Summary: New research has shown that Alzheimer’s disease impacts the brain in two main phases: an earlier, continuous phase that damages find cell types and a later phase marked by quick, widespread damage as symptoms emerge.
In the first stage, simple changes occur carefully, including the loss of certain antagonistic neurons, which may lead to neural loop dysfunction. The second phase coincides with the emergence of the symptoms and the accumulation of Alzheimer’s marks, such as plaques and tangles.
This finding will reshape how Alzheimer’s is understood by experts, helping them develop targeted treatments for each disease stage. Advanced biological and mind mapping techniques used in this study provide a detailed picture of the cellular basis of Alzheimer’s progression.
Important Facts:
- Alzheimer’s unfolds in two stages: a silent first period and a clinical later stage.
- First changes include the loss of antagonistic neurons, which perhaps alter neural circuits.
- Studies suggest potential for phase-specific Alzheimer’s treatments and testing.
Origin: NIH
According to new research funded by the National Institutes of Health ( NIH), using advanced brain mapping techniques, Alzheimer’s disease may cause brain damage in two distinct phases.
Researchers who came across this new perspective claim that the first, earlier phase occurs slowly and quietly, harming just a few prone cell types before people experience memory issues.
In comparison, the following, late stage causes injury that is more commonly dangerous and coincides with the appearance of symptoms and the rapid accumulation of lesions, strands, and other Alzheimer’s marks.
The fact that the brain’s most severe damage occurs well before symptoms is a challenge in diagnosing and treating Alzheimer’s disease is one. The ability to detect these early changes means that, for the first time, we can see what is happening to a person’s brain during the earliest periods of the disease”, said Richard J. Hodes, M. D., director, NIH National Institute on Aging.
The findings will fundamentally alter scientists ‘ understanding of how Alzheimer’s causes harm to the brain and help inform the development of novel treatments for this devastating disorder.
Scientists analyzed the brains of 84 people, and the results, published in , Nature Neuroscience, suggest that damage to one type of cell, called an inhibitory neuron, during the early phase may trigger the neural circuit problems that underlie the disease. Additionally, the study confirmed previous findings about how Alzheimer’s damages the brain and identified many new changes that may happen during the disease.
Specifically, the scientists used advanced genetic analysis tools to study the cells of the middle temporal gyrus, a part of the brain that controls language, memory and vision. Many of the changes that are typically seen during Alzheimer’s have been shown to be present in the gyrus.
Researchers have also thoroughly mapped it for control donors, which is a part of the brain. The scientists developed a genetic and cellular timeline of what occurs throughout the disease by comparing the data from control donors to those from those who had Alzheimer’s.
Studies have long suggested that Alzheimer’s disease progresses in several stages, with increases in cell death, inflammation, and an accumulation of proteins in the form of plaques and tangles.
In contrast, this study suggests that the brain is altered by the disease in two “epochs” or “phases,” with many of the previously studied changes occurring quickly in the second phase. This occurs in tandem with the development of memory problems and other symptoms.
The results also suggest that the initial changes occur gradually and “quietly” in the initial stages of the process before any symptoms become apparent. These changes include the slow accumulation of plaques, brain immune system activation, neuronal signal-transmitting cellular insulation, and the death of somatostatin ( SST ) inhibitory neurons.
The last finding was surprising to the researchers. Traditionally, scientists have thought that Alzheimer’s primarily damages excitatory neurons, which send activating neural signals to other cells. calming signals are sent to other cells by inhibiting neurons.
The authors of the paper made the hypothesis that a loss of SST inhibitory neurons might lead to the neurochemical changes that underlie the disease.
Recently, a separate NIH-funded brain mapping , study by researchers at MIT , found that a gene called REELIN may be associated with the vulnerability of some neurons to Alzheimer’s. Additionally, it demonstrated that star-shaped brain cells, or astrocytes, can help protect against the harm caused by the disease.
Researchers analyzed brains that are part of the , Seattle Alzheimer’s Disease Brain Cell Atlas , ( SEA-AD), which is designed to create a highly detailed map of the brain damage that occurs during the disease.
The project was led by Mariano I. Gabitto, Ph. D., and Kyle J. Travaglini, Ph. D., from the Allen Institute, Seattle. The scientists used tools — developed as part of the , NIH’s , Brain Research Through Advancing Innovative Neurotechnologies® , ( BRAIN ) Initiative , – , Cell Census Network ( BICCN)  , — to study more than 3.4 million brain cells from donors who died at various stages of Alzheimer’s disease. Tissue samples were obtained from the , Adult Changes in Thought , study and the , University of Washington Alzheimer’s Disease Research Center.
This study demonstrates how the NIH’s BRAIN Initiative’s new technologies are transforming how we think about conditions like Alzheimer’s. According to John Ngai, Ph. D., scientists were able to use these tools to identify the earliest cellular changes in the brain, giving researchers a more comprehensive picture of what occurs throughout the course of the disease. D., director of The BRAIN Initiative®.
The new information uncovered by this study may aid global scientists and drug developers in developing diagnostics and treatments for specific Alzheimer’s and other dementia stages.
Funding: This study was funded by NIH grants:  , U19AG060909,  , P30AG066509,  , U19AG066567,  , U01AG006781. The Nancy and Buster Alvord Endowment provided additional funding. The Rush University Alzheimer’s Disease Center, Chicago, Il, shared donor metadata from the Religious Orders Memory/Memory and Aging Project.
Researchers can obtain data from the SEA-AD study by going to the study’s website:  , https: //portal. brain-map. org/explore/seattle-alzheimers-disease.
About this Alzheimer’s disease research news
Author: Christopher Thomas
Source: NIH
Contact: Christopher Thomas – NIH
Image: The image is credited to Neuroscience News
Original Research: Open access.
” Integrated multimodal cell atlas of Alzheimer’s disease” by Gabitto, M. I et al. Nature Neuroscience
Abstract
Integrated multimodal cell atlas of Alzheimer’s disease
Alzheimer’s disease ( AD ) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied.
In order to study middle-tetoral gyrus cell types in 84 donors with varying AD pathologies, we use multiomics, spatial genomics, and reference atlases from the BRAIN Initiative.
This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years.
We placed donors along a disease pseudoprogression score using quantitative neuropathology.
Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ , inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells, and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ , and Vip+ , inhibitory neuron subtypes.
These findings were carried out in other significant AD studies.
