Key Information
Abstract
Background
Growth-associated protein 43 (GAP-43) is a key protein involved in neuronal growth and synaptic plasticity. Alterations in GAP-43 levels have been associated with Alzheimer’s Disease (AD), potentially reflecting synaptic dysfunction. We evaluated the potential of GAP-43 as a biomarker for AD and explored its association with amyloid-beta (Aβ) levels, as well as its correlation with Aβ plaque burden in the brain.
Methods
We screened 1,639 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. A total of 226 individuals met the eligibility criteria and were enrolled. Participants were classified into three groups: 77 cognitively normal (CN) individuals, 111 with mild cognitive impairment (MCI), and 38 with a diagnosis of AD. The associations between cerebrospinal fluid (CSF) GAP-43 levels with other biomarkers as well as [¹⁸F] AV-45 (Florbetapir) PET Standardized Uptake Value Ratios (SUVR) were investigated.
Results
Our findings revealed significantly elevated CSF GAP-43 levels in individuals with AD compared to CN and MCI groups. Furthermore, GAP-43 levels showed a significant positive correlation with tau pathology. Notably, we observed a significant association between GAP-43 and [¹⁸F] Florbetapir PET SUVR in the MCI group, suggesting that GAP-43 may serve as a reliable biomarker in the early stages of AD.
Conclusion
This study provides evidence supporting the role of GAP-43 as a potential biomarker for AD, particularly in relation to predicting the amyloid pathology pattern in the brain in the MCI stage.
Keywords: Alzheimer’s disease, Mild cognitive impairment, Growth associated protein 43, Positron emission tomography
Introduction
Dementia is a major global health concern, with approximately affecting 46.8 million people worldwide. This number is projected to increase to 74.7 million by 2030, and to 131.5 million by 2050. The annual incidence of new dementia cases is estimated at 9.9 million globally [1external link, opens in a new tab]. Alzheimer’s disease (AD), the most common form of dementia, remains a complex disorder, with its exact pathogenesis not fully understood. However, current evidence suggests that AD is strongly associated with the extracellular accumulation of amyloid-beta (Aβ) plaques and the intracellular formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein [2external link, opens in a new tab, 3external link, opens in a new tab]. These protein aggregates lead to neuronal damage and synaptic loss. Early diagnosis of AD is critical, as disease-modifying treatments are most effective during the mild cognitive impairment (MCI) stage [4external link, opens in a new tab]. Due to the complexity of AD and its overlapping clinical features with other forms of dementia, particularly in its early phases, identifying reliable early diagnostic markers is crucial.
Aβ, a peptide of 36 to 43 amino acids, is generated by the enzymatic cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase [5external link, opens in a new tab–8external link, opens in a new tab]. Aβ naturally aggregates in the extracellular space, forming oligomers, protofibrils, and mature amyloid fibrils [9external link, opens in a new tab–13external link, opens in a new tab]. Plasma Aβ levels and cerebral β-amyloidosis have been shown to correlate with AD pathology and can serve as predictive biomarkers [14external link, opens in a new tab–16external link, opens in a new tab]. Moreover, Aβ accumulation is sensitive to disease stage, with lower levels of Aβ-42 detected in cerebrospinal fluid (CSF) during the preclinical phase of AD [17external link, opens in a new tab, 18external link, opens in a new tab].
Growing evidence suggests that Growth Associated Protein 43 (GAP-43) levels are significantly elevated in the brains of AD patients compared to healthy individuals [19external link, opens in a new tab–21external link, opens in a new tab]. This elevation in GAP-43 levels has been observed in regions affected by AD pathology, including the hippocampus, amygdala, and cerebral cortex [22external link, opens in a new tab]. The correlation between GAP-43 levels and the presence of NFT and Aβ plaques suggests that GAP-43 may reflect the extent of disease progression [20external link, opens in a new tab]. GAP-43 is a protein involved in synaptic plasticity and axonal growth, and its altered expression is indicative of synaptic dysfunction and neurodegeneration, making it a potential biomarker for AD [23external link, opens in a new tab]. Notably, GAP-43 is crucial during early brain development, playing a key role in neurite outgrowth, synaptogenesis, and neuronal plasticity. Given that AD pathology begins years before clinical symptoms manifest, the detection of altered GAP-43 levels in the early stages of the disease suggests its potential as an early biomarker for AD [24external link, opens in a new tab].
While [18F] Fludeoxyglucose (FDG) PET is a valuable tool for diagnosing AD, Amyloid PET imaging, specifically [¹⁸F] AV45, is considered the gold standard for in vivo detection of amyloid plaques. Florbetapir ([¹⁸F] AV45) is a PET ligand that binds specifically to Aβ-42 with high affinity, allowing for the quantification and localization of Aβ deposition in the brain [25external link, opens in a new tab]. The association between Florbetapir PET findings and postmortem Aβ burden has been well established, making it a gold standard for evaluating Aβ deposition in vivo [26external link, opens in a new tab].