Alzheimer’s Disease Progresses in Two Phases

A brain mapping study funded by the National Institutes of Health (NIH) has revealed that Alzheimer's disease (AD) induces brain damage in two distinct phases. Published in Nature Neuroscience, the research provides a detailed cellular-level map of the condition.

The early impact of Alzheimer's disease

AD is a progressive neurodegenerative disorder characterized by a gradual decline in memory, thinking skills and the ability to perform everyday tasks. The condition affects an estimated 6.9 million Americans.

The exact cause of AD remains uncertain. However, research has highlighted the role of two key proteins in the brain: amyloid and tau. These proteins accumulate abnormally, forming amyloid plaques and tau tangles, interfering with normal brain function. The buildup of these structures disrupts communication between neurons and triggers inflammation, ultimately leading to the death of brain cells.  

Although the accumulation of these proteinopathies has been extensively studied, the specific brain cell populations they affect remain poorly understood, specifically those impacted before symptoms begin to show.

“One of the challenges to diagnosing and treating Alzheimer’s is that much of the damage to the brain happens well before symptoms occur,” said Dr. Richard J. Hodes, the director of the National Institute on Aging at NIH.

“By studying research subjects across the spectrum of AD, including those in the earliest stages of disease, we hope to identify vulnerable cells early in the disease process, long before a person develops symptoms,” said co-author Dr. C. Dirk Keene, a professor and Nancy and Buster Alvord endowed chair in neuropathology at the University of Washington.

Creating a genetic and cellular timeline of AD

Using advanced single-cell genomic technologies and novel machine-learning models, the team analyzed over 3.4 million cells from 84 people to map the cellular changes that occur as AD progresses.

The study focused on a region of the cortex called the middle temporal gyrus (MTG), which is involved in language, memory and visual processing. The MTG is also a transition zone where early AD pathology, such as the buildup of toxic protein fragments, progresses into more advanced neurodegeneration associated with the disease.

The AD brain cells from the MTG were compared with healthy brain cells to create a genetic and cellular timeline of what happens throughout the disease.

“You could say that we created a pathology clock that tells not only what changes are happening in this cortical region, but when. We now have a framework to arrange the sequence of events as Alzheimer’s pathology increases over time,” said lead author Dr. Mariano Gabitto, an assistant investigator at the Allen Institute.

AD occurs in two distinct phases

It was previously thought that AD progresses in several stages, marked by a gradual increase in cell death, inflammation and the accumulation of protein. Surprisingly, the new study found the disease alters the brain in just two distinct phases, with many of the traditionally studied changes happening during the second phase.

In the first phase, the researchers identified inflammatory changes in the brain’s immune and support cells, microglia and astrocytes, and a slow accumulation of plaques. Additionally, they found the death of somatostatin-expressing inhibitory neurons (SST neurons) – a specific type of inhibitory interneuron that helps dampen neural activity – occurred very early in the disease. 

“The loss of these ‘SST neurons’ was a surprise. Most of the field has focused on microglia, and a loss of excitatory neurons that make long-range connections across the cortex and other brain regions. Instead, we find it is specific types of inhibitory neurons that are the earliest neuronal casualties in this part of the brain,” said co-author Dr. Ed Lein, a senior investigator at the Allen Institute for Brain Science.

A decline in cortical oligodendrocytes, the cells responsible for insulating nerve fibers and enhancing communication in the brain, was also observed. This loss was followed by the activation of a repair mechanism aimed at restoring the damaged insulation.

The later stage of AD was associated with a much larger loss of neurons, including both excitatory and inhibitory neurons. The cell loss was concentrated in the upper layers of the cortex, indicating a cascade effect in which the loss of particularly vulnerable cells may lead to the gradual loss of neighboring cells over time.

“The initial triggers of disease may involve pathological proteins or microglial activation, but it is loss of specific types of neurons and the connections they make that lead to cognitive decline,” said Lein. 

Can we stop Alzheimer’s in its tracks?

“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 Hodes.

The authors suggest the loss of SST neurons may start a “domino effect”, eventually leading to the widespread neuronal loss seen in AD.

“Armed with this information, maybe we could target not only molecules like tau and amyloid, but also vulnerable cell types. Perhaps we could protect them and prevent their degeneration, and the whole downstream cascade of events,” said Lein.

Reference: Gabitto MI, Travaglini KJ, Rachleff VM, et al. Integrated multimodal cell atlas of Alzheimer’s disease. Nat Neurosci. 2024. doi: 10.1038/s41593-024-01774-5

This article is a rework of a press release issued by the National Institutes of Health. Material has been edited for length and content.