Alzheimer’s disease (AD), a severe neurodegenerative disease of the central nervous system that usually occurs in senile and pre-senile patients, is characterized by progressive loss of thinking, memory, language, and impairment of cognitive ability. It is the most common form of dementia in old age, with about 60% to 80% of the dementia diagnosed in people over 65 years old being attributed to it [1]. New cases of AD are projected to increase to more than 1 million by 2050, which will place an enormous financial burden on families and society [2]. Mild cognitive impairment (MCI) is an intermediate stage in which a person has problems with memory, language, or other cognitive functions that can be detected by others or by testing but is not serious enough to affect the activities of daily living [3]. If it is not prevented from progressing in a timely manner, such subjects are at a significantly increased risk of evolving toward AD at the rate of 15–25% over two years [4, 5]. However, there are neither disease-modifying therapies nor successful late-stage clinical trials currently available [6]. It is believed that continuous pathophysiological changes begin many years prior to clinical symptom onset, thus further investigations is required with the aim of discovering a practical biomarker for the early diagnosis and detection of AD.

Neurofilaments (Nfs) are intermediate filamentous proteins, expressed in neurons and particularly abundant in axons, responsible for the structural stability of axon morphology, forming the neuronal cytoskeleton, and maintaining cytoarchitecture and transport functions [7]. Nfs are divided by molecular weight into three subunits, the neurofilament heavy, medium, and light chains [8]. Neurofilament light chain (NfL) has the lowest molecular weight, and is thought to be the leading Nfs for stabilization of axonal structure and the promotion of axon growth [9, 10]. There are many studies demonstrating that NfL levels are higher in AD patients than controls, associated with poorer cognitive performance, and short survival time in demented patients [11]. NfL was used as a specifically diagnostic biomarker, meanwhile, it is potentially a valuable tool for the detection of the initial pathological changes associated with AD, even at the MCI stage, while in the differential diagnosis, monitoring, and prognosis of AD. Recently, there has been great interest in the utility of NfL in plasma as a biomarker for AD. It avoids the invasiveness of cerebrospinal fluid (CSF) sampling, which is restricted in its clinical application [12].

This meta-analysis aimed to investigate whether NfL in peripheral blood is accompanied by improved levels of AD or MCI and to evaluate NfL as a cognitive biomarker for the diagnosis of AD and MCI. The findings reported here may be used for risk assessment and assessment of disease progression, even for clinically aided diagnosis of MCI or AD. Plasma NfL levels were measured in three groups of patients, AD, MCI, and healthy subjects, obtained from cross-sectional and longitudinal studies.

Alzheimer’s patients have a long, mild pre-clinical phase of cognitive impairment before showing the clinical symptoms typical of dementia. A clinical performance on memory impairment characterized as amnestic MCI (aMCI), a subtype of MCI, has increasingly been accepted as a high-risk condition for conversion to AD. Unfortunately, currently there are no effective treatments available to halt, slow, or reverse the progression of AD. Consequently, there is a significant clinical need for rapid and non-invasive diagnostic biomarkers to identify AD or MCI patients. Low levels of NfL can be detected in the blood and CSF of normal persons, with an increased concentration of NfL correlated with age. Recent research suggests that NfL is abnormally released into the CSF and blood with damage and degeneration following damage to various central and peripheral neurons [10]. The exact mechanism is not completely understood, although it most probably involves the destruction of cell membrane integrity. Recently, studies have suggested that NfL levels in the CSF and blood play an important role in patients with AD or MCI. In this study, due to the fact that it is inexpensive and simple to acquire, meta-analysis was used to explore the peripheral blood, for the development of diagnostic biomarkers of patients with AD or MCI. Plasma NfL levels may serve as one of the most promising fluid biomarkers for the validation of AD or MCI diagnosis [44]. Further, some animal studies have also reported that NfL is a potentially reliable biomarker for the severity of neuronal apoptosis [20, 45]. Although there is a potential rationale that NfL can be regarded as a measure of the intensity of ongoing AD or MCI, the data remain controversial. Other work corroborates that there is no significant association between plasma NfL and cognitive decline [46]. Here, a total of 24 studies were extracted from the literature for this meta-analysis, and the following findings were obtained: Firstly, the level of NfL in plasma of patients with AD and MCI increased, simultaneously, and it was higher in patients with AD than in MCI subjects. Secondly, the concentration of NfL in plasma increased with cognitive decrease and was negatively correlated with MMSE scores. These findings provide clinical evidence that peripheral NfL levels can potentially be used as a biomarker for AD and MCI.

In the last few years, new biomarkers have emerged for the early diagnosis of AD, among which plasma NfL has recently been considered as a diagnostic and prognostic biomarker for the preclinical stages of AD [47]. NfL levels in the plasma are closely related to several traditional biomarkers of AD, including amyloid beta (A$\beta$)${}_{42}$, A$\beta$${}_{42/40}$, and A$\beta$${}_{42}$/t-tau (total tau) [48]. NfL is a strongly proposed marker for the detection of neuronal injury or loss before the onset of the clinical symptoms of AD and cognitive dysfunction, brain atrophy, and disease progression monitored by the increase of the plasma NfL level [49], unlike the pathological mechanism of A$\beta$ and Tau. Neuronal damage and neuronal death are an important characteristic of AD pathology from the beginning of the presymptomatic stage of AD, and cognitive functions are associated with dendritic and axonal integrity [50]. Axonal integrity and transport are directly associated with the degree of cognitive decline and neurodegeneration [51]. Therefore, NfL as a structural component of axons could be a promising tool for early diagnosis of AD. There is a growing body of evidence that axonal degeneration is an indicator of AD progression, affecting both brain structure and cortical metabolism, thus influencing AD’s cognition [52]. Additionally, recent studies have demonstrated that the expression of NfL in plasma is elevated in patients with AD and is significantly associated with the degree of A$\beta$ and tau in the CSF and positron emission tomography [31]. Here, the level of NfL was analysed in plasma of patients with AD and MCI and was found to be significantly higher than in HC. Additionally, a meta-analysis also found that blood NfL levels are higher in AD when compared to HC [53]. However, another study has shown that there was no association between plasma NfL levels in MCI and HC subjects [54]. They included small sample size to clarify whether blood NfL was a reliable biomarker, whereas here 24 articles were included, giving a larger patient number for analysis. A series of regression and subgroup analyses were also employed to confirm the conclusion reported here. Consequently, plasma NfL may have the potential to reflect axonal degeneration and be employed as a biomarker for AD and MCI.

In summary, these findings further validated that NfL in plasma can be used as a significant cognitive biomarker that distinguishes patients with AD and MCI from HC, but that the different ranges of NfL are unable to identify the different stages of the disease; therefore, in the future, other studies are needed to define the optimal range of plasma NfL values for prediction at the different stages of the disease.

There were several limitations to the meta-analysis reported here. Firstly, despite an exhaustive literature search, it is possible that some studies may have been missed and some publications had to be excluded due to small sample size and low quality. Secondly, the trim-and-fill-method which detects and adjusts for publication bias may affect the robustness of the results reported here. Thirdly, a high heterogeneity was found in this meta-analysis where comparison of AD with HCs and MCI with HCs may have reduced its statistical power.

The results of this meta-analysis suggest that there was a significant difference of plasma NfL between AD, MCI and the healthy controls and that there was a correlation between plasma NfL and cognitive dysfunction levels. From these results, it can be concluded that plasma NfL can serve as a biomarker for AD or MCI, but it cannot discriminate AD from other dementias or neurodegenerative diseases. Given the limited data, more cohort studies are required to confirm the results reported here.

AD, Alzheimer’s disease; MCI, mild cognitive impairment; Nfs, neurofilaments; NfL, neurofilament light; CSF, cerebrospinal fluid; PRISMA, Preferred Reporting Items for Systematic Review and Meta-analysis; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; NIA-AA, National Institute on Aging and Alzheimer’s Association; Simoa, single molecule array; MMSE, Mini-Mental State Examination; NOS, Newcastle-Ottawa scale; SMD, standardized mean difference; CI, confidence interval; A$\beta$, amyloid beta; HC, healthy controls.

The datasets analyzed in this article are available upon request to: zmnb1989@163.com.

MZ and ZF designed the review. XL and JL collected and analyzed the data. CC was responsible for the result analysis and make figures. ZF and CC supervised the procedures. MZ wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

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This research was funded by Zhejiang Medicine and Health Science and Technology Project, grant number 2020KY848; the Project of NINGBO Leading Medical & Health Discipline, grant number 2022-B12.

The authors declare no conflict of interest.