Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease
Open accessAbstract
Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.
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CSF NRGN has been linked to AD progression.
“which is important because CSF NRGN has been linked to AD progression. 45”
From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [45]
Elevated CSF concentrations of total tau and tau phosphorylated at amino acids 181 and 217 are surprisingly AD-specific; tau-associated FTD subtypes do not have elevated CSF t-tau and p-tau concentrations, at least not to the levels present in AD.
“It has been shown that elevated CSF concentrations of total tau (t‐tau) and tau phosphorylated at amino acids 181 and, more recently, 217 (p‐tau181 and p‐tau217, respectively) are surprisingly AD‐specific; tau‐associated FTD subtypes do not have elevated CSF t‐tau and p‐tau concentrations, 57 , 58 , 59 , 60 at least not to the levels present in AD.”
From New developments of biofluid‐based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia (2022) · cites this paper as [58]
Several studies revealed elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.
“Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.547,548”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [547]
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- Authors
- Portelius, E., Zetterberg, H., Skillbäck, T., Törnqvist, U., Andreasson, U., Trojanowski, J. Q., Weiner, M. W., Shaw, L. M., & Mattsson, N.
- Affiliations
- University of Gothenburg (SE)
- UCL Queen Square Institute of Neurology (GB)
- University of Pennsylvania (US)
- San Francisco VA Medical Center (US)
- Lund University (SE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-09-15
- Volume
- 138
- Issue
- 11
- Pages
- 3373-3385
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4643642
- OpenAlex
- W2140431554
- Cited by
- 279
- References
- 37
- Citations by year
- 2026: 11 · 2025: 25 · 2024: 27 · 2023: 13 · 2022: 29 · 2021: 36 · 2020: 37 · 2019: 24 · 2018: 29 · 2017: 22 · 2016: 24 · 2015: 2
- FWCI
- 20.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, P30AG010129, K01AG030514, P30AG010124)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- neurogranin, cerebrospinal fluid biomarkers, Alzheimer's disease, mild cognitive impairment, cognitive decline, synaptic dysfunction, postsynaptic proteins, neurodegeneration, hippocampal volume, cortical glucose metabolism, brain atrophy, disease progression prediction, pre-dementia, ADNI cohort, immunoassay validation, Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, hippocampal atrophy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebral Cortex, Cognition, Female, Hippocampus, Humans, Longitudinal Studies, Male, Middle Aged, Neuropsychological Tests, Organ Size, Prognosis, Disease Progression, Positron-Emission Tomography, Neurogranin, Cognitive Dysfunction
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