Alzheimer’s disease may damage the brain in two distinct phases, based on new research funded by the National Institutes of Health (NIH) using sophisticated brain mapping tools.
According to researchers who discovered this new view, the first, early phase happens slowly and silently — before people experience memory problems — harming just a few vulnerable cell types. In contrast, the second, late phase causes damage that is more widely destructive and coincides with the appearance of symptoms and the rapid accumulation of plaques, tangles, and other Alzheimer’s hallmarks.
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. The gyrus has been shown to be vulnerable to many of the changes traditionally seen during Alzheimer’s. It is also a part of the brain that researchers have thoroughly mapped for control donors. By comparing control donor data with that from people who had Alzheimer’s, the scientists created a genetic and cellular timeline of what happens throughout the disease.
Traditionally, studies have suggested that the damage caused by Alzheimer’s happens in several stages characterized by increasing levels of cell death, inflammation and the accumulation of proteins in the form of plaques and tangles. In contrast, this study suggests that the disease changes the brain in two “epochs” — or phases — with many of the traditionally studied changes happening rapidly during the second phase. This coincides with the appearance of memory problems and other symptoms.
The results also suggest that the earliest changes happen gradually and “quietly” in the first phase before any symptoms appear. These changes include slow accumulation of plaques, activation of the brain’s immune system, damage to the cellular insulation that helps neurons send signals and the death of cells called 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. Inhibitory neurons send calming signals to other cells. The paper’s authors hypothesized how loss of SST inhibitory neurons might trigger the changes to the brain’s neural circuitry 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. It also showed that star-shaped brain cells called astrocytes may provide resilience to or resist the harm caused by the disease.
