Franzmeier N, Dehsarvi A, Steward A, Biel D, Dewenter A, Roemer SN, Wagner F, Groß M, Brendel M, Moscoso A, Arunachalam P, Blennow K, Zetterberg H, Ewers M, Schöll M. Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer's disease. Nat Commun. 2024 Jan 3;15(1):202. PubMed.
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University of Gothenburg
The recent article by Franzmeier et al. demonstrated, with a series of very elegant analyses, that the synaptic biomarker GAP-43 associates with the spreading and accumulation of Aβ-related tau pathology. The study somewhat challenges the perhaps more “traditional” framework that synaptic changes are downstream of amyloid and tau pathologies in the AD pathophysiological process. While not refuting this idea, this study adds to the body of evidence supporting that synaptic alterations are—also—upstream events, promoting/accelerating the propagation of tau pathology throughout the brain in the presence of amyloid. It could be insightful to explore the Aβ GAP-43 interaction beyond amyloid plaques, proxied by PET, such as with CSF Aβ42/40. Regardless, this work nicely adds pieces to the complex AD puzzle by proposing/supporting information about disease mechanisms.
Adding to this topic, we, and others, have shown that different synaptic biomarkers may be similarly associated with other AD-related biomarkers, cross-sectionally (Wang et al., 2024). However, to my knowledge, it is not known how comparable these biomarkers are when more mechanistic approaches are considered or how similarly they affect/predict/reflect longitudinal changes in AD pathology. Although I personally do not believe that the synaptic biomarkers alone will, at the current research stage, be able to predict changes in AD pathology, they can be valuable if evaluated in more complex contexts as done here by Franzmeier and colleagues.
Surprisingly, the results lack validation, despite the availability of similar data in other cohorts. But I am certain this article will spark interest in future studies exploring the role of synaptic biomarkers in AD.
References:
Wang YT, Ashton NJ, Servaes S, Nilsson J, Woo MS, Pascoal TA, Tissot C, Rahmouni N, Therriault J, Lussier F, Chamoun M, Gauthier S, Brinkmalm A, Zetterberg H, Blennow K, Rosa-Neto P, Benedet AL. The relation of synaptic biomarkers with Aβ, tau, glial activation, and neurodegeneration in Alzheimer’s disease. https://doi.org/10.21203/rs.3.rs-3797679/v1 (version 1) Research Square
View all comments by Andrea L. BenedetFudan University
The take-home message from this research article is that in AD, synaptic changes, manifested by increased levels of the presynaptic protein GAP-43, are closely associated with the accelerated spread of tau pathology. The study found that higher levels of GAP-43 in cerebrospinal fluid (CSF) are linked to faster Aβ-related tau accumulation and spreading across brain regions closely connected to tau epicenters. This suggests that GAP-43-related synaptic changes play an important role in the progression of AD, and targeting these synaptic changes could be a potential strategy for preventing the spread of tau pathology and, consequently, progression of the disease.
Previous studies have associated GAP-43 with tau pathology in AD. A surprising result of this study is the specific association of GAP-43 with the spread of tau pathology across connected brain regions, rather than a general, diffuse accumulation of tau. This indicates that GAP-43-related synaptic changes do not lead to a widespread tau accumulation but specifically facilitate its spread along neural pathways. This finding is particularly significant because it underscores the role of synaptic integrity and activity in the progression of AD, moving beyond the traditional focus on Aβ and tau accumulation alone.
These results emphasize the importance of considering synaptic health and integrity in AD pathophysiology. Furthermore, they suggest that CSF GAP-43 could serve as a potential biomarker for predicting the spread of tau pathology. This could be valuable for the development of therapeutic strategies and for monitoring progression.
View all comments by Qiang QiangUniversity of California, San Diego
In this paper, the authors conducted an interesting secondary analysis of CSF and longitudinal tau PET data from ADNI. CSF levels of GAP-43, a presynaptic protein important in neurodevelopment and in axonal regeneration, are increased in MCI and AD, and higher baseline levels have been shown to predict faster cognitive decline and neurodegeneration e.g., seen as MRI atrophy and FDG PET hypometabolism (Öhrfelt et al., 2023). Although GAP-43 plays roles during brain development, expression remains high in hippocampus and neocortex in adulthood, and increases with aging. The new analysis mapped longitudinal changes in tau PET in an ADNI cohort of amyloid-positive and -negative controls and MCI/mild AD patients, many of whom had more than two serial tau PET images. Higher baseline CSF GAP-43 was a predictor of faster accumulation of tau, after controlling for several additional variables, including CSF P-tau181. Another recent secondary analysis of ADNI data found that APOE e4 carriers had higher levels of baseline GAP-43 and worse trajectories of cognitive decline (Lan et al., 2023).
The extent to which baseline CSF GAP43 predicted tau spread was statistically significant, although there was a fair amount of variability. Longitudinal studies of CSF GAP-43 have suggested that levels in CSF may plateau, therefore it appears to have potential as an early prognostic marker in AD. The new findings examining tau PET extend the prior work, and align with findings that support the spread of tau through connected tracts and pathways. Since levels of GAP-43 are increased in some models of hyperexcitability (e.g., rodents with seizures), the authors hypothesize that CSF GAP-43 is a marker related to hyperexcitable presynaptic neurons that contribute to spread of pathological tau. To address the question of whether GAP-43 is playing an active role in aberrant excitation or is passively released as a result of synaptic damage (with or without excitation being an important mechanism), model systems will need to be interrogated.
References:
Öhrfelt A, Benedet AL, Ashton NJ, Kvartsberg H, Vandijck M, Weiner MW, Trojanowski JQ, Shaw LM, Zetterberg H, Blennow K, Alzheimer's Disease Neuroimaging Initiative. Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals. Neurology. 2023 Jan 17;100(3):e275-e285. Epub 2022 Oct 3 PubMed.
Lan G, Du J, Chen X, Wang Q, Alzheimer’s Disease Neuroimaging Initiative, Han Y, Guo T. Association of APOE-ε4 and GAP-43-related presynaptic loss with β-amyloid, tau, neurodegeneration, and cognitive decline. Neurobiol Aging. 2023 Dec;132:209-219. Epub 2023 Sep 23 PubMed.
View all comments by Douglas GalaskoDenali Therapeutics
This new report by Franzmeier et al. is a beautiful continuation of investigations into the important interplay between Aβ, tau, and neuronal hyperexcitability in the context of Alzheimer's disease. There have long been reports of how the presence of Aβ can impact the types of tau aggregates and tau seeding potential in the brain, though this work has been largely tested in preclinical models. Expanding this concept to humans using the power of in-life longitudinal PET imaging of both AD pathologies helps set the stage for what is arguably one of the most exciting pillars of the manuscript—the use of GAP-43 as a fluid biomarker to understand more fully the disease mechanism(s), instead of solely capturing disease pathologies.
Coming from a more tau-centric background, I have long been very interested in how Aβ, tau, and sub-epileptiform activity may all be related, not only from a therapeutics perspective but also in the hunt for better pathway engagement and disease modification biomarkers for AD. It is very exciting to now see human data supporting what some preclinical models have previously suggested: that there is indeed an underlying mechanism of Aβ-induced synaptic hyperexcitability that contributes to the disease pathogenesis that is mediated, at least in part, through tau.
Of course, these analyses will need to be validated with larger datasets, but the data presented herein are a crucial step in the right direction. The authors do a great job of outlining some key next steps, including better understanding the timing of CSF GAP-43 increases as it relates to Aβ and tau pathological loads across different brain regions. I am also very curious and interested in how CSF GAP-43 levels may change in response to certain AD therapeutics, including anti-Aβ monoclonal antibodies and/or MAPT anti-sense oligonucleotides. Looking forward to seeing more GAP-43 biomarker data in the coming years.
View all comments by Sarah DeVosSeoul National University Bundang Hospital
This paper reported very interesting findings that higher CSF GAP43 levels were associated with faster Aβ-related tau accumulation and spreading to connectivity-associated regions. This suggests a clear relation of the presynaptic protein to amyloid (A) and tau (T) pathology in AD. To comprehend the underlying mechanisms of the contribution, examining the expression pattern of GAP43 gene, encoding the protein, according to A/T stages can provide additional clues.
We recently demonstrated that GAP43 expression levels were significantly lower in A+/T+ and marginally lower in A+/T- compared to A-/T- in brain bulk tissue (Pyun et al., 2023). Moreover, at the cell-type level, GAP43 expression levels were lower in astrocytes, microglia, and oligodendrocytes in A+/T+ compared to A-/T-, but not in excitatory and inhibitory neurons.
These results highlight the need to elucidate the discrepancy between decreased cortical GAP43 gene expression and increased CSF GAP43 protein expression in AD to discern the specific mechanistic role of GAP43 in AD, which might be situated along complex pathways. Additionally, lower GAP43 expression levels in glial cells of A+/T+, but not in neurons, may indicate that the GAP43-related synaptic pathway in AD could involve glial cells rather than neurons. Further studies on these points would broaden our understanding of the role of GAP43 in AD.
References:
Pyun JM, Park YH, Wang J, Bice PJ, Bennett DA, Kim S, Saykin AJ, Nho K. Aberrant GAP43 Gene Expression Is Alzheimer Disease Pathology-Specific. Ann Neurol. 2023 May;93(5):1047-1048. Epub 2023 Mar 21 PubMed.
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