Protein found in spinal fluid may help predict mild cognitive impairment before symptoms appear

A protein that supports brain cell communication may help predict the onset of mild cognitive impairment, according to an NIA-funded study. Findings were published in Annals of Neurology.

Illustration of hand below floating brain.

Mild cognitive impairment (MCI) is a condition in which older adults experience memory or thinking problems that are greater than normal for their age, but these symptoms are not severe enough to interfere with normal daily activities. For people with Alzheimer’s disease, MCI is an early stage of the disease before cognitive decline becomes more pronounced. In these individuals, MCI is the result of toxic changes in the brain caused by Alzheimer’s. These changes may begin a decade or more before symptoms such as memory problems appear.

Currently, scientists are studying biomarkers — biological signs of disease found in brain images, cerebrospinal fluid, and blood — to detect this damage earlier on. So far, most biomarker tests for Alzheimer’s have been designed to measure levels of beta-amyloid and tau proteins, two pathological hallmarks of the disease.

A team of researchers led by Johns Hopkins University are exploring whether neuronal pentraxin 2 (NPTX2), a protein that supports synaptic communication points between nerve cells in the brain, could also help spot early signs of MCI. For years, scientists have known that loss of synapses strongly correlates with cognitive impairment caused by Alzheimer’s. More recently, they have found that NPTX2 levels also decline with cognitive impairment and the disease.

In this new study, the scientists investigated whether early changes in NPTX2 levels could be used to predict the onset of MCI in middle-aged people who had no signs of cognitive impairment. To explore this, they researched participants in the Johns Hopkins’ Biomarkers for Older Controls at Risk for Dementia (BIOCARD) study. The participants, who did not have dementia when they entered the study, went through annual clinical and cognitive assessments for an average of 16 years. These data were then compared to NPTX2 levels found in the participants’ cerebrospinal fluid, a liquid that flows through the nervous system.

Further analysis suggested that the ability of NPTX2 to predict mild cognitive impairment works independently of beta-amyloid or tau levels and may enhance predictions when combined with those hallmarks. Overall, the results indicate that more studies are needed to understand the role of NPTX2 in the neurobiology of dementia, including Alzheimer’s. Future studies should test NPTX2’s role in larger, more diverse study groups.

This research was supported by NIA grants U19-AG033655 and P30-AG005146.

These activities relate to NIH’s Alzheimer’s and Related Dementias Research Implementation Milestones:

1.F, “Population Studies: Inclusion of non-AD cohorts.”
9.B, “Biomarkers: Next generation CNS and biofluid markers.”
9.H, “Biomarkers: Early detection measures.”

Reference: Soldan A, et al. NPTX2 in cerebrospinal fluid predicts the progression from normal cognition to mild cognitive impairment. Annals of Neurology. 2023; 94(4):620-631. doi: 10.1002/ana.26725.