Front.Aging Neurosci: Effects of cerebrospinal fluid neurogranulin and APOE4 on mild cognitive impairment and pathology of Alzheimer's disease

Neurogranulin (Ng) in cerebrospinal fluid (CSF) has become an important biomarker for cognitive decline in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD
).

Zhang Hua's team at Chongqing Medical University verified the comparison of positive versus negative APOE4 increased by CSF Ng under normal circumstances, and also reported the relationship between
Ng in CSF relying on APOE4 to reflect neurodegenerative lesions.

Extracellular deposition of amyloid (Aβ) and the formation of neurofibrillary tangles within the cell of the superphosphorylated Tau protein are the main pathological features of AD, but the etiology and pathogenesis are unknown, and there have been many genome-wide studies that have shown that the APOE4 allele is associated with AD and is the most consistent genetic risk factor
to date.

Compared to non-carriers, APOE4 carriers tend to exhibit accelerated declines in
cognitive abilities.

In addition, in clinical trials of modified treatments for AD disease, synapsin biomarkers can potentially monitor disease progression and assess the effect of drugs on
synaptic dysfunction and degeneration.

In patients with mild cognitive impairment (MCI), high concentrations of Ng predict cognitive decline
during clinical follow-up.

In this study, the authors divided 250 participants into cognitive normal (CN) APOE4 negative (CNε4−)/APOE4 positive (CNε4+), MCI APOE4 negative (MCIε4−)/MCI ε4 positive (MCIε4+), AD APOE4 negative (ADε4−)/APOE4 positive (ADε4+), subject characteristics are shown in Table 1
.

Table 1 Participant characteristics statistics

1.

Compared with CNε4−, the Ng level of CSF in the MCIε4+, ADε4−, and ADε4+ groups was significantly increased
.

Figure 1 CSF-Ng levels by group

2.

Using the participant operation curve (ROC) analysis to detect CSF biomarkers associated with clinical diagnosis, CSF Ng, T-tau, and P-tau had higher diagnostic accuracy for MCI and similar
accuracy in the AD group.

Figure 2 ROC analysis test results

3.

Of the subjects who underwent the longitudinal assessment, 18 developed an MCI or AD during follow-up, and 73 MCI participants developed AD
during follow-up.

4.

High levels of CSF Ng are associated with low MMSE (mental status examination) scores, and cerebrospinal fluid Ng from different diagnostic groups is not associated with ventricular volume by FDG-PET (Figures 3A, B).

Figure 3 FDG-PET test results

Discussion

There were four main findings in this study: First, among APOE4-positive participants, Ng levels in the MCIε4+ group were significantly higher than in the MCIε4- group, however, there was no correlation in the CN and AD groups
.

Interestingly, in the MCI group, APOE-positive CSF Ng concentrations were significantly higher than in the negative group, but in the AD and CN groups, there was no such difference between APOE positive and negative CSF Ng, suggesting that CSF Ng may be an early marker of AD-associated synaptic degeneration, suggesting that the role of CSF Ng in the pathophysiology of MCI may be related
to APOE4 status.

Previous studies have shown that CSF-Ng is particularly elevated and abnormal Aβ levels are particularly pronounced in MCI and AD patients, however, the relationship between CSF-Ng and Aβ remains pathologically controversial, with some studies showing that CSF-Ng is positive or negative for Aβ42 or Aβ40 in AD patients, but other studies have also reported that CSF-Ng levels are not associated
with Aβ42 in AD samples.
In this study, CSF-Ng had no correlation
with Aβ except for the CNε4− group.
The most likely outcome is that synaptic damage caused by Aβ is weakly associated
with degenerative synaptic degeneration.

Consistent with previous studies, the authors found that elevated CSF-Ng levels were associated
with T-tau and P-tau in each diagnostic method.
Interestingly, in the MCI group, T-tau and P-tau concentrations increased significantly among APOE4 carriers, but there was no significant difference
in T-tau and P-tau concentrations between the AD group and the CN group.
The results suggest that axonal injury due to Tau or APOE4, particularly in patients with MCI, may be associated with synaptic degeneration, so the important issue is to identify CSF biomarkers (eg, Ng, Aβ, T-tau and P-tau in the MCI population).

The authors next attempted to examine whether CSF-Ng improved the differential diagnosis of dementia levels in patients with MCI and AD, and compared with traditional AD biomarkers such as CSF-T-tau and P-tau, all biomarkers were able to differentiate MCIε4+ from the CNε4− group, ADε4− with the CNε4− group, and ADε4+ from CNε4−, but could not distinguish between the MCIε4− and CNε4− groups
.

In terms of diagnostic accuracy, the different manifestations of CSF-Ng on MCI may be due to the fact that fewer MCIε4− subjects develop AD, and more MCIε4+ subjects develop AD
.
Tau proteins are known to be mainly distributed in the cell bodies and axons of neurons, however recent evidence suggests that Tau is also a dendritic protein
.
This raises an important question: What is the role of Tau proteins after synapses?

Recent data suggest that tau in dendrites appears to modulate the shaping mechanisms
of memory storage.
Persistent changes in synaptic plasticity are thought to be cell-related factors in memory storage, and in memory-related synaptic plasticity phenomena, synaptic strength can be long-term enhancement (LTP) or long-term inhibition (LTD), and these changes can last from hours to days, Ng is a postsynaptic protein, expressed mainly in the cortex and hippocampus, located in dendritic spines, which play a key role
in regulating LTP and learning.

Thus, the accuracy of CSF-Ng and Tau diagnosis alone or in combination is similar, as they may capture different variable elements
of the same neurodegenerative degeneration process in AD.
In addition, CSF-Ng could not significantly predict CN to MCI or AD and MCI to AD conversion, suggesting that CSF-Ng is insensitive in predicting progression to AD in patients with cognitively normal MCI
.

In summary, the authors suggest that the role of CSF-Ng in the pathophysiology of MCI may be related
to AOPE4.
Future research will further explore the relationship between the two and its related mechanisms, providing more evidence
for the potential role of Ng in clinical studies, trials and practices of neurodegenerative diseases such as AD.