Cerebrospinal fluid markers help clinicians identify who has the pathology of amyloid and tangles in Alzheimer's disease. However, no CSF ​​markers were found to be successfully tracked in cognitive decline. A new candidate might help. On March 31, a scientist led by Tony Whis Corey at Stanford University, California, reported that on March 31, the ratio of two synaptic proteins, YWHAG and NPTX2, increases with age, and that Alzheimer's disease promotes this change. The authors view protein ratio as a promising indicator of cognitive impairment.

  • Proteomics identifies synaptic proteins in cerebrospinal fluid. The ratio of those two increases with age.
  • Alzheimer's disease can accelerate this increase.
  • This ratio identifies those who are most vulnerable to cognitive decline.

“There's a measuring tool here. [synaptic dysfunction] Wyss-Coray said: August 2024 News).

Currently, first author Hamilton Ohio and colleagues at Icahn School of Medicine in Mount Sinai, New York, identified these potential markers from 3,397 participants in six case-control cohorts during a proteomic analysis of CSF. Initial analysis of 7,289 proteins from the University of Washington's Night Alzheimer's Disease Research Center and 716 samples in ADNI studies, OH was upregulated and 721 downregulated proteins were discovered. CDR correlations were not dependent on CSF P-TAU181/Aβ42, suggesting that these markers simply do not reflect amyloid and/or TAU pathology.

Most upregulated proteins, including YWHAG.1, also known as 14-3-3γ, are involved in synaptic function, similar to neuronal pentraxin2, the most downregulated protein. Scientists have previously linked NPTX2 to cognitive decline (see Xiao et al. , 2017; September 2023 News; September 2024 News).

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Up and down. Higher levels of YWHAG, particularly YWHAG.1 and NPTX2, are associated with greater cognitive impairment independent of P-TAU181/Aβ42. [Courtesy of Oh et al., Nature Medicine, 2025.]

Of all these proteins, the YWHAG:NPTX2 ratio was optimally mapped for cognitive impairment. This relationship persisted when the authors extended their analysis to a cohort of sporadic advertising people being studied at Stanford and to the dominantly inherited Alzheimer's disease network, an autosomal dominant AD cohort. OH and colleagues discovered that there was PTAU181:Aβ42 The ratio only explained 10% of cognitive decline among people with AD. YWHAG:NPTX2 ratio could account for 36% of the decline.

We are interested in how YWHAG and NPTX2 are associated with Tau Tangle loading better reflect cognitive decline and memory loss than brain amyloid plaque loading or phosphorylated Tau levels in CSF. The researchers have been changed to Biofinder-2. Tau pet scans and CSF were simultaneously photographed in this Swedish cohort. Biofinder-2 did not measure CSF YWHAG levels, so the authors were dependent on the relevant protein YWHAZ. They found that the CSF YWHAZ:NPTX2 ratio was higher than the control for all individuals with moderate tangle loads. Needless to say, some people with high proportions who have been tested negative for PET tangles suggest that the levels of two synaptic proteins change early in the disease.

To see how these two synaptic markers change over time, OH and colleagues looked at CSF YWHAG:NPTX2 in both normal aging and AD. Cross-sectional analysis of cognitively normal individuals showed that the proportion increased with age approximately 30 years before the increase in P-TAU181/Aβ42. YWHAG: Cognitively normal Diane participants who carried an advertising mutation in families where NPTX2 ran higher than age-matched healthy non-carriers. This was true even before the carrier showed signs of amyloid or tangle buildup. Young mutation carriers had a higher age ratio when they began to show symptoms (image below). Among people with sporadic AD, there were also higher proportions of those carrying the APOE4 allele. Paul Wally of Johns Hopkins University in Baltimore thought the scope of prediction was important. “I think that's true [the YWHAG;NPTX2 ratio] Predicting cognitive decline over the years in all the different groups they saw, including APOE4 and people in family ads, means that anything that releases these proteins into CSF ​​is part of a pathological process,” he told Alzforum.

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A marker of decline. CSF YWHAG:NPTX2 ratio drifts upwards with age. [Courtesy of Oh et al., Nature Medicine, 2025.]

The authors found that CSF YWHAG:NPTX2 is a more powerful predictor of cognitive decline than traditional AD indicators, among all cohorts with longitudinal cognitive data. People with Aβ and tau pathology were four times more vulnerable to cognitive impairment, whereas those with a higher YWHAG:NPTX2 ratio were 15 times more likely.

The authors proposed a staging system for predicting the likelihood of cognitive decline over 15 years, hoping to allow for more subtle predictions of future cognitive impairments. They established a YWHAG: no NPTX2 cutoff indicating stage 0, or no cognitive decline. Stage 1 or mild cognitive impairment. Stage 2 or mild dementia, and Stage 3 or moderate to severe dementia. They considered it to be stage-1, a cognitively normal person with the lowest proportion. The authors then tested how this staging system was supported at Knight ADRC and Andi Cohorts, including baseline and follow-up cognitive screening. 397 amyloid and P-TAU181 positive (A+T)1+) Individuals who were cognitively normal at baseline and stage 1 were 2.7 times more likely to be worsened on follow-up cognitive tests than those at stage 0. Stage 2 individuals had a 4.9-fold risk of disability. Out of 186 a+t1+People with mild cognitive impairment at baseline were 73% less likely to have cognitive decline than those in stage 1, and those in stage 2 were 2.3 times worse (image below). YWHAG: The higher the NPTX2 stage, the more likely a person will decline regardless of their amyloid and tau readings (image below).

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Predictions of decline. Among people who are A+ T1+ at baseline, the higher the YWHAG:NPTX2 stage, the less likely they will remain cognitively intact. This is true whether you have an MCI (left) or a cognitive impairment (right). [Courtesy of Oh et al., Nature Medicine, 2025.]

“The YWHAG:NPTX2 ratio works remarkably well as a predictor of cognitive impairment progression, even in presymptomatic AD,” writes Morgan Shen of the Broad Institute in Cambridge, Massachusetts.

Doug Gallaghco, San Diego, of the University of California, was impressed by the thorough analysis. He believes that the relationship between YWHAG:NPTX2 and cognitive can be seduced in more detail because the author relies on CDR. Galasko says it is a rough measure of cognitive function.

What explains the correlation between these synaptic proteins and cognition? The authors compared the YWHAG:NPTX2 ratio with the levels of three known CSF markers of neuroproliferation: neurofilament light, neurologlanin, and growth-associated protein 43 (GAP-43). This ratio explained 28% more variation in cognitive impairment in Alzheimer's disease than the combination of the three markers. Surprisingly, all three neurodegenerative markers associated with AD were negatively correlated with GAP-43 and neurologlanin with the YWHAG:NPTX2 ratio, whereas NFL was positively correlated with it. The authors concluded that two synaptic proteins address distinct pathology, presumably synaptic loss and tau toxicity. YWHAG is involved in the development of neurofibrillar entanglements (see Otero-Garcia et al. , 2022). On his part, Nick Safried of Emory University in Atlanta, Georgia, considers a negative correlation with GAP-43 to be promising. “We are trying to explain the variance of cognitive decline beyond the core ATN. [amyloid, tau, and neurodegeneration] The framework, because we don't want to completely rely on amyloid, tau, neurofilament,” he said. [a person’s] The gradient of decline, you need some other markers beyond amyloid and tau. ”

Wyss-Coray says comparable plasma biomarkers are more practical for diagnostic purposes, and his lab has already begun searching. Alas, plasma YWHAG1:NPTX2 does not correlate with cognition, but another plasma signature was performed. At Knight-Adrc, Stanford, Religious Order Research/Memory Aging Project, the global neurodegenerative proteome consortium, and community cohorts, participants at atherosclerosis risk were likely to score seven times higher on CDR. The signature contained hundreds of proteins, but I think, oh, I might be able to narrow it down to make the assay more practical. — Lauren Schneider

Lauren Schneider is a freelance writer in New York City.

News Quotes

  1. Nulisa – A new proteomic method to improve biomarker analysis
  2. CSF Proteome Panels Predict Decline Better than Classic Advertising Biomarkers
  3. CSF proteins find mutation carriers in Alzheimer's disease decades before symptoms

Paper quote

  1. Xiao MF, Xu D, Craig MT, Pelkey ​​KA, Chien CC, Shi Y, Zhang J, Resnick S, Pletnikova O, Salmon D, Brewer J, Edland S, Wegiel J, Tycko B, Savonenko A, Reeves RH, Troncoso JC.
    NPTX2 and cognitive impairment in Alzheimer's disease.
    Elif. March 23, 2017; 6
    PubMed.
  2. Otero-Garcia M, Mahajani SU, Wakhlooo D, Tang W, Tang WQ, Pan J, Oberhauserer J, Madrai AE, Shakouri T, Deg Y, He Z, Lowry WE, Swarup V, Swarup V, Coobs II.
    Molecular signatures underlying neurofibrillary entanglements in Alzheimer's disease.
    Neurons. 2022 Sep 21; 110 (18): 2929-2948.e8. EPUB 2022 July 25th
    PubMed.