New biological marker of early-stage Alzheimer's disease uncovered - medicalxpress

Brain regions showing differences of PCx connectivity between MCI and HC. Credit: Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03550-2.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and a decline in mental functions. These symptoms are known to arise from an abnormal buildup of proteins known as amyloid and tau, which can damage or gradually destroy neurons and the connections between them.

Interestingly, past studies have uncovered a link between AD and a reduced or altered sense of smell. In fact, an impaired ability to smell is often one of the early signs of AD and could thus help to diagnose the disorder early.

Researchers at Shenzhen MSU-BIT University, Children's Hospital of Chongqing Medical University and other institutes recently set out to further explore the link between AD and olfactory dysfunction. Their findings, published in Molecular Psychiatry, pinpoint specific brain circuits involved in scent processing and memory that appeared to be altered before the first serious symptoms of the disorder appear. In particular, they uncovered changes in the connections between the piriform cortex (PCx), a brain region that supports the processing of smells, and the infralimbic (IL) cortex, which is involved in memory and decision-making.

"The mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood," wrote Yan Yan, Da Song and their colleagues. "We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits."

A working model for PCx-IL engram cell circuits dynamic transmission impairment associated with olfactory memory deficits in early stage of AD. Credit: Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03550-2

Exploring the underpinnings of olfactory dysfunction in AD

Yan Song and their colleagues studied brain scans that were collected from people with AD using a noninvasive imaging technique known as functional magnetic resonance imaging (fMRI). This technique measures activity in different parts of the brain by detecting variations in the levels of oxygen in the blood, as well as blood flow.

"Clinical fMRI data revealed that connectivity between the PCx and the IL was impaired during the early mild cognitive impairment (MCI) stage of AD," wrote Yan, Song and their colleagues.

The researchers later set out to explore the mechanisms underpinning olfactory dysfunction in the early stages of AD in more depth. To do this, they examined the brains of genetically engineered mice that exhibit AD-like characteristics, also known as 5xFAD mice, using optogenetic and single-cell RNA sequencing techniques. Optogenetic tools allow scientists to activate specific neurons using light, while single-cell RNA- sequencing can be used to track the activity of genes in individual brain cells.

"Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice," wrote the authors. "In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations."

The researchers also looked at whether glutamate signaling and the function of synapses were altered in the 5xFAD mouse model of AD. Notably, they found that the function of a specific glutamate receptor, called the AMPA receptor, was impaired, which appeared to weaken the transmission of information via synapses.

"Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice," wrote Yan, Song and their colleagues. "These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD."

Informing the early diagnosis and treatment of AD

The recent work by Yan, Song and their colleagues pinpoints specific brain circuits that appear to be altered in AD and in a mouse model of the disorder before obvious symptoms start emerging. In particular, it shows that the connections between the PCx and the IL, which are involved in the processing of smells and memory, respectively, appear to weaken before humans with AD or 5xFAD mice start experiencing significant memory loss or cognitive decline.

In the future, this study could open new possibilities for the early diagnosis of AD, while also potentially informing the development of new treatments. Further research could try to shed further light on the differences in brain connectivity and molecular alterations that can be observed in the brain of patients with AD in the initial stages of the disease. 

by Ingrid Fadelli, Medical Xpress

edited by Gaby Clark, reviewed by Robert Egan

Source: New biological marker of early-stage Alzheimer's disease uncovered