Alzheimer's disease is the most common form of dementia and one of the great mysteries of modern neuroscience. Despite decades of research, many aspects of how exactly this neurodegenerative disease destroys the brain remain unclear. Traditionally, it was believed that the disease, which affects at least 10 million people worldwide (according to the World Health Organization), develops in stages through inflammation, cell death and the accumulation of proteins in the form of plaques. All of these processes lead to the degradation of memory, behavior and thinking. Now, a team of scientists from the Allen Institute in Seattle (USA) and other institutions has discovered that the disease destroys the brain in two stages – the first phase occurs unnoticed, before symptoms appear, and the second is characterized by direct destruction of the brain.
A groundbreaking genetic analysis has provided new insights into how Alzheimer's disease damages the brain. Image: news.mit.edu
Contents
- 1 Two steps that destroy the brain
- 2 Damage to inhibitory neurons
- 3 Multimodal map and brain damage
- 4 What next?
Two stages that destroy the brain
A study recently published in Nature Neuroscience offers a revolutionary look at how Alzheimer's progresses and which brain cells are most vulnerable to it. By analyzing brain tissue samples obtained posthumously from donors with a confirmed diagnosis, the research team found that the disease progresses in two distinct stages.
The first stage (phase) is characterized by a slow increase in inflammation. This means that the gradual increase in inflammation in the brain occurs unnoticed, without the manifestation of symptoms such as memory and thinking impairment. Notably, the first phase affects only certain cells – inhibitory neurons (more on these later).
Alzheimer's disease progresses in two stages. Image: newsnetwork.mayoclinic.org
Rapid brain damage occurs in the second stage of the diseaseand is accompanied by the manifestation of symptoms, through the accumulation of beta-amyloid plaques and neurofibrillary tangles of tau protein in the brain (recall that beta-amyloid plaques interrupt the activity that maintains the normal functioning of brain cells, and tau protein accumulations inside neurons kill cells). These processes destroy neural circuits and lead to the loss of cognitive functions.
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Damage to inhibitory neurons
The team analyzed the genetic activity of individual cells extracted from the middle temporal gyrus, a brain region heavily involved in language processing and semantic memory. In total, they analyzed samples of more than 3.4 million cell nuclei from 84 donors with Alzheimer's disease at various stages. The donors were an average age of 88, with 51 women and 33 men.
Then, rather than comparing the analyzed tissues to healthy individuals, the team assessed the donors' quantitative neuropathology and ranked them on a pseudoprogression scale – that is, the progression of symptoms and brain damage – and developed a a multimodal map of brain cells in Alzheimer's disease that reflects the genetic and cellular chronology of changes throughout the disease.
Genetic analysis of brain cells has revealed the types of cells that are most likely to be affected by the disease. Image: Courtesy of The Allen Institute, Seattle
This has allowed scientists to identify specific types of cells that are most likely to be affected by this form of dementia – so-called inhibitory neurons, which play a key role in regulating brain activity by deactivating or calming other neurons. This is the most exciting part of the discovery: previously, most studies focused on excitatory neurons (brain cells that activate other neurons).
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The results of the analysis showed that specific damage to inhibitory neurons in the first stage of Alzheimer's disease disrupts neural circuits, contributing to severe brain damage in the second stage. The discovery will allow the disease to be diagnosed before symptoms appear and new therapeutic strategies and drugs to be developed to prevent or slow the progression of the disease to irreversible brain damage.
Multimodal Map and Brain Damage
The creation of a multimodal map of brain cells (or atlas called the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD)) has provided a comprehensive understanding of which cell types are most vulnerable and where in the tissue microstructure they are located. The discovery was made possible by combining different types of data (genomic, transcriptomic, epigenomic, and spatial).
Interestingly, the first phase of the disease also involves activation of microglia, the brain's immune cells, and reactive astrocytes. On the one hand, this means that the brain is trying to protect itself from initial damage, on the other hand, it means that inflammation and further damage to neurons may increase.
Alzheimer's disease is incurable. All that can be done today is to slow its progression. Image: newscientist.com
In the second, more rapid phase of the disease, there is an exponential increase in pathology. This means that the accumulation of beta-amyloid plaques and neurofibrillary tangles of tau protein leads to severe damage to neurons and a pronounced loss of cognitive function. The second stage of the disease is also characterized by the loss of excitatory neurons and other types of inhibitory neurons.
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Understanding that Alzheimer's disease progresses in two distinct stages, and identifying the cell types affected at each stage, provides new opportunities for developing targeted therapeutic strategies. For example, treatments that reduce inflammation and protect inhibitory neurons early on may slow or prevent further progression of the disease.
The findings fundamentally change our understanding of how Alzheimer's disease damages the brain and may help develop new treatments for this neurodegenerative disease, said Richard Hodes, director of the National Institute on Aging (NIH), who was not involved in the study.
Importantly, the findings from the new study have been confirmed in other large studies, strengthening the credibility and significance of the new research. Thus, as technology advances, the ability to study one of the most difficult to understand neurodegenerative diseases is increasing.
Alzheimer's disease is a severe form of dementia. Image: dementech.com
Modern genome sequencing and spatial transcriptomics techniques allow scientists to map changes in the brain at the cellular level and identify previously unknown phases of the disease, along with new potential “targets” for intervention and therapy.
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What's next?
The new study's findings represent a significant step forward in our understanding of Alzheimer's disease, and the creation of a multimodal map allows scientists to see a more complete picture of how the disease affects the brain at a micro level. While much work remains to be done, particularly in developing new treatments, studies like these bring us closer to unraveling the mysteries of this complex disease and opening up new avenues for intervention.
Now that scientists have a clearer picture of the cell types and processes involved in the early stages of the disease, the next step will be to develop diagnostic tools to detect these changes in living patients. This approach could involve developing biomarkers or imaging techniques that can detect early inflammation or loss of inhibitory neurons. Therapeutic strategies that preserve inhibitory neuron function may also hold promise.
Beating dementia is no easy task. Image: alzheimer.ie
Alzheimer's disease is one of the most serious medical problems. First described in 1907 by German psychiatrist Alois Alzheimer, there is no cure, but scientists hope that sooner or later they will be able to defeat it. Of course, success in the fight against the disease requires the joint efforts of researchers from different fields of science and medicine. Expanding publicly available resources, such as the new multimodal map, facilitates the exchange of knowledge and accelerates progress in this field.
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While scientists and doctors have a long way to go, the results of this new study bring us closer to the day when Alzheimer's disease will be treatable or even preventable. Understanding how it develops at the cellular level opens doors to new possibilities and inspires optimism for healthy aging.