The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer's Disease

Cerebrospinal fluid (CSF) measurements of neurogranin (Ng) have emerged as a promising biomarker for cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The apolipoprotein E epsilon 4 (APOE epsilon 4) allele is by far the most consistent genetic risk factor for AD. However, it is not known whether the pathophysiological roles of Ng in MCI or AD are related to APOE epsilon 4. We stratified 250 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) epsilon 4 negative (CN epsilon 4-), CN epsilon 4 positive (CN epsilon 4+), MCI epsilon 4 negative (MCI epsilon 4-), MCI epsilon 4 positive (MCI epsilon 4+), AD epsilon 4 negative (AD epsilon 4-), and AD epsilon 4 positive (AD epsilon 4+). CSF Ng levels were significantly increased in APOE epsilon 4 carriers compared to APOE epsilon 4 non-carriers with MCI. In addition, CSF Ng identified MCI epsilon 4+ versus CN epsilon 4-, but not MCI epsilon 4- versus CN epsilon 4-. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI epsilon 4+ group. Our findings support the use of CSF Ng as a biomarker of synaptic pathology for AD. We propose that the roles of CSF Ng in the pathophysiology of MCI may be related to APOE epsilon 4.