzheimer’s in various ways. The most well known part of the immune response to Alzheimer’s is what occurs near the beginning of disease onset: in a process called neuroinflammation, the brain reacts to the presence of molecules like amyloid and tau by instigating a reaction from the immune system. Dying neurons also release signal molecules called DAMPs, which alert our microglial cells that something is going wrong around them (Wu, 2021). Microglia are then activated and begin to engulf amyloid and tau proteins, as well as debris from dead neurons.
Microglia have been a recent focal point of Alzheimer’s research due to their increasingly clear role in the brain’s inflammatory response to the disease, as well as how their activity can help slow disease progression. Initially, microglia are protective against Alzheimer’s disease progression because they clear up amyloid plaques and other aggregated proteins (Pereira, 2022). However, the constant accumulation of protein aggregates leads to chronic microglial activation and therefore chronic neuroinflammation. Due to this process, microglia in later stages of Alzheimer’s become ineffective at their job and can even promote faster disease progression. Microglia tend to exhibit this detrimental behavior near the late stages of Alzheimer’s disease, when amyloid plaques and tau tangles are so numerous and neuron death is so widespread that their activity is no longer preventative. Chronic inflammation can even cause extra damage to the brain, making the later stages of the disease get worse faster.
Researching New AD Treatments
Information like this can seem unhelpful or hopeless – after all, what can we do if our own cells cannot continuously combat Alzheimer’s progression? Learning things like this can be scary, but it can also provide hope. Everything that teaches us more about Alzheimer’s disease and the workings behind it also teaches us more about how we can research and treat the disease. We know that the immune system and the inflammatory response are involved in the progression of Alzheimer’s, and that the most obvious mechanism of this is that microglia clear up debris that accumulates in the brain. We also know that there are certain genes that increase the risk of Alzheimer’s, but it is not always clear how these are related to each other. For example, the APOE gene is so highly associated with late-onset Alzheimer’s that there is genetic testing available to see if people carry a mutation that puts them at risk (Fortea, 2024). The TREM2 gene, which codes for a protein involved in microglia activation, also has variants that increase Alzheimer’s risk, which were correlated with both earlier onset and faster disease progression (Jonsson et. al., 2013).
The more we learn about genes like this through genomic profiling, cell culture, PET scans, and other scientific endeavors, the more we will be able to understand the intricacies of the immune response’s role in Alzheimer’s disease. In the near future, treatments may begin targeting both amyloid/tau accumulation and inflammatory modulators like TREM2, hopefully providing more specific and effective Alzheimer’s medication.
References
Fortea, J., Pegueroles, J., Alcolea, D. et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease. Nat Med 30, 1284–1291 (2024). https://doi.org/10.1038/s41591-024-02931-w.
Jack Jr. C.R., Andrews J.S., et. al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 20(8), 5143-5169 (2024). https://doi.org/10.1002/alz.13859.
Johnsonn, T.., Stefansson, H., et. al. Variant of TREM2 Associated with the Risk of Alzheimer's Disease. New England Journal of Medicine 368, 107-116 (2013). https://doi.org/10.1056/NEJMoa1211103.
Leng, F., Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol 17, 157–172 (2021). https://doi.org/10.1038/s41582-020-00435-y
Mayo Clinic Staff. Alzheimer's stages: How the disease progresses. Mayo Clinic (2023). https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-stages/art-20048448
Pereira, J.B., Janelidze, S., Strandberg, O. et al. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease pathology. Nat Aging 2, 1138–1144 (2022). https://doi.org/10.1038/s43587-022-00310-z.
Woodburn, S.C., Bollinger, J.L. & Wohleb, E.S. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation 18, 258 (2021). https://doi.org/10.1186/s12974-021-02309-6.
Wu, K.M., Zhang, Y.R., et. al. The role of the immune system in Alzheimer’s disease. Ageing Research Reviews 70, (2021). https://doi.org/10.1016/j.arr.2021.101409.
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