New Insights into Early Biomarkers and Cellular Changes in Alzheimer's Disease Progression

A recent study conducted by researchers at BGI Genomics' Institute of Intelligent Medical Research (IIMR) has advanced our understanding of Alzheimer's Disease (AD) by identifying early indicators of brain damage and cellular transformations that occur throughout disease progression. Published in the journal Protein & Cell in early June 2025, the research highlights crucial biological markers and neuronal alterations that could pave the way for earlier diagnosis and innovative treatment strategies.

The study involved analyzing over 1,663 single-cell transcriptomes across early, middle, and late stages of AD, focusing on the entorhinal cortex and hippocampus—regions critical for memory and known to be affected early in AD. Utilizing high-precision Smart-seq2 sequencing technology enabled detection of subtle changes in gene expression and cell activity well before significant brain damage becomes evident.

One noteworthy discovery was that mitochondrial dysfunction occurs early in vulnerable brain areas, even preceding amyloid plaque formation, a hallmark of AD. Interestingly, mitochondria seem to temporarily re-activate later in disease stages, possibly as a compensatory response which may be too late to prevent neuron loss.

The gene MEG3, involved in mitochondrial regulation and energy utilization, was found to be overexpressed during initial disease stages, especially in stellate neurons of the entorhinal cortex. Elevated MEG3 levels may contribute to neuronal death by inhibiting mitochondrial synthesis and energy production, making it a potential early biomarker for AD.

An unexpected and significant finding was the emergence of neurons producing GFAP, a protein typically specific to astrocytes. These GFAP-expressing neurons, first identified in the hippocampal CA3 region, progressively spread throughout the brain's memory circuits and exhibit loss of their original neuronal identity—supporting a novel "glial barrier hypothesis". The activation of typical plaque-induced genes in these altered neurons underscores their association with AD pathology.

This comprehensive cellular mapping sheds light on the initial, invisible biochemical shifts—such as energy imbalance and gene activity changes—that lead to degrading neuronal function and memory loss. Identifying these early changes offers promising avenues for developing diagnostic markers and interventions aimed at preserving brain function before irreversible damage occurs.

Ultimately, this research underscores that AD may commence much earlier than previously suspected, driven by subtle cellular and molecular deviations. Recognizing these early signs could assist in early detection and open new pathways to prevent or slow disease progression—bringing hope for future treatments targeting the earliest disease mechanisms.