Spinal fluid protein predicts mild cognitive impairment and early dementia

New targets for treating and preventing Alzheimer's and dementias.


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A relatively low level of the protein NPTX2 is not only likely to be a standalone risk factor for MCI and Alzheimer’s dementia, but it also improves the prediction of cognitive impairment after considering levels of conventional biomarkers and well-known genetic risk factors for Alzheimer’s.

The study may offer new targets for treating or preventing Alzheimer’s and other dementias. Researchers from Johns Hopkins Medicine found that measures of NPTX2 in CSF fluid were predictive of MCI onset within or even beyond seven years before the onset of symptoms in over 250 mostly middle-aged persons.

Researchers found that low spinal fluid levels of a protein associated with learning and memory may serve as an early indicator of moderate cognitive impairment (MCI) in mice years before symptoms appear.

MCI, characterized by minor memory loss or difficulties with other cognitive processes, affects up to 18% of persons over 60. People with MCI can perform most typical everyday tasks. However, they are at a higher risk of developing Alzheimer’s disease or other forms of dementia. Alzheimer’s dementia is anticipated to affect 6.7 million Americans aged 65 and older, which is expected to double by 2050. 

The rising prevalence of dementias has increased the necessity of finding better and early predictors and targets for treatments that can prevent or delay development. There is currently only one FDA-approved medicine on the market that has been shown to even slightly reduce the symptoms of Alzheimer’s in its early stages, and there are no treatments or preventives.

Anja Soldan, Ph.D., associate professor of neurology at the Johns Hopkins University School of Medicine and corresponding author of the study, said, “Our research shows declining levels of NPTX2 occur many years before the emergence of MCI or Alzheimer’s symptoms, which raises the possibility of developing new therapeutics that target NPTX2. Additionally, it appears that this protein is not a specific marker to just Alzheimer’s, and these findings may be relevant to other neurodegenerative diseases. So if we can find ways of increasing levels of NPTX2, then it could be applied to identify early and possibly treat other types of memory loss or cognitive impairment.”

The National Institutes of Health and Johns Hopkins Medicine recruited participants for the study. Baseline medical and cognitive evaluations were performed on 269 cognitively normal adults, and spinal fluid samples were collected biannually. At baseline, the average age of participants was 57.7 years, with 59% being white, 59% female, the majority being college educated, and 75% having a close relative with Alzheimer’s.

Seventy-seven subjects progressed from baseline to MCI or dementia within or after seven years. 88% of participants were diagnosed with Alzheimer’s as a primary or secondary cause of dementia. Those who progressed to MCI had, on average, about 15% lower levels of NPTX2 at baseline compared to those who remained unimpaired, a difference that remained significant after accounting for baseline Alzheimer’s biomarker levels.

Soldan said, “Currently, we only have drugs that modify mild symptoms of Alzheimer’s disease and nothing right now to give people who are cognitively normal but at higher risk. But when and if that changes, accurately predicting such risk will play a large role in targeting treatments.”

He also cautioned that “we’re a long way out” from a simple way to test spinal fluid samples for NPTX2 levels routinely, and further research is needed to determine what factors alter the protein’s levels. Potential root causes could be genetics, lifestyle factors, or a combination. He also underscored the new study’s limitations, including the racial and educational makeup of the study population.

The result shows that In Cox regression models,Lower NPTX2 levels linked to earlier MCI symptom onset.

The National Institutes of Health funded the study.

Journal Reference:

  1. Anja Soldan, Sungtaek Oh, et al. NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment. Annals of Neurology.DOI: 10.1002/ana.26725


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