Protein could predict cognitive decline 7 years before Alzheimer's symptoms

• New research investigated the potential of NPTX2, a protein found in the fluid surrounding the brain, to predict the onset of memory and thinking problems.
• Scientists studied individuals who were initially in good mental health, but later some of them developed mild cognitive impairment (MCI) or dementia.
• The study revealed that lower levels of NPTX2 were associated with an earlier onset of MCI symptoms.
• The findings also showed that NPTX2 levels seem to change over time alongside other markers related to Alzheimer’s disease.

A new study and its findings may hold promise for early detection of Alzheimer’s disease and understanding cognitive decline.

To understand the brain changes associated with mild cognitive impairment and dementia, the researchers measured the levels of a protein called NPTX2 in cerebrospinal fluid (CSF), or in other words, the fluid that surrounds the brain.

The researchers saw that lower levels of NPTX2 was linked to an earlier onset cognitive decline. NPTX2 levels also changed over time alongside other markers related to Alzheimer’s disease.

The study was published in the Annals of Neurology.

Measuring Alzheimer’s markers in cerebrospinal fluid

The study team collected fluid from the brain (CSF) from 269 people who were initially in good mental health and part of the BIOCARD Study.

The average age of these participants at the beginning of the study was about 57.7 years, and they were followed for an average of 16.3 years.

Out of these individuals, 77 eventually developed mild cognitive impairment (MCI) or dementia.

During the study, the researchers examined three related parts (peptides) of the NPTX2 protein using a technique called quantitative parallel reaction monitoring mass spectrometry.

They also measured the levels of three other markers commonly associated with Alzheimer’s disease: Aβ42/Aβ40, p-tau181, and t-tau.

These measurements were taken from the same CSF samples using a Lumipulse automated electrochemiluminescence assay.

By analyzing these data, the researchers aimed to better understand the changes in these markers over time and their potential connection to the development of MCI and dementia in the studied participants.

Linking NPTX2 levels over time to cognitive problems

They found that individuals with lower levels of the NPTX2 protein in their brain fluid (CSF) tended to experience cognitive problems and memory decline (MCI) earlier than those with higher levels of NPTX2.

This association was significant both for people who progressed to MCI within seven years from the start of the study and for those who developed it after seven years.

The researchers also discovered that the baseline levels of NPTX2 helped predict when the symptoms of MCI would appear, even when taking into account other well-known Alzheimer’s disease markers found in the CSF.

This suggests that the levels of these markers might be related to changes in NPTX2 and could play a role in the development of cognitive problems.

First author Anja Soldan, Ph.D., associate professor of neurology at Johns Hopkins University, explained the key findings to Medical News Today, saying, “our study shows that low levels of the protein ‘neuropentraxin 2’ (or NPTX2) measured in the cerebrospinal fluid among cognitively healthy middle-aged and older adults may predict later onset of mild cognitive impairment (MCI).”

“[NPTX2] has previously been linked to learning and memory in mice. Our research adds evidence that low levels of this protein in humans may be an early predictor of MCI years before symptoms appear. Of note, our findings show that low levels of the protein improve the prediction of cognitive impairment even after accounting for levels of traditional biomarkers of Alzheimer’s disease (i.e., those related to amyloid plaques and tau tangles) and well-established genetic risk factors for late-onset Alzheimer’s disease.”
— Dr. Anja Soldan

Dr. Soldan explained that the NPTX2 protein was “predictive of subsequent symptoms of MCI both within and beyond seven years before symptoms occurred.”

Limitations

The study does have a number of limitations.

“[N]amely that participants were primarily white, well-educated, and have a strong family history of dementia. It is unclear, therefore, whether the findings generalize to other populations,” said Dr. Soldan.

Santosh Kesari, Ph.D., neurologist at Providence Saint John’s Health Center in Santa Monica, California, and regional medical director for the Research Clinical Institute of Providence Southern California, who was not involved in the study, told MNT that “identifying blood or CSF biomarkers that predict developing dementia are critical in order to intervene earlier by preventative approaches or treat at the earliest onset of cognitive issues or even before when patients are cognitively normal.”

“[The researchers] found that lower levels of NPTX2 predicts risk of mild cognitive impairment (early sign of dementia) independent of known prognostic markers p-tau and APO-E4. NPTX2 is a protein found in synapses of neurons and is important for neural activity and, thus, a marker that correlates with synapse health, a lower level indicates less healthy brain function.”
— Dr. Santosh Kesari

Could this mean new drugs for Alzheimer’s?

Dr. Soldan highlighted that “at present, there is only one FDA-approved drug on the market known to even modestly slow symptoms of Alzheimer’s disease in its early stages, and there are no cures or ways to prevent the disease.”

“Our research shows that lower levels of NPTX2 occur many years prior to the onset of MCI or dementia due to Alzheimer’s disease, which raises the possibility of developing therapeutics that target NPTX2.”

“Additionally, since this protein does not appear to be a specific marker for Alzheimer’s disease, our findings may be relevant to other neurodegenerative diseases,” Dr. Soldan explained.

However, we are not yet able to measure brain levels of NPTX2 routinely in the clinic, though there is important work underway to develop sensitive ways of measuring it in blood instead of in cerebrospinal fluid. We also know very little about what factors influence levels of NPTX2 in the brain, but this is another important area of research.
— Dr. Anja Soldan

Dr. Kesari agreed, saying, “NPTX2 may turn out to be a good target of drug development to prevent cognitive decline and will need to be further tested and validated in future studies.”

NPTX2 will be further investigated in future studies. Ultimately, more research is needed.

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