‘Emerging’ Biomarker May Predict MCI Years Before Symptoms

Measuring levels of the synaptic protein NPTX2 in cerebrospinal fluid (CSF) may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear, new research indicates.

“Our study shows that low NPTX2 levels are predictive of MCI symptom onset more than 7 years in advance, including among individuals who are in late middle age,” study investigator Anja Soldan, PhD, associate professor of neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

NPTX2 is still considered an “emerging biomarker” because knowledge about this protein is limited, Soldan noted.

Prior studies have shown that levels of NPTX2 are lower in people with MCI and dementia than those with normal cognition, and that low levels of this protein in people with MCI are associated with an increased risk of developing dementia.

“Our study extends these prior findings by showing that low protein levels are also associated with the onset of MCI symptoms,” Soldan said.

The study was published online June 22 in Annals of Neurology.

New Therapeutic Target?

The researchers measured NPTX2, as well as amyloid beta 42/40, phosphorylated (p)-tau181, and total (t)-tau in CSF collected longitudinally from 269 cognitively normal adults from the BIOCARD study.

The average age at baseline was 57.7 years. Nearly all were white, 59% were women, most were college educated, and three quarters had a close relative with Alzheimer’s disease (AD).

During a mean follow-up average of 16 years, 77 participants progressed to MCI or dementia within or after 7 years of baseline measurements.

In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR], 0.76; P = .023). This association was significant for progression within 7 years (P = .036) and after 7 years from baseline (P = .001), the investigators report.

Adults who progressed to MCI had, on average, about 15% lower levels of NPTX2 at baseline compared with adults who remained cognitively normal.

Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (P < .01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status.

Higher baseline levels of p-tau181 and t-tau were associated with higher baseline NPTX2 levels (both P < .001) and with greater declines in NPTX2 over time, suggesting that NPTX2 may decline in response to tau pathology, the investigators suggest.

Soldan said NPTX2 may be “a novel target” for developing new therapeutics for AD and other dementing and neurodegenerative disorders, as it is not an AD specific protein.

“Efforts are underway for developing a sensitive way to measure NPTX2 brain levels in blood, which could then help clinicians identify individuals at greatest risk for cognitive decline,” she explained.

“Other next steps are to examine how changes in NPTX2 over time relate to changes in brain structure and function and to identify factors that alter levels of NPTX2, including genetic factors and potentially modifiable lifestyle factors,” Soldan said.

“If having higher levels of NPTX2 in the brain provides some resilience against developing symptoms of Alzheimer’s disease, it would be great if we could somehow increase levels of the protein,” she noted.

Caveats, Cautionary Notes

Commenting on this research for Medscape Medical News, Christopher Weber, PhD, Alzheimer’s Association director of global science initiatives, said, “Research has shown that when NPTX2 levels are low, it may lead to weaker connections between neurons and could potentially affect cognitive functions, including memory and learning.

“This new study found an association between lower levels of NPTX2 in CSF and earlier time to MCI symptom onset, and when combined with other established Alzheimer’s biomarkers, they found that NPTX2 improved the prediction of Alzheimer’s symptom onset,” Weber said.

“This is in line with previous research that suggests NPTX2 levels are associated with an increased risk of progression from MCI to Alzheimer’s dementia,” Weber said.

However, he noted some limitations of the study. “Participants were primarily White, highly educated, and therefore findings may not be generalizable to a real-world population,” he cautioned.

Weber said it’s also important to note that NPTX2 is not considered an Alzheimer’s-specific biomarker, but rather a marker of synaptic activity and neurodegeneration. “The exact role of NPTX2 in predicting dementia is unknown,” Weber told Medscape Medical News.

He said more studies with larger, more diverse cohorts are needed to fully understand its significance as a biomarker or therapeutic target for neurodegenerative diseases, as well as to develop a blood test for NPTX2.  

The study was supported by the National Institutes of Health. Soldan and Weber report no relevant financial relationships.

Ann Neurol. Published online June 22, 2023. Abstract.

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