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GAP-43 is associated with faster amyloid-related tau accumulation in meta ROIs Scatterplots illustrating the interaction between amyloid-PET (i.e., centiloid) and CSF GAP-43 levels on tau-PET changes in a global cortical ROI (A), as well as in a temporal meta ROI (B). Regression models were corrected for age, sex, diagnosis, and CSF p-tau181. Note that all interactions were computed using continuous GAP-43 measures across the entire study cohort (N = 93), median split was only performed for visualization. β-values reflect standardized regression weights. All T- and two-sided p-values were derived from linear regression. Linear model fits (i.e., least squares line) are indicated together with 95% confidence intervals displayed as error bands. Source data are provided as a Source Data file. PET Positron Emission Tomography, SUVR Standardized uptake value ratio, CSF cerebrospinal fluid, GAP-43 Growth-associated protein 43.
Source publication
In Alzheimer’s disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity...
Citations
... Under normal conditions, growth-associated protein 43 (GAP-43), also known as F1, B-50, or neuromodulin, plays a pivotal role in regulating synaptic plasticity, neuronal growth, and memory formation (Holahan 2017;Kanazir et al. 1996;Holahan 2015). However, recent research has underscored its significant involvement in Alzheimer's disease (AD) dementia, identifying GAP-43 as a crucial biomarker for synaptic dysfunction and disease progression (Franzmeier et al. 2024;Öhrfelt et al. 2023;Qiang et al. 2022;Zhu et al. 2023). ...
... Evidence suggests that elevated cerebrospinal fluid (CSF) levels of GAP-43 are strongly linked to worse cognitive outcomes, accelerated brain atrophy, and a heightened risk of progression to dementia, particularly in amyloid-beta (Aβ)positive individuals (Öhrfelt et al. 2023;Lan et al. 2023;Sandelius et al. 2019;Dhiman et al. 2020). Furthermore, GAP-43 has been shown to amplify Aβ-driven tau propagation across brain regions, promoting the spread of tau pathology along synaptic pathways (Franzmeier et al. 2024). This effect is especially prominent in APOE-ε4 carriers, where higher baseline and longitudinal increases in GAP-43 are associated with greater hippocampal atrophy and cognitive decline, driven by Aβ accumulation and phosphorylated tau (pTau) pathologies (Öhrfelt et al. 2023;Lan et al. 2023). ...
... For instance, a study involving cognitively normal, AD dementia patients, and individuals with other neurodegenerative diseases cases, found that GAP-43 levels were strongly correlated with the presence of Aβ plaques and tau neurofibrillary tangles, particularly in the hippocampus, amygdala, and cortex (Sandelius et al. 2019). In another study spanning normal aging and AD dementia, amyloid-PET and longitudinal tau-PET imaging revealed that higher CSF GAP-43 levels accelerated Aβ-related tau spread, particularly near tau epicenters, suggesting that GAP-43-mediated synaptic remodeling drives the propagation of amyloid pathology (Franzmeier et al. 2024). ...
Growth-associated protein 43 (GAP-43), a key regulator of synaptic plasticity, neuronal growth, and memory, has recently been identified as a crucial biomarker for synaptic dysfunction in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. This study aimed to explore the mechanisms underlying GAP-43’s role in cognitive impairment by examining the relationship between CSF GAP-43 levels and amyloid-β (Aβ) accumulation in brain regions like the frontal, temporal, and parietal lobes. This study included 332 participants sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), categorized into three groups: 93 cognitively normal (CN), 218 with MCI, and 21 with AD dementia. Cognitive status was assessed with ADAS-Cog 13, CSF GAP-43 levels via ELISA, and Aβ accumulation using florbetapir PET imaging and Syngo.PET for SUVr values in key brain regions. The results revealed that CSF GAP-43 levels were highest in the AD dementia group, followed by the MCI group, and lowest in the CN group, with a significant difference (p < 0.001), indicating a link between elevated CSF GAP-43 and cognitive impairment. In MCI group, CSF GAP-43 positively correlated with Aβ accumulation in all regions: Globally (β = 0.362, p < 0.001), frontal (β = 0.388, p < 0.001), temporal (β = 0.382, p < 0.001), and parietal lobes (β = 0.344, p < 0.001). In contrast, the AD dementia group exhibited negative correlations between CSF GAP-43 levels and Aβ accumulation, significantly in the frontal (β = − 0.513, p = 0.035) and parietal lobes (β = − 0.513, p = 0.035), suggesting a shift in the CSF GAP-43-Aβ relationship in AD dementia. Mediation analysis, adjusted for age, gender, education, and ApoE ɛ4 status, revealed that elevated CSF GAP-43 is linked to increased cognitive impairment via increasing Aβ accumulation solely in MCI, with significant effects in global (β = 0.0894, CI: [0.0427, 0.1457]), frontal (β = 0.0895, CI: [0.0422, 0.1443]), temporal (β = 0.0941, CI: [0.0466, 0.1522]), and parietal (β = 0.0499, CI: [0.0100, 0.0945]) regions. Thus, elevated CSF GAP-43 may contribute to cognitive impairment by promoting Aβ accumulation in individuals with MCI, while in AD dementia, it may be associated with reduced Aβ accumulation, potentially reflecting a compensatory or disease-stage-dependent effect. This dynamic relationship suggests that GAP-43 could play a dual role in neurodegeneration, influencing Aβ pathology differently across disease stages.
... p d f ). All baseline data had to be obtained within a timeframe of 6 months, in line with our previous studies using ADNI data [46][47][48][49][50]. This time window was chosen to maximize observations with complete neuroimaging and clinical data within a given timeframe. ...
Background
Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson’s disease but also one of the most common co-pathologies in Alzheimer’s disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline.
Methods
In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau 181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline.
Results
αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity ( p < 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau 181 increases ( p = 0.005) and higher tau-PET levels in AD-typical brain regions ( p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation ( p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology.
Conclusions
Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.
... 69 Elevated Gap43 levels in the cerebrospinal fluid of AD patients correlate with accelerated tau protein accumulation, cognitive decline, and worsening symptoms, underscoring Gap43's crucial role in synaptic activity and cognitive function. [70][71][72][73] This study is the first to confirm increased Gap43 mRNA levels in the hippocampus of PND mice and to identify Gap43 as essential for esketamine treatment. This suggests that modulating hippocampal Gap43 and its effects on synaptic activity and plasticity may be critical for esketamine's therapeutic effects in PND. ...
Background
Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.
Methods
The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.
Results
The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.
Conclusion
We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine’s treatment of PND.
... This protein has been characterized as a critical mediator of nerve growth and repair, particularly under conditions of injury and regeneration, making its upregulation a hallmark of neuronal plasticity [40]. These studies underline the biological relevance of GAP-43 in adaptive responses to neural injury and degeneration [41]. ...
Background: Degenerative spinal stenosis is a common condition associated with structural degeneration and pain, yet its molecular underpinnings remain incompletely understood. Growth-associated protein 43 (GAP-43), a key player in neuronal plasticity and regeneration, may serve as a biomarker for disease progression and pain severity. This study investigates the expression of GAP-43 at the mRNA and protein levels in the ligamentum flavum of affected patients. Methods: Samples were collected from 96 patients with degenerative spinal stenosis and 85 controls. GAP-43 mRNA expression was analyzed using reverse transcription–quantitative polymerase chain reaction (RT-qPCR), while protein levels were quantified via enzyme-linked immunosorbent assay (ELISA) and Western blot. Pain severity was assessed using the visual analog scale (VAS), and associations with lifestyle factors were analyzed. Results: GAP-43 mRNA expression was significantly downregulated in the study group compared to the controls (fold change = 0.58 ± 0.12, p < 0.05), with an inverse correlation to VAS pain severity (fold change = 0.76 at VAS 4 vs. 0.36 at VAS 10). Conversely, GAP-43 protein levels were markedly elevated in the study group (5.57 ± 0.21 ng/mL) when compared to controls (0.54 ± 0.87 ng/mL, p < 0.0001). Protein levels were also correlated with lifestyle factors, including smoking and alcohol consumption (p < 0.05). Conclusions: GAP-43 shows potential as a biomarker for pain severity and disease progression in degenerative spinal stenosis, in a manner influenced by lifestyle factors. Further research is needed to explore its diagnostic and therapeutic applications.
... 41,50 Accumulation of putative toxic tau species has been observed at the presynapse and postsynapse of individuals with AD dementia, 51 and synapse dysfunction has been suggested to be a key driver of the spread of AD pathology in critical brain regions. 52 Moreover, recent in vitro studies in primary tauopathy models have proposed that synapse dysfunction may precede the buildup of toxic tau and neurodegeneration. 53 Notably, severe and region-specific synapse loss has also been described in a subset of primary tauopathies in which synapse degeneration is a strong determinant of disease severity and progression. ...
Synapse preservation is key for healthy cognitive ageing, and synapse loss represents a critical anatomical basis of cognitive dysfunction in Alzheimer’s disease (AD), predicting dementia onset, severity, and progression. Synapse loss is viewed as a primary pathologic event, preceding neuronal loss and brain atrophy in AD. Synapses may, therefore, represent one of the earliest and clinically most meaningful targets of the neuropathologic processes driving AD dementia. The synapse loss in AD is highly selective and targets particularly vulnerable synapses while leaving others, termed resilient, largely unaffected. Yet, the anatomic and molecular hallmarks of the vulnerable and resilient synapse populations and their association with AD neuropathologic changes (e.g. amyloid-β plaques and tau tangles) and memory dysfunction remain poorly understood. Characterising the selectively vulnerable and resilient synapses in AD may be key to understanding the mechanisms of cognitive preservation versus loss and enable the development of robust biomarkers and disease-modifying therapies for dementia.
... Hypothetically, synaptic oligomeric tau might be the very first stage of phosphorylated tau containing dystrophic neurites, surrounding the amyloid plaques in AD [12]. Furthermore, it appears that the association of Alzheimer amyloid (Aβ42) with tau pathology is significantly increased among persons with high CSF concentrations of GAP43, an established biomarker of presynaptic terminal damage [13]. Finally, in animal models, microglia and astrocytes engulf more synapses among mice with both amyloid and tau pathology [14][15][16]. ...
... Two of these proteins are pre-synaptic markers (ADAM23, SYT1), one is predominantly pre-synaptic (SNAP25), and one is post-synaptic (ADAM22). Other analyses in a subset of this cohort's participants explored the association between CSF GAP43 and PET imaging markers of AD, extending recent findings in persons with AD dementia [13]. We examined the first four proteins in relation to the classic CSF biomarkers of AD pathology, Aβ42, and total-as well as (181)P-tau. ...
... Combined with the results reported here, these findings suggest that synaptic depletion is coincident with the progression of classical AD biomarkers in CSF and PET imaging. They concur with other observations of an association between the terminal-associated protein GAP43 and longitudinal tau- PET findings in persons with dementia [13]. Our observation of associations between the CSF synaptic proteins and PET amyloid deposition was less impressive, in accord with the notion that earlier amyloid pathology may trigger both synaptic and tau pathology (the order of the two effects being presently unknown). ...
... 30,31 All plasma biomarker measurements were blinded to clinical diagnosis at the Shenzhen Bay Laboratory was measured by an in-house enzyme-linked immunosorbent assay (ELISA) as described previously. 33,34 The optimal cutoff value for CSF p-tau181 was defined at 23 pg/mL after comparing measures of Aβ-CU participants (n = 313) with Aβ+ CI participants (n = 421), as described in Figure S1B. ...
INTRODUCTION
Novel fluid biomarkers for tracking neurodegeneration specific to Alzheimer's disease (AD) are greatly needed.
METHODS
Using two independent well‐characterized cohorts (n = 881 in total), we investigated the group differences in plasma N‐terminal tau (NT1‐tau) fragments across different AD stages and their association with cross‐sectional and longitudinal amyloid beta (Aβ) plaques, tau tangles, brain atrophy, and cognitive decline.
RESULTS
Plasma NT1‐tau significantly increased in symptomatic AD and displayed positive associations with Aβ PET (positron emission tomography) and tau PET. Higher baseline NT1‐tau levels predicted greater tau PET, with 2‐ to 10‐year intervals and faster longitudinal Aβ PET increases, AD‐typical neurodegeneration, and cognitive decline. Plasma NT1‐tau showed negative correlations with baseline regional brain volume and thickness, superior to plasma brain‐derived tau (BD‐tau) and neurofilament light (NfL) in Aβ‐positive participants.
DISCUSSION
This study suggests that plasma NT1‐tau is an Aβ‐dependent biomarker and outperforms BD‐tau and NfL in detecting cross‐sectional neurodegeneration in the AD continuum.
Highlights
Plasma N‐terminal tau (NT1‐tau) was specifically increased in the A+/T+ stage.
Plasma NT1‐tau was positively associated with greater amyloid beta (Aβ) and tau PET (positron emission tomography) accumulations.
Higher plasma NT1‐tau predicted greater tau burden and faster Aβ increases.
Plasma NT1‐tau was more related to neurodegeneration than plasma brain‐derived tau (BD‐tau) and neurofilament light (NfL).
... These findings suggest that elevated CSF levels of GAP-43 may be indicative of synaptic dysfunction and neurodegeneration, as reflected by altered brain structure and connectivity in AD-related brain regions [51]. Additionally, multiple studies have shown that elevated baseline levels of CSF GAP-43 are linked to a more aggressive neurodegenerative process, a quicker rate of cognitive decline, and a higher risk of progressing to dementia [12,17,[52][53][54][55][56][57][58]. Since cognitive decline in AD continuum is partly attributed to synaptic dysfunction, GAP-43 is under scrutiny as a marker for both synaptic dysfunction and neurodegeneration. ...
Mild Cognitive Impairment (MCI) is a neurological condition characterized by a noticeable decline in cognitive abilities that falls between normal aging and dementia. Along with some biomarkers like GAP-43, Aβ, tau, and P-tau, brain activity and connectivity are ascribed to MCI; however, the link between brain connectivity changes and such biomarkers in MCI is still being investigated. This study explores the relationship between biomarkers like GAP-43, Aβ, tau, and P-tau, and brain connectivity. We enrolled 25 Participants with normal cognitive function and 23 patients with MCI. Levels of GAP-43, Aβ1–42, t-tau, and p-tau181p in the CSF were measured, and functional connectivity measures including ROI-to-voxel (RV) correlations and the DMN RV-ratio were extracted from the resting-state fMRI data. P -values below 0.05 were considered significant. The results showed that in CN individuals, higher connectivity within the both anterior default mode network (aDMN) and posterior DMN (pDMN) was associated with higher levels of the biomarker GAP-43. In contrast, MCI individuals showed significant negative correlations between DMN connectivity and levels of tau and P-tau. Notably, no significant correlations were found between Aβ levels and connectivity measures in either group. These findings suggest that elevated levels of GAP-43 indicate increased functional connectivity in aDMN and pDMN. Conversely, elevated levels of tau and p-tau can disrupt connectivity through various mechanisms. Thus, the accumulation of tau and p-tau can lead to impaired neuronal connectivity, contributing to cognitive decline.
... Specifically, Franzmeier and colleagues observed that GAP-43 levels in the CSF of AD patients were associated with a more rapid accumulation of Aβ-related Tau. In other words, the effect of Aβ on Tau deposition was greater in the presence of high levels of GAP-43 in the CSF, highlighting the role of this presynaptic protein as a biomarker of synaptic dysfunction in AD [74]. ...
Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer's disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing AD and assessing the progression of the neurodegenerative state. In this context, exercise is known to be an effective non-pharmacological management strategy for AD that can counteract cognitive decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in counteracting neurodegeneration in AD.
... Specifically, Franzmeier and colleagues observed that GAP-43 levels in the CSF of AD patients were associated with a more rapid accumulation of Aβ-related Tau. In other words, the effect of Aβ on Tau deposition was greater in the presence of high levels of GAP-43 in the CSF, highlighting the role of this presynaptic protein as a biomarker of synaptic dysfunction in AD [74]. ...
Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer’s disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing AD and assessing the progression of the neurodegenerative state. In this context, exercise is known to be an effective non-pharmacological management strategy for AD that can counteract cognitive decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in counteracting neurodegeneration in AD.
