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In the Pipeline-Mild Cognitive Impairment
Neurogranin Predicts Rate of Cognitive Decline in Individuals at Risk for Alzheimer's Disease


Investigators reported that high levels of neurogranin predicted both memory and executive function declines in patients with mild cognitive impairment. Independent commentators say neurogranin could potentially serve as a biomarker and diagnostic tool for Alzheimer's disease.

High levels of neurogranin in the cerebrospinal fluid predicted the rate of cognitive decline in patients with mild cognitive impairment (MCI), according to a new study in the February 2 online issue of Neurology. But can neurogranin offer something as an Alzheimer's disease biomarker that amyloid-beta (Abeta) 42 and tau cannot? Probably yes, experts told Neurology Today, though more work will be needed to make it clinically robust enough for the job.

Total tau, phosphorylated tau, and Abeta 42, the so-called “core” biomarkers of AD, have all been linked to central pathophysiological processes in the disease. However, their levels are not tightly correlated with the rate of cognitive deterioration, said the lead investigator of the new study Xiaoyan Sun, MD, PhD, assistant professor of clinical neurology at the University of Miami Miller School of Medicine in Florida.

“We need biomarkers for studying clinical progression,” said Dr. Sun.

Discovered in the 1990s, neurogranin is a post-synaptic protein that plays a role in learning and memory. More recently, elevation of neurogranin in the cerebrospinal fluid (CSF) has been shown to be a specific feature of MCI and AD, and longitudinal studies have linked elevated neurogranin with risk for progression to Alzheimer's disease.


To test whether neurogranin would predict the rate of cognitive loss, Dr. Sun used the dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal study that, in addition to imaging data, has collected biosamples and neuropsychological assessments from hundreds of patients with MCI and Alzheimer's disease. She conducted an association study on 111 individuals with normal cognition, and 193 individuals with MCI at baseline, and then yearly for up to eight years using these data.

As has been reported in previous studies, baseline neurogranin levels differed between controls, with an average of 352 picograms per milliliter, and MCI patients, with 494 pg/mL, Dr. Sun found; higher neurogranin levels were associated with worse baseline memory scores, even after adjusting for age, sex, education, and apolipoprotein E4 (APOE4) status. But the association disappeared once the data were adjusted for tau and Abeta 42, which is likely because the underlying disease process drives changes in all three, Dr. Sun suggested.

Next, she asked how neurogranin changed over the course of the disease, and whether those changes were correlated with decline in either memory or executive function, or both. She found that an elevation in neurogranin at baseline predicted decline in both, again after accounting for age, sex, education, and APOE4, but not after accounting for Abeta 42 or tau. She also found that the higher the baseline level of neurogranin, the faster the rate of decline; MCI patients in the higher two tertiles lost memory faster than those in the lowest tertile. Those in the highest tertile also lost executive function faster than those in the lower two.

While neurogranin was predictive of cognitive decline in those who already had MCI, it was not predictive for those with baseline normal cognition. In that group, neither memory nor executive function losses were associated with higher levels of neurogranin at baseline.

It will be important to replicate these data in a community sample, Dr. Sun noted, since ADNI participants are self-selected and not necessarily representative of all MCI patients. The association of neurogranin with other aspects of cognitive function, including language ability, should be investigated if the data are available, she added.

Dr. Sun's study itself builds on previous work on longitudinal changes in neurogranin in AD. In 2016, Anne Fagan, PhD, and colleagues at Washington University and elsewhere, reported in JAMA Neurology that elevation of CSF neurogranin differentiated early Alzheimer's disease patients from controls, correlated with brain atrophy, predicted future cognitive impairment in controls, and predicted the rate of cognitive decline in AD patients. Unlike in Dr. Sun's study, however, the addition of neurogranin to tau strengthened predictive ability.


DR. ANNE FAGAN said one strength of the Sun paper is the large size of the MCI cohort it studied, and that it showed in an independent sample that neurogranin is potentially a valuable biomarker for risk of cognitive decline. Additionally, she said, the demonstration that neurogranins predictive ability disappeared when controlling for Abeta 42 and tau is potentially quite significant when considering its potential use in clinical trials.


“It is important to fully vet novel biomarkers that can cause cognitive impairment” such as neurogranin, said Dr. Fagan, research associate professor of neurology at Washington University School of Medicine in Saint Louis, MO, who was not involved in this study. “The question of added value is the big question.”

One strength of the Sun paper, Dr. Fagan said, is the large size of the MCI cohort it studied, and that it showed in an independent sample that neurogranin is potentially a valuable biomarker for risk of cognitive decline. Additionally, she said, the demonstration that neurogranin's predictive ability disappeared when controlling for Abeta 42 and tau is potentially quite significant when considering its potential use in clinical trials.

“It was very astute of the authors to test that directly. If you are using a drug that is targeting the metabolism of tau, for example, you can't use CSF tau as an outcome measure” of progression, she said. In such a trial, neurogranin might be an ideal proxy for neuronal dysfunction or cell loss. “That's where the real utility of these biomarkers is in clinical trials. That's what they may bring to the table,” she said.

While the direction of neurogranin change and the correlation with cognitive decline was similar in studies by both Drs. Sun and Fagan, the absolute value of the protein detected in the CSF differed dramatically. Using a different antibody assay, Dr. Fagan and colleagues found about five times as much of the protein in both controls and patients as did Dr. Sun. Similar between-group variations have been reported by each of the small handful of other labs currently measuring neurogranin in AD and MCI patients.

Different studies have shown similar results that CSF neurogranin levels are associated with cognitive function, Dr. Sun said, but the variation of neurogranin levels between assays seems to be significant. “We don't have standardized assays for detection, so they don't all pick up the same epitopes,” which likely accounts for a large proportion of the differences. “That's a problem for neurogranin becoming a clinically useful biomarker.”

Assuming the problem can be solved, it will still be important to better understand the timing of change in neurogranin levels, and whether they respond differently in different diagnostic or demographic subgroups. “That level of detailed analysis is going to be required before we know whether neurogranin can offer something extra” in tracking cognitive decline, Dr. Fagan said.

“Typically, up to 20 percent of randomized patients in trials have diseases other than Alzheimer's disease,” noted Robert Rissman, PhD, associate professor of neurosciences and director of the Alzheimer's Disease Cooperative Study Biomarker Core at the University of California, San Diego.

“Having an early biomarker than can potentially identify individuals who will have changes specific to Alzheimer's disease, one that is not observed to change with normal aging, would greatly help refine clinical trials recruitment and design. If neurogranin can be used to distinguish synaptic loss associated with Alzheimer's disease, this would be a large step forward for the field.”

Lucilla Parnetti, MD, PhD, professor of neurology and head of the Center for Memory Disturbances at the University of Perugia, Italy, commented that the replication of previous findings of neurogranin elevation opens the possibility of including this biomarker in the CSF panel already used for diagnosing Alzheimer's disease. “This potentially provides an added value in predicting cognitive outcome,” he said, especially since it seems to change more dynamically with disease progression than the core markers.


• Headley A, DeLeon-Beneditti A, Dong C, et al on behalf of the Alzheimer's Disease Neuroimaging Initiative. Neurogranin as a predictor of memory and executive function in MCI patients Neurology 2018; Epub 2018 Feb 2.
    • Tarawneh R, D'Angelo G, Crimmins D, et al. Diagnostic and prognostic utility of the synaptic marker neurogranin in Alzheimer disease JAMA Neurol 2016;73(5):561–571.