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Exploring Braak’s Hypothesis of Parkinson’s Disease
Open accessAbstract
Parkinson’s disease (PD) is a neurodegenerative disorder for which there is no cure. Most patients suffer from sporadic PD, which is likely caused by a combination of genetic and environmental factors. Braak’s hypothesis states that sporadic PD is caused by a pathogen that enters the body via the nasal cavity, and subsequently is swallowed and reaches the gut, initiating Lewy pathology (LP) in the nose and the digestive tract. A staging system describing the spread of LP from the peripheral to the central nervous system was also postulated by the same research group. There has been criticism to the Braak’s hypothesis, in part because not all patients follow the proposed staging system. Here, we review literature that either supports or criticizes the Braak’s hypothesis, focused on the enteric route, digestive problems in patients, the spread of LP on a tissue and a cellular level, and the toxicity of the protein αSynuclein (αSyn), which is the major constituent of LP. We conclude that the Braak’s hypothesis is supported by in vitro, in vivo and clinical evidence. However, we also conclude that the staging system of Braak only describes a specific subset of patients with young onset and long duration of the disease.
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“GI symptoms may predate motor features by years, consistent with the concept that α-synuclein pathology can involve the ENS and vagal/brainstem autonomic nuclei early in disease (Rietdijk et al., 2017; Travagli et al., 2020).”
From Autonomic nervous system and gastrointestinal manifestations with an emphasis on gastric dysfunction (2026) · cites this paper as Rietdijk et al., 2017
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“Systems which we would classify as triggered by external factors are any that involve infection, such as acquired prion disease (aggregation is initiated by the introduction of an infectious prion), but also those proposed models in which bacterial infections trigger neurodegenerative disease, or in which inflammation…”
BackgroundAntibody-based therapies for Huntington’s disease: current status and future directions
Denis, H. L., David, L. S., & Cicchetti, F. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104569 · Cited by 33
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Olfactory dysfunction is associated with motor function only in tremor-dominant Parkinson’s disease
Nabizadeh, F., Pirahesh, K., & Khalili, E. (2022) · Neurological Sciences · doi:10.1007/s10072-022-05952-w · Cited by 22
“Measurement of olfactory dysfunction has some benefits including the ease of olfactory testing, high prevalence, persistence throughout the disease, and in line with Braak’s theory, it is one of the earliest biomarkers of PD [6, 7].”
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Tsao, H.-H., Huang, C., & Wu, Y. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105358 · Cited by 23
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“The reliability of this staging system, however, has been challenged over the years with evidence suggesting that the staging of LP may be governed by a combination of selective vulnerability and a possible lack of compensatory mechanisms in place in regions with low synaptic connectivity (Halliday and McCann, 2009; H…”
BackgroundJeon, H., Kim, H.-Y., Bae, C., Lee, Y., & Kim, S. (2020) · Journal of Medicinal Food · doi:10.1089/jmf.2019.4640 · Cited by 22
“7 Although alpha-synuclein (aSyn) in the synaptic membrane is involved in neuronal communication, 8 the over-production of aSyn and the accumulation of misfolded aSyn in Lewy bodies contribute to the pathogenesis of PD, 9 Moreover, dysfunction of the GI system induces the expression of aSyn.”
The intertwined relationship between circadian dysfunction and Parkinson's disease
Duret, L. C., & Nagoshi, E. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2024.10.006 · Cited by 21
Fakhri, S., Piri, S., Majnooni, M. B., Farzaei, M. H., & Echeverría, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.621099 · Cited by 21
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Kim, J. H., Choi, Y., Lee, S.-M., & Oh, M. S. (2024) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2024.215 · Cited by 22
“This hypothesis was further supported by the observation that many patients with PD experience gastrointestinal disturbances, including constipation and nausea, often years prior to the onset of motor symptoms (Rietdijk et al ., 2017).”
The multiple functions of PrPC in physiological, cancer, and neurodegenerative contexts
Grimaldi, I., Leser, F. S., Janeiro, J. M., da Rosa, B. G., Campanelli, A. C., Romão, L. F., & Lima, F. R. S. (2022) · Journal of Molecular Medicine · doi:10.1007/s00109-022-02245-9 · Cited by 21
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“Rietdijk et al. (2017) analyzed postmortem tissue of 110 PD patients with focus on pathologic αSyn distribution.”
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Jankovic, J. J. (2017) · Immunotherapy · doi:10.2217/imt-2017-0146 · Cited by 19
Societal Burden and Persisting Unmet Needs of Parkinson’s Disease
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Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson’s Disease?
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“Considerable preclinical, clinical and laboratory evidence supports Braak ’ s hypothesis of PD progression, although the speci fi c mechanisms, stages and pathways still have to be elucidated (13, 14).”
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“Consequently, this will result in dysregulation in homeostasis, activating various immunological mechanisms that might promote α Syn aggregation [33,102].”
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“3) Pathological heterogeneity: disease progression on the histological level is not uniform in all PD patients (Rietdijk 2017), and not all patients with PD develop dyskinesia.”
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The Impact of microRNAs on Mitochondrial Function and Immunity: Relevance to Parkinson’s Disease
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The Relationship Between Speech Characteristics and Motor Subtypes of Parkinson's Disease
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Morphological Features of Human Dendritic Spines
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RNA‐Based Therapies for Neurodegenerative Diseases Targeting Pathogenic Proteins
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“Braak's hypothesis proposes that the progression of PD is associated with the sequential emergence of symptoms, beginning with premotor manifestations, followed by psychiatric and cognitive symptoms in later stages (Braak et al. 2003; Rietdijk et al. 2017).”
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Pedrão, L. F. A. T., Medeiros, P., Leandro, E. C., & Falquetto, B. (2024) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2024.1419108 · Cited by 13
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Gait performance and non-motor symptoms burden during dual-task condition in Parkinson’s disease
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“According to the Braak’s hypothesis, the spread of α-synuclein pathology via the vagal nerve and the dorsal motor nucleus of the vagus in the medulla oblongata and the spread of pathology within the central nervous system from lower brainstem regions, towards the substantia nigra, and eventually the neocortex, lead to…”
BackgroundThe Microbiome–Neurodegeneration Interface: Mechanisms, Evidence, and Future Directions
Böckels, L., Alexa, D., Antal, D. C., Gațcan, C., Alecu, C., Kacani, K., Cretu, R. A., Piseru, E.-A., Bîlcu, R. V., & Cuciureanu, D. I. (2026) · Cells · doi:10.3390/cells15020135 · Cited by 13
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Pesticides and the Gut Microbiota: Implications for Parkinson’s Disease
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“Gastrointestinal dysfunction (Antonini et al., 2012; Rietdijk et al., 2017) is a highly prevalent early disease manifestation which has gained increasing interest in light of the possible pathogenetic role of the enteric nervous system (ENS), a specialized neural and glial network (Warnecke et al.,…”
BackgroundPerdaens, O., & Pesch, V. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312637 · Cited by 12
Acero, N., Ortega, T., Villagrasa, V., Leon, G., Mingarro, D. M., Castillo, E., González‐Rosende, M. E., Borrás, S., Rı́os, J. L., Bosch‐Morell, F., et al. (2023) · Phytotherapy Research · doi:10.1002/ptr.7727 · Cited by 13
“…inhibitors, anticholinergic drugs, neurotrophic factors, etc.), surgical treatments, behavioural therapy, or a combination of different treatment options (Church, 2021; Jankovic & Tan, 2020; Rietdijk, Perez-Pardo, Garssen, van Wezel, & Kraneveld, 2017; Ríos, Onteniente, Picazo, & Montesinos, 2016).”
Tng, T. J. W., Wong, B. W. Y., Sim, E. H. Y., Tan, E., Goh, W. W. B., & Lim, K. (2024) · Translational Medicine Communications · doi:10.1186/s41231-024-00169-9 · Cited by 10
“The gut microbiome is an exciting area to explore for PD given the emerging acceptance of a gut-brain axis in the pathogenesis of sporadic PD [16, 137].”
BackgroundTechaniyom, P., Korsirikoon, C., Rungruang, T., Pakaprot, N., Prombutara, P., Mukda, S., Kettawan, A., & Kettawan, A. (2024) · Food Science & Nutrition · doi:10.1002/fsn3.4265 · Cited by 13
“Studies suggest that α - synuclein pathology propagates from the intestinal colon to higher-order brain regions via the enteric nervous system (Rietdijk et al., 2017 ).”
Jagodic, A., Kršek, A., Schleicher, L. M. S., & Batičić, L. (2025) · Gastrointestinal Disorders · doi:10.3390/gidisord7020028 · Cited by 11
“Consistent with Braak’s hypothesis, an epidemiological study on patients undergoing truncal or selective vagotomy found that those who underwent complete truncal vagotomy had a reduced risk of developing PD, highlighting the vagus nerve’s key role in PD pathogenesis [124,125].”
Wang, H., Wang, Q., Xu, H., Wu, Y., Cheung, S., Xu, Q., Pan, C., Cao, J., Cao, Z., Yang, R., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adp4625 · Cited by 10
Pelzer, E. A., Florin, E., & Schnitzler, A. (2019) · Frontiers in Neural Circuits · doi:10.3389/fncir.2019.00050 · Cited by 12
Donlon, E., Lynch, R., Murphy, O. C., Farrell, M., Noel, J., Keogan, M. T., O'Connell, M., & Lynch, T. (2021) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.13321 · Cited by 10
“Several studies have identified discrepancies in the proposed Braak stages, yet this hypothesis remains important in our understanding of the nature of synucleinopathies.(7) One population based study demonstrated that just over one half of PD patients conformed to the Braak stages.”
BackgroundChowdhury, S., Wu, G., Lu, Z., Kumar, R., & Ledeen, R. W. (2023) · Biomedicines · doi:10.3390/biomedicines11010209 · Cited by 10
Initiation and Transmission of α-Synuclein Pathology in Parkinson’s Disease
Mazurskyy, A., & Howitt, J. A. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02896-0 · Cited by 10
Ahmadi, S., Hasani, A., Khabbaz, A., Poortahmasebi, V., Hosseini, S., Yasdchi, M., Mehdizadehfar, E., Mousavi, Z. B., Hasani, R., Nabizadeh, E., et al. (2024) · Biogerontology · doi:10.1007/s10522-024-10136-4 · Cited by 9
“Increased oxidative stress caused by gut dysbiosis can stimulate intestinal neurons and glial cells and lead to α-Syn folding and accumulation as a result of increased intestinal inflammation (Rietdijk et al. 2017).”
Nguyen, N., Yuan, M., Hu, H., Xiao, Z., Fan, T., Yan, T., Li, Y., Zhou, H.-C. “., Pellois, J., & Wang, Y. (2024) · Advanced Composites and Hybrid Materials · doi:10.1007/s42114-024-01013-2 · Cited by 9
“Braak’s theory proposes a staging system for PD progression, suggesting an ascending pattern of affected brain areas according to different stages [38].”
Blauwendraat, C., Noyce, A. J., Mata, I. F., Screven, L. A., Solle, J. C., Dumanis, S. B., Riley, E. A. U., Periñán, M. T., Okubadejo, N. U., Klein, C., et al. (2025) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2025.07.014 · Cited by 11
“…an infection introduced through the nasal cavity and first affects the peripheral nervous system before progressing to the central nervous sys-tem, 9 has been influential in that cross-sectional pathological data have been assembled into different stages from the brainstem to the cortex, with…”
Yang, L., Fan, S., Sun, L., Han, J., Wang, M., & Yu, T. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1643305 · Cited by 9
“Some researchers have proposed that the pathological mechanisms of PD may originate in the gut, with α -Syn pathology spreading to the brain in a bottom-up manner (39).”
Microbiota and probiotics: chances and challenges – a symposium report
Ruxton, C. H. S., Kajita, C., Rocca, P., & Pot, B. (2023) · Gut Microbiome · doi:10.1017/gmb.2023.4 · Cited by 10
“, 2020): either a direct central nervous system phenotype, or an indirect intestinal phenotype where leaky gut and endotoxemia lead tomucosal inflammation, microbiome changes and, eventually, α-synuclein accumulation (Rietdijk et al., 2017; Scheperjans et al., 2018).”
BackgroundNutrition and Gut–Brain Pathways Impacting the Onset of Parkinson’s Disease
Terenzi, D., Muth, A.-K., & Park, S. Q. (2022) · Nutrients · doi:10.3390/nu14142781 · Cited by 11
Li, P., Wezel, R. J. A. V., He, F., Zhao, Y., & Wang, Y. (2023) · Frontiers in Neuroinformatics · doi:10.3389/fninf.2023.1135300 · Cited by 9
“The Braak stages show that some prodromal nonmotor symptoms (NMS), such as constipation and sleep disorder, can occur before Lewy bodies (LB) appear in the substantia nigra of the brain stem (Rietdijk et al., 2017).”
BackgroundHalbherr, S., Lerch, S., Bellwald, S., Polakova, P., Bannert, B., Roumet, M., Charles, R., Walter, M. A., Bernasconi, C., Halbherr, V. L., et al. (2025) · PLoS Medicine · doi:10.1371/journal.pmed.1004472 · Cited by 8
“Histologically, PD is characterized by alpha-synuclein containing neuronal inclusions called Lewy bodies that propagate through the brain resulting in impaired function of numerous systems [3,4].”
Umamahesan, C., Pilcicka, A., Yick, J., Baker, K., Smith, M. H., Taylor, D. M., Ma, Y., Mullish, B. H., Marchesi, J. R., Gilbert, S., et al. (2025) · Biochemical Journal · doi:10.1042/bcj20240621 · Cited by 8
“Here, we confine ourselves to what is driving the process, rather than the spread as described by the pattern of neuronal loss in PD and staged distribution in subtypes [5–8].”
The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms
Aranda-Abreu, G. E., Rojas-Durán, F., Hernández‐Aguilar, M. E., Herrera‐Covarrubias, D., Tlapa-Monge, L. R., & Mestizo-Gutiérrez, S. L. (2026) · NeuroSci · doi:10.3390/neurosci7010007 · Cited by 11
“This pattern aligns with the non-motor symptoms of PD—such as anosmia and constipation—that precede dopaminergic impairment [149].”
Matarazzo, M., Borghammer, P., Elsayed, I., Goldman, J. G., Huang, Y., Lohmann, K., Svenningsson, P., Kalia, L. V., Berg, D., & Kordower, J. H. (2026) · Movement Disorders · doi:10.1002/mds.70324 · Cited by 11
Keyser, K. D., Letter, M. D., Santens, P., Talsma, D., Botteldooren, D. B., & Bockstael, A. (2021) · Journal of Neural Transmission · doi:10.1007/s00702-021-02305-3 · Cited by 8
Food Contamination: An Unexplored Possible Link between Dietary Habits and Parkinson’s Disease
Caioni, G., Cimini, A., & Benedetti, E. (2022) · Nutrients · doi:10.3390/nu14071467 · Cited by 9
Alberts, T., Antipova, V., Holzmann, C., Hawlitschka, A., Schmitt, O., Kurth, J., Stenzel, J., Lindner, T., Krause, B. J., Wree, A., et al. (2022) · Toxins · doi:10.3390/toxins14020094 · Cited by 8
Cocchi, M., Mondo, E., Romeo, M., & Traina, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063253 · Cited by 9
Clinical Evaluation of Sleep Disorders in Parkinson’s Disease
Lauretani, F., Testa, C., Salvi, M., Zucchini, I., Giallauria, F., & Maggio, M. G. (2023) · Brain Sciences · doi:10.3390/brainsci13040609 · Cited by 8
The intestinal luminal sources of α-synuclein: a gastroenterologist perspective
Lerner, A. (2021) · Nutrition Reviews · doi:10.1093/nutrit/nuab024 · Cited by 9
Changes in the gut microbiome associated with infliximab in patients with bipolar disorder
Bharwani, A., Szamosi, J. C., Taylor, V. H., Lee, Y. L., Bala, A., Mansur, R. B., Subramaniapillai, M., Surette, M. G., & McIntyre, R. S. (2021) · Brain and Behavior · doi:10.1002/brb3.2259 · Cited by 8
“…diseases was also recently highlighted in studies showing the presence of Lewy bodies in the enteric nervous system in alpha synuclein knock-in transgenic model and early-stage Parkinson’s disease, preceding central nervous system manifestations (Rietdijk et al., 2017; Sampson et al., 2016).”
BackgroundDigital Eye-Movement Outcomes (DEMOs) as Biomarkers for Neurological Conditions: A Narrative Review
Graham, L., Vitório, R., Walker, R. W., Barry, G., Godfrey, A., Morris, R., & Stuart, S. (2024) · Big Data and Cognitive Computing · doi:10.3390/bdcc8120198 · Cited by 11
Leem, Y., Park, J., Park, J., Kim, D., Park, J.-M., Kim, S., Kang, J. L., & Kim, H.-S. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117871 · Cited by 7
Adaptive immunity in the pathogenesis and treatments of Parkinson’s disease
Du, X., Akter, S., Oludipe, D. B., Sil, S., Zhang, C., Gendelman, H. E., & Mosley, R. L. (2025) · NeuroImmune Pharmacology and Therapeutics · doi:10.1515/nipt-2025-0008 · Cited by 8
“The “gut-first” hypothesis, proposed by Braak and colleagues, suggests that α -syn aggregates may originate in the enteric nervous system (ENS) and propagate to the CNS via the vagus nerve [60–62].”
Fan, Y., Xiao, B., Zhou, H., Liu, Z., Wang, L., Jin, W., Yin, Y., & Mao, X. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.108031 · Cited by 7
Siu, A. C. W., Paudel, K. R., Singh, G., Gupta, G. K., Singh, S. K., Chellappan, D. K., Rubis, G. D., Pathak, S., Oliver, B. G. G., Dua, K., et al. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05428-3 · Cited by 11
“These findings align with the Braak hypothesis, which suggests that PD pathology originates in the gut and spreads to the brain through the enteric nervous system or vagus nerve in a prion-like manner [199].”
Metadata
- Authors
- Rietdijk, C. D., Perez-Pardo, P., Garssen, J., van Wezel, R. J. A., & Kraneveld, A. D.
- Affiliations
- Utrecht University (NL)
- Corresponding author
- Kraneveld, Aletta D.
- Venue
- Frontiers in Neurology
- Publisher
- Frontiers Media SA
- Published
- 2017-02-13
- Volume
- 8
- Pages
- 37-37
- ISSN
- 1664-2295 (ISSN-L)
- PMC
- PMC5304413
- OpenAlex
- W2588841770
- Cited by
- 395
- References
- 153
- Citations by year
- 2026: 41 · 2025: 56 · 2024: 65 · 2023: 43 · 2022: 50 · 2021: 50 · 2020: 30 · 2019: 32 · 2018: 18 · 2017: 10
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Twente Research Information (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, Braak hypothesis, Lewy body pathology, sporadic Parkinson's disease, gut-brain axis, alpha-synuclein toxicity, Lewy bodies, neurodegeneration, early-onset Parkinson's disease
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