Identifying Early Alzheimer’s Pathology

Long before symptoms emerge, the underlying pathology of Alzheimer’s disease (AD) is well underway. An MIT study published today in Communications Biology has pinpointed the brain regions with the earliest emergence of amyloid in 5XFAD mice.

“Alzheimer’s is a neurodegenerative disease, so in the end you can see a lot of neuron loss,” says Wen-Chin Huang, co–lead author of the study. “At that point, it would be hard to cure the symptoms. It’s really critical to understand what circuits and regions show neuronal dysfunction early in the disease. This will, in turn, facilitate the development of effective therapeutics.”

Recently, research groups have been tracing amyloid’s path in the brain by using technologies such as positron emission tomography and then looking at brains post-mortem, but the new study presents an unbiased look at the entire brain as early as one month of age. The study reveals that amyloid plaques begin in deep brain regions such as the mammillary body, the lateral septum, and the subiculum before making its way along specific brain circuits that ultimately lead it to the hippocampus and cortex.

The team used SWITCH, a technology developed by Chung, to label amyloid plaques and to clarify the whole brains of 5XFAD mice so that they could be imaged in fine detail at different ages. The team was consistently able to see that plaques first emerged in the deep brain structures and then tracked along circuits such as the Papez memory circuit to spread throughout the brain by 6–12 months. They also directly validated some of their findings in human tissue.

The team also performed experiments to determine whether the accumulation of plaques they observed was of real disease-related consequence for neurons in affected regions. One of the hallmarks of AD is a vicious cycle in which amyloid makes neurons too easily excited, and overexcitement causes neurons to produce more amyloid. The team measured the excitability of neurons in the mammillary body of 5XFAD mice and found that they were more excitable than otherwise similar mice that did not harbor the 5XFAD set of genetic alterations.

Finally, in a preview of a potential future therapeutic strategy, the researchers found that genetically silencing neurons in the mammillary body of 5XFAD mice resulted in their neurons producing less amyloid.