The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease

J Alzheimers Dis. 2016 Jul 6;53(4):1523-38. doi: 10.3233/JAD-160227.


Background: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers.

Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios.

Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychological (MMSE) examinations for at least one year.

Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio.

Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.

Keywords: Alzheimer’s disease; BACE1 protein; ELISA; biomarkers; cerebrospinal fluid; mild cognitive impairment; neurogranin; prognostic; ratio.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / complications*
  • Amyloid Precursor Protein Secretases / cerebrospinal fluid*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Area Under Curve
  • Aspartic Acid Endopeptidases / cerebrospinal fluid*
  • Cognitive Dysfunction / cerebrospinal fluid*
  • Cognitive Dysfunction / etiology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Male
  • Mental Status Schedule
  • Neurogranin / cerebrospinal fluid*
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • tau Proteins
  • Neurogranin
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human