New study uncovers brain damage progression in Alzheimer's disease

A new study led by scientists from BGI Genomics' Institute of Intelligent Medical Research (IIMR) has identified early biomarkers and disease neurons associated with Alzheimer's Disease (AD) pathology.

The study was published in the journal Protein & Cell in early June. The findings provide deeper insights into the spatiotemporal changes in the brain and may help guide future strategies for early intervention and prevention of AD.

Neurons Change in Alzheimer's

AD is a progressive brain disorder that gradually destroys memory, thinking ability, and daily functioning. As the disease worsens, certain types of brain cells, especially neurons, become more vulnerable and eventually stop working properly. Most earlier studies compared healthy and AD-affected brains only at the very late stage of the disease.

In this new study, researchers analyzed over 1,663 single -cells transcriptomes from early, middle, and late stages of AD. The analysis specifically looks at a brain region called the EC-HPC circuit (including the entorhinal cortex and hippocampus) that plays a key role in memory and is known to be hit early by AD.

The researchers used Smart-seq2, a high-depth single-cell sequencing technology that delivers more precise genetic data per cell than conventional methods. This approach enabled them to detect subtle shifts in cellular activity throughout different stages of the disease, including early phases before visible brain damage appears.

Energy Breakdown Happens Early

The brain uses a lot of energy, and its cells rely heavily on mitochondria, the tiny structures inside cells that act like power plants. In this study, scientists found that mitochondria in vulnerable brain areas began to fail early in the disease, even before the buildup of amyloid plaques, one of the hallmarks of AD.

Later in the disease, mitochondria seem to become more active again. This may be the brain’s way of trying to fight back against worsening damage, but it may come too late to stop neurons from dying.

MEG3 Gene in Early Neuron Damage

A gene called MEG3 is involved in regulating mitochondrial health and energy use. Abnormal MEG3 expression is associated with mitochondrial dysfunction, lower ATP production, and increased oxidative stress, which can damage neurons. In AD, this gene becomes overactive, especially in the early stages and particularly in a type of memory-critical neuron called stellate neurons in the entorhinal cortex.

The study showed that MEG3 levels rise during the early stages of AD. MEG3 is abnormally overexpressed in the early stage of AD, which may cause the death of stellate neurons by inhibiting mitochondrial biosynthesis and energy metabolism.

As the disease progresses and neurons die, MEG3 levels appear to decrease. This pattern suggests that MEG3 might be a warning signal of early brain changes, and targeting it could offer a way to protect neurons before the damage is irreversible.

Neurons Resemble Astrocytes

One of the most surprising discoveries was that a large number of neurons—up to 38% in certain brain regions—began producing glial fibrillary acidic protein (GFAP), a protein usually exclusive to astrocytes.

Astrocytes typically maintain brain homeostasis by clearing debris and supporting neuronal health, but in AD, their dysfunction often compromises neighboring neurons. In this study, GFAP+ neurons first emerged in the hippocampal CA3 region of AD brains, progressively increased in number with pathological progression, and spread along the EC-HPC circuit to the entorhinal cortex.

These neurons not only take on astrocytic traits but also lose their typical neuronal features, such as NeuN and Snap25, and start expressing stem-like genes. Based on these findings, the authors propose a novel "glial barrier hypothesis" for AD pathology: when neurons take on glial-like properties, they lose their original identity and function. These altered neurons may fail to form proper connections, disrupting brain communication and contributing to memory loss.

The significant activation of plaque-induced genes (PIG) in GFAP+ neurons, together with the detection of GFAP+ cells in control samples with incidental diffuse-like plaques by the authors, indicates a close association between GFAP+ neurons and AD pathology.

Guide Research for Potential Trackers

This research paints a more detailed picture of how AD develops—from the earliest, invisible shifts in energy use and gene activity to the later stages of cell death and memory loss. By identifying neurons that begin acting like astrocytes, especially in early disease stages, scientists now have a potential new marker for tracking Alzheimer’s progression.

More importantly, this could lead to new treatment strategies—for example, by stopping neurons from losing their identity, correcting energy imbalances, or regulating genes like MEG3.

Alzheimer’s may begin much earlier than we thought, with subtle but damaging changes in how brain cells use energy and communicate. These findings give researchers new clues to catch the disease early—and maybe, one day, stop it before it steals memories and lives.

 

About BGI Genomics

BGI Genomics, headquartered in Shenzhen, China, is the world's leading integrated solutions provider of precision medicine. Our services cover more than 100 countries and regions, involving more than 2,300 medical institutions. In July 2017, as a subsidiary of BGI Group, BGI Genomics (300676.SZ) was officially listed on the Shenzhen Stock Exchange.

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