A new study published in Nature Neuroscience1 has uncovered significant insights into the progression of Alzheimer’s disease (AD), providing a new understanding of how the disease damages the brain. Funded by the National Institutes of Health (NIH) and led by researchers from the Allen Institute, this study used advanced brain mapping and genetic tools to explore the cellular-level changes that occur throughout AD. The findings reveal that Alzheimer’s progresses in two distinct phases, offering potential avenues for early diagnosis and treatment strategies.
Currently more than 55 million people are living with dementia worldwide,2 with AD is the most common type, affecting at least 27 million people.3 Alzheimer’s is characterized by a gradual decline in cognitive functions such as memory, thinking skills and daily activities. Although it is well-known that the accumulation of amyloid plaques and tau tangles in the brain plays a central role in the disease, this study has revealed that the damage does not occur as a continuous process. Instead, the researchers have identified two distinct phases in which brain cell damage unfolds.
The first phase, which occurs silently before clinical symptoms such as memory problems arise, involves subtle cellular changes. During this early stage, a slow accumulation of amyloid plaques and inflammatory changes take place, with a specific focus on the death of somatostatin-expressing inhibitory neurons (SST neurons). These neurons play a crucial role in regulating neural activity by dampening excessive signals, and their loss may initiate the early neural dysfunction associated with AD.
The second phase is marked by rapid progression and more widespread destruction. This phase coincides with the emergence of cognitive symptoms and the more dramatic accumulation of protein plaques and tangles, which cause the breakdown of communication between neurons and the death of various brain cells. The involvement of immune cells, such as microglia and astrocytes, is also heightened during this phase, contributing to the inflammatory response and further brain damage.
To map the cellular changes, the research team analyzed over 3.4 million brain cells from 84 individuals at different stages of AD. By comparing the brain cells of Alzheimer’s patients to healthy control samples, the researchers created a detailed genetic timeline of the disease’s progression. Their focus was on the middle temporal gyrus, which is essential for language, memory and vision, and is especially vulnerable to Alzheimer’s-related changes.
The findings challenge previous assumptions that excitatory neurons (which promote neural activity) were the primary targets in the early stages of AD. Instead, the early loss of inhibitory SST neurons provides new insights into how Alzheimer’s begins, potentially opening up options for targeted interventions that could protect these vulnerable cells or slow their degeneration.
The identification of these two distinct phases of Alzheimer’s progression represents a significant shift in how scientists understand the disease. The early, “silent” phase offers an opportunity to detect and intervene before the onset of noticeable symptoms. By focusing on these early cellular changes, researchers hope to develop treatments that can delay or prevent the progression of the disease, ultimately reducing its devastating impact on patients.
References:
- Gabitto, M.I., Travaglini, K.J., Rachleff, V.M. et al. Integrated multimodal cell atlas of Alzheimer’s disease. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01774-5
- Dementia. World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia (accessed Oct 22, 2024).
- Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet. 2011;377):1019–31.
Disclosures: This article was created by the touchNEUROLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
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