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

Yulan Fan,Hua Zhang,Jing Luo,Maowen Ba,Joseph Therriault,Ying Gao

doi:10.3389/fnagi.2021.667899

Abstract

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 ε4 (APOE ε4) 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 APOEε4. We stratified 250 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) ε4 negative (CN ε4−), CN ε4 positive (CN ε4+), MCI ε4 negative (MCI ε4−), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4−), and AD ε4 positive (AD ε4+). CSF Ng levels were significantly increased in APOE ε4 carriers compared to APOE ε4 non-carriers with MCI. In addition, CSF Ng identified MCI ε4+ versus CN ε4−, but not MCI ε4− versus CN ε4−. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI ε4+ 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 ε4.

Highlights

Alzheimer’s disease (AD) is a leading cause of dementia
There was no similar finding between cognitively normal (CN) ε4− and CN ε4+, or between AD ε4− and AD ε4+
Mini-Mental State Examination (MMSE) scores were lower in mild cognitive impairment (MCI) ε4−, MCI ε4+, AD ε4−, and AD ε4+ groups compared with CN ε4− and CN ε4+ subjects, and lower in AD ε4− and AD ε4+ groups compared with MCI ε4− and MCI ε4+

Summary

Introduction

Alzheimer’s disease (AD) is a leading cause of dementia. Extracellular depositions of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau are the major pathological characteristics of AD (Jack et al, 2018). Compared with Aβ deposits and neurofibrillary tangles, synapse loss in the hippocampus is more closely related to the degree of cognitive impairment (Scheff et al, 2006, 2007). In mild cognitive impairment (MCI) patients, high CSF Ng concentrations at baseline can predict cognitive decline during clinical follow-up (Portelius et al, 2015). High CSF Ng levels at baseline are associated with longitudinal reductions in hippocampal volume and cortical glucose metabolism during clinical follow-up in MCI (Portelius et al, 2015). In MCI patients who progress to dementia, increased CSF Ng concentrations are related to accelerated deterioration of Alzheimer’s disease assessment scale (ADAS) (Portelius et al, 2015). Another study has demonstrated CSF Ng is correlated with brain atrophy (Tarawneh et al, 2016)

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