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RAB10: an Alzheimer’s disease resilience locus and potential drug target
Open accessAbstract
Abstract: Alzheimer’s disease (AD) is mainly a late-onset neurodegenerative disorder. Substantial efforts have been made to solve the complex genetic architecture of AD as a means to identify therapeutic targets. Unfortunately, to date, no disease-altering therapeutics have been developed. As therapeutics are likely to be most effective in the early stages of disease (ie, before the onset of symptoms), a recent focus of AD research has been the identification of protective factors that prevent disease. One example is the discovery of a rare variant in the 3'-UTR of RAB10 that is protective for AD. Here, we review the possible genetic, molecular, and functional role of RAB10 in AD and potential therapeutic approaches to target RAB10. Keywords: Alzheimer’s disease, RAB10, retromer, APP, resilience, GTPase
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes genetic, molecular, and functional evidence that RAB10, a small GTPase regulating vesicular trafficking, contributes to Alzheimer's disease pathogenesis, and that a rare protective variant (rs142787485) in its 3′-UTR plus reduced Rab10 expression lowering Aβ42 make it a candidate resilience locus and drug target. The authors argue that inhibiting RAB10 via small molecules, antibodies, or antisense oligonucleotides is a plausible therapeutic avenue, though blood–brain barrier delivery and specificity remain obstacles.
Key findings
- A rare variant (rs142787485) in the 3′-UTR of RAB10 was identified in whole-genome sequencing of elderly APOE ε4 carriers who escaped AD within high-risk pedigrees, conferring resilience to AD (Ridge et al).
- Silencing Rab10 expression in a cell model of APP metabolism significantly decreased Aβ42 and the Aβ42/40 ratio; an RNAi screen of RABs showed RAB10 silencing reduces Aβ without altering sAPPβ levels.
- Independent of the SNP, individuals with a neuropathologic AD diagnosis had significantly higher RAB10 levels than neuropathology-free controls, though total RAB10 staining did not differ between AD and control brains in a separate study.
- pRAB10-Thr73 (phosphorylated by LRRK2) colocalized with neurofibrillary tangles, granulovascular degeneration, neuropil threads, and dystrophic neurons, and dystrophic neurons near amyloid plaques stained positive for pRAB10-Thr73 while plaques themselves were negative; the LRRK2–RAB10 pathway also causes Aβ overproduction.
Methods
Narrative review; no primary data collection or new analysis. The authors synthesize prior genetic (linkage, whole-genome sequencing, GWAS), molecular/cell-model, and neuropathological literature on RAB10, APP processing, retromer function, and candidate therapeutic modalities (small molecules, antibodies, antisense oligonucleotides). No systematic search strategy, inclusion criteria, or meta-analysis is described.
Limitations
The paper states no formal limitations section. Evident from the text: it is a non-systematic narrative review without a described search protocol; the central genetic evidence rests largely on a single prior study (Ridge et al) and the protective variant's mechanism is not established; the authors note it "remains unclear whether this represents excess activation or aberrant function of RAB10"; and the therapeutic proposals are speculative, with the authors acknowledging challenges of specificity, side-effect balance, and blood–brain barrier delivery (molecules generally need high lipid solubility and <400 Da to diffuse across the BBB, antibodies do not cross at therapeutic concentrations, and antisense oligonucleotides require intrathecal delivery).
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 42 cited sources checked · 0 supported · 0 flagged
- Premisecitation
In Caenorhabditis elegans, RAB10 is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor recycling in postsynaptic membranes.
“In Caenorhabditis elegans, RAB10 is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor recycling in postsynaptic membranes.49”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Glodowski DR Chen CCH Schaefer H Grant BD Rongo C RAB-10 regulates glutamate receptor recycling in a cholesterol-dependent endocytosis pathway Mol Biol Cell 2007 18 11 4387 4396 17761527 PMC2043545
- Interpretationreasoning
Genetic and molecular evidence supports a role for RAB10 in Alzheimer's disease pathogenesis.
“Thus, genetic and molecular evidences support a role for RAB10 in AD pathogenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: Higher RAB10 levels in Alzheimer’s disease brains contribute causally to pathogenesis rather than being a consequence of disease.
- Interpretationcitation
pRAB10-Thr73 is associated with Alzheimer's disease pathology.
“Thus, while pRAB10-Thr73 is associated with AD pathology, it remains unclear whether this represents excess activation or aberrant function of RAB10.”
Quote in the paperSubstantial claim - Premisecitation
Total RAB10 staining does not differ between AD and control brains.
“Total RAB10 staining, however, did not differ between AD and control brains.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
- Premisecitation
A rare variant rs142787485 in the 3′-UTR of RAB10 confers resilience to Alzheimer's disease.
“Ridge et al identified a rare variant (rs142787485) in the 3′-UTR of RAB10 that confers resilience to AD.10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Ridge PG Karch CM Hsu S Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience Genome Med 2017 9 1 100 29183403 PMC5706401
- Premisecitation
Colocalization of pRAB10-Thr73 and phosphorylated tau in AD brain structures is not complete; some neuropil threads or dystrophic neurons contain only phosphorylated tau or only pRAB10-Thr73.
“However, this colocalization of pRAB10-Thr73 and phosphorylated tau was not complete, with some instances showing neuropil threads or dystrophic neurons containing only phosphorylated tau or only pRAB10-Thr73.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
- Premisecitation
RAB10 is activated by phosphorylation at Thr73, mediated by LRRK2.
“RAB10 is activated by phosphorylation at Thr73, which is mediated by LRRK2, a protein kinase associated with Parkinson’s disease.38,39”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
- cites [39] Eguchi T Kuwahara T Sakurai M LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis Proc Natl Acad Sci U S A 2018 115 39 E9115 E9124 30209220 PMC6166828
- Premisecitation
RAB10 is involved in transport of proteins from the early endosome to the trans-Golgi network.
“RAB10 is involved in transport of proteins from the early endosome to the trans-Golgi network (TGN), where it may also function in the retromer pathway.58”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] Babbey CM Ahktar N Wang E Chen CCH Grant BD Dunn KW Rab10 regulates membrane transport through early endosomes of polarized Madin-Darby canine kidney cells Mol Biol Cell 2006 17 7 3156 3175 16641372 PMC1483048
- Premisecitation
In a cell model of APP metabolism, silencing Rab10 expression significantly decreases Aβ42 and the Aβ42/40 ratio.
“In a cell model of APP metabolism, silencing of Rab10 expression leads to a significant decrease in Aβ42 and the Aβ42/40 ratio, consistent with prior reports.10,36”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Ridge PG Karch CM Hsu S Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience Genome Med 2017 9 1 100 29183403 PMC5706401
- cites [36] Udayar V Buggia-Prévot V Guerreiro RL A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production Cell Rep 2013 5 6 1536 1551 24373285 PMC4004174
- Premisecitation
pRAB10-Thr73 colocalizes with neurofibrillary tangles, granulovascular degeneration, neuropil threads, and dystrophic neurons in AD brains.
“pRAB10-Thr73 was observed to colocalize with neurofibrillary tangles in AD brains as well as with granulovascular degeneration, neuropil threads, and dystrophic neurons.38”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
- Premisecitation
Individuals with a neuropathologic diagnosis of AD have significantly higher levels of RAB10 than neuropathology-free controls, independent of the RAB10 SNP.
“Interestingly, independent of the RAB10 SNP, individuals with a neuropathologic diagnosis of AD exhibited significantly higher levels of RAB10 compared to neuropathology-free controls.10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Ridge PG Karch CM Hsu S Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience Genome Med 2017 9 1 100 29183403 PMC5706401
- Premisecitation
Retromer dysfunction alters Aβ40 secretion, resulting in an increased Aβ42/40 ratio.
“In addition, the retromer also appears to have a differential effect on Aβ isoforms, with evidence that retromer dysfunction alters Aβ40 secretion, which results in increasing the Aβ42/40 ratio.66”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Sullivan CP Jay AG Stack EC Retromer disruption promotes amyloidogenic APP processing Neurobiol Dis 2011 43 2 338 345 21515373 PMC3114192
- Premisecitation
Small GTPases similar to RAB10 have been successfully targeted using small molecules.
“Small GTPases similar to RAB10 have been successfully targeted using small molecules in the past.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [75] Gibbs JB Oliff A Kohl NE Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic Cell 1994 77 2 175 178 8168127
- Premisecitation
Retromer complex dysfunction promotes APP accumulation in neurons and Aβ production.
“Retromer complex dysfunction promotes APP accumulation in neurons and Aβ production.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Sullivan CP Jay AG Stack EC Retromer disruption promotes amyloidogenic APP processing Neurobiol Dis 2011 43 2 338 345 21515373 PMC3114192
- Premisecitation
The retromer complex and its receptors can transport APP and BACE1 from endosomes to the trans-Golgi network, ultimately regulating production of Aβ.
“The retromer complex and its receptors can transport APP and BACE1 from endosomes to the TGN, ultimately regulating production of Aβ.60”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Zhang QY Tan MS Yu JT Tan L The role of retromer in Alzheimer’s disease Mol Neurobiol 2016 53 6 4201 4209 26215837
- Premisecitation
In vitro reduction of Rab10/RAB10 expression using shRNA and RNAi has been successful.
“As discussed previously, in vitro reduction of Rab10/RAB10 expression using shRNA and RNAi has been successful.36”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Udayar V Buggia-Prévot V Guerreiro RL A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production Cell Rep 2013 5 6 1536 1551 24373285 PMC4004174
- Premisecitation
A molecule with high lipid solubility and molecular mass <400 Da generally can diffuse across the blood-brain barrier.
“A molecule with high lipid solubility and molecular mass <400 Da generally can diffuse across the BBB.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] Pardridge WM The blood-brain barrier: bottleneck in brain drug development NeuroRx 2005 2 1 3 14 15717053 PMC539316
- Premisecitation
Antisense oligonucleotides do not readily cross the blood-brain barrier.
“Antisense oligonucleotides do not readily cross the BBB.73”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [73] Phillips JA Craig SJ Bayley D Christian RA Geary R Nicklin PL Pharmacokinetics, metabolism, and elimination of a 20-mer phosphoro-thioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration Biochem Pharmacol 1997 54 6 657 668 9310342
- Premisecitation
Antibodies do not cross the blood-brain barrier at therapeutic concentrations.
“Antibodies do not cross the BBB at therapeutic concentrations.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [71] Atwal JK Chen Y Chiu C A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo Sci Transl Med 2011 3 84 84ra43 21613622
- cites [72] Zhang Yj Y Kenrick YM Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target Sci Transl Med 2011 384 84 ra44 21613623
- Premisecitation
An RNAi screen of RABs that modify APP processing revealed that silencing RAB10 reduces Aβ without altering sAPPβ levels.
“An RNAi screen of RABs that modify APP processing revealed that the silencing of RAB10 reduces Aβ without altering sAPPβ levels.36”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Udayar V Buggia-Prévot V Guerreiro RL A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production Cell Rep 2013 5 6 1536 1551 24373285 PMC4004174
- Premisecitation
Stabilization of the retromer in human-induced pluripotent stem cell-derived neurons with the pharmacologic chaperone R33 significantly reduces Tau phosphorylation in a manner correlated with, but ultimately independent of, Aβ production.
“Stabilization of the retromer in human-induced pluripotent stem cell-derived neurons through the use of the pharmacologic chaperone R33 has been shown to significantly reduce the phosphorylation of Tau in a manner that correlated with, but ultimately independent of, Aβ production.68”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] Young JE Fong LK Frankowski H Petsko GA Small SA Goldstein LSB Stabilizing the retromer complex in a human stem cell model of Alzheimer’s disease reduces TAU phosphorylation independently of amyloid precursor protein Stem Cell Reports 2018 10 3 1046 1058 29503090 PMC5919412
- Interpretationreasoning
Inhibition of RAB10 is a potential therapeutic avenue for Alzheimer's disease.
“The function of RAB10 in intracellular trafficking and evidence that a reduction of Rab10 results in a reduction of the Aβ42/40 ratio makes inhibition of RAB10 a potential therapeutic avenue.”
- Also stated in: § Conclusion · plain
“Here we have outlined the potential role of RAB10 in AD pathology and the case for RAB10 inhibition as a therapeutic intervention for AD.”
Quote in the paperSubstantial claim- Rests on an assumption: The protective effect of the RAB10 3′-UTR variant is mediated by reduced RAB10 expression or activity.
- Rests on an assumption: Findings from cell and animal models of RAB10/Aβ processing generalize to human Alzheimer’s disease.
- Rests on an assumption: RAB10 can be therapeutically inhibited in humans without unacceptable toxicity.
- Also stated in: § Conclusion · plain
- Premisecitation
In mouse models, reduction of a single retromer component Vps26 is sufficient to increase soluble Aβ and APP.
“In mouse models, reduction of a single component within the retromer complex, Vps26, is sufficient to increase soluble Aβ and APP.67”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Muhammad A Flores I Zhang H Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and a accumulation Proc Natl Acad Sci U S A 2008 105 20 7327 7332 18480253 PMC2386077
- Premisecitation
Intrathecal bolus injection is an effective method for ensuring distribution of antisense oligonucleotides in neurons and glial cells in the brain.
“However, at present, intrathecal bolus injection is an effective method for ensuring distribution in neurons and glial cells in the brain.74”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] Rigo F Chun SJ Norris DA Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates J Pharmacol Exp Ther 2014 350 1 46 55 24784568 PMC4056267
- Premisecitation
The LRRK2-RAB10 signaling pathway causes overproduction of Aβ.
“The LRRK2-RAB10 signaling pathway also causes an overproduction of Aβ.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
- It may state two separate claims as one. 7
- Probably not a substantial claim. 7
It may state two separate claims as one.
PremisecitationDuring neuronal development, RAB10 associates with plasmalemmal precursor vesicles linked to kinesin 1 via JIP1, and this complex mediates anterograde transport of RAB10-positive vesicles to axonal tips, promoting axonal growth.
“During neuronal development, RAB10 associates with plasmalemmal precursor vesicles, which are linked to kinesin 1 via c-Jun N-terminal protein kinase-interacting protein 1.48 Together this complex mediates anterograde transport of RAB10-positive vesicles to axonal tips, promoting axonal growth.48”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Deng CY Lei WL Xu XH Ju XC Liu Y Luo ZG JIP1 mediates anterograde transport of Rab10 cargos during neuronal polarization J Neurosci 2014 34 5 1710 1723 24478353 PMC8186508
It may state two separate claims as one.
PremisecitationRab10 is essential for development; mice are embryonic lethal when both alleles are deleted.
“Rab10 plays essential functional roles in development: mice are embryonic lethal when both alleles are deleted.42”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Lv P Sheng Y Zhao Z Targeted disruption of Rab10 causes early embryonic lethality Protein Cell 2015 6 6 463 467 25860786 PMC4444807
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRAB10 plays a role in maintenance and regulation of endoplasmic reticulum morphology.
“In addition, RAB10 plays a role in maintenance and regulation of endoplasmic reticulum (ER) morphology.43–45”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [43] English AR Voeltz GK Rab10 GTPase regulates ER dynamics and morphology Nat Cell Biol 2013 15 2 169 178 23263280 PMC3582403
- cites [44] Chang J Blackstone C Rab10 joins the ER social network Nat Cell Biol 2013 15 2 135 136 23377026
- cites [45] Schuldt A Membrane dynamics: ER trailblazing by RAB10 Nat Rev Mol Cell Biol 2013 14 2 63 23271010
It may state two separate claims as one.
PremisecitationDystrophic neurons near amyloid plaques stain positive for pRAB10-Thr73, while amyloid plaques themselves are negative for pRAB10.
“Interestingly, dystrophic neurons near amyloid plaques stained positive for pRAB10-Thr73, while the amyloid plaques themselves were negative for pRAB10.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Yan T Wang L Gao J Rab10 phosphorylation is a prominent pathological feature in Alzheimer’s disease J Alzheimers Dis 2018 63 1 157 165 29562525 PMC6008156
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationRAB10 function is linked to neuronal morphology and polarization, playing a critical role in axonal development and dendrite arborization.
“RAB10 function has also been linked to neuronal morphology and polarization, playing a critical role in axonal development and dendrite arborization.46,47”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Liu Y Xh X Chen Q Myosin Vb controls biogenesis of post-Golgi Rab10 carriers during axon development Nat Commun 2005 2013 4 23770993
- cites [47] Zou W Yadav S Devault L Jan YN Sherwood DR RAB-10-dependent membrane transport is required for dendrite arborization PLoS Genet 2015 11 9 e1005484 26394140 PMC4578882
Probably not a substantial claim.
PremisecitationThe retromer complex regulates transport of protein cargo from endosomes to the trans-Golgi network by the retrograde pathway or to the cell surface through the recycling pathway.
“The retromer complex regulates transport of protein cargo from endosomes to the TGN by the retrograde pathway or to the cell surface through the recycling pathway.60”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Zhang QY Tan MS Yu JT Tan L The role of retromer in Alzheimer’s disease Mol Neurobiol 2016 53 6 4201 4209 26215837
It may state two separate claims as one.
PremisecitationAPP is retrieved from the cell surface and trafficked to early endosomes where it is initially cleaved by BACE1 to generate β-CTF; β-CTF is then trafficked via retromer-dependent transport to the trans-Golgi network, facilitating γ-secretase cleavage to produce Aβ40.
“APP is thought to be retrieved from the cell surface and trafficked to the early endosomes where it is initially cleaved by β-site APP-cleaving enzyme 1 (BACE1) to generate a C-terminal fragment (β-CTF).61,62 The β-CTF fragments are then trafficked via retromer-dependent transport to the TGN, which facilitates further cleavage by γ-secretase to produce Aβ40.63”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [61] Huse JT Pijak DS Leslie GJ Lee VM Doms RW Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer’s disease beta-secretase J Biol Chem 2000 275 43 33729 33737 10924510
- cites [62] Kinoshita A Fukumoto H Shah T Whelan CM Irizarry MC Hyman BT Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes J Cell Sci 2003 116 16 3339 3346 12829747
- cites [63] Choy RWY Cheng Z Schekman R Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network Proc Natl Acad Sci U S A 2012 109 30 E2077 E2082 22711829 PMC3409748
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe development of anti-Aβ therapeutics remains the primary approach to treating Alzheimer's disease.
“The development of anti-Aβ therapeutics remains the primary approach to treating AD based on our current understanding of the earliest features of this disease.69”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 2002 297 5580 353 356 12130773
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe amyloid hypothesis proposes that accumulation of Aβ triggers the cascade of events that lead to Alzheimer's disease.
“The amyloid hypothesis, which proposes that the accumulation of Aβ triggers the cascade of events that lead to AD, has been the focus of AD therapeutic development for decades.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 2002 297 5580 353 356 12130773
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAPOE ε2 confers resilience to Alzheimer's disease, while the ε3 allele is considered neutral risk.
“Conversely, APOE ε2 confers resilience to AD, while the ε3 allele is considered neutral risk.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Corder EH Saunders AM Strittmatter WJ Gene dose of apo-lipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 5123 921 923 8346443
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAPOE ε2 and APP-A673T are among the variants with the strongest protective effect against Alzheimer's disease.
“Those with the strongest protective effect include APOE ε2 and APP-A673T.34,35”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] Corder EH Saunders AM Risch NJ Protective effect of apoli-poprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 2 180 184 7920638
- cites [35] Jonsson T Atwal JK Steinberg S A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline Nature 2012 488 7409 96 99 22801501
The paper relies on this without support.
Therapeutics are likely to be most effective in the early stages of Alzheimer’s disease before symptom onset.
“As therapeutics are likely to be most effective in the early stages of disease (ie, before the onset of symptoms), a recent focus of AD research has been the identification of protective factors that prevent disease.”
The paper relies on this without support.
The protective effect of the RAB10 3′-UTR variant is mediated by reduced RAB10 expression or activity.
“Ridge et al identified a rare variant (rs142787485) in the 3′-UTR of RAB10 that confers resilience to AD.10 In a cell model of APP metabolism, silencing of Rab10 expression leads to a significant decrease in Aβ42 and the Aβ42/40 ratio, consistent with prior reports.10,36”
The paper relies on this without support.
Higher RAB10 levels in Alzheimer’s disease brains contribute causally to pathogenesis rather than being a consequence of disease.
“Interestingly, independent of the RAB10 SNP, individuals with a neuropathologic diagnosis of AD exhibited significantly higher levels of RAB10 compared to neuropathology-free controls.10 Thus, genetic and molecular evidences support a role for RAB10 in AD pathogenesis.”
The paper relies on this without support.
Findings from cell and animal models of RAB10/Aβ processing generalize to human Alzheimer’s disease.
“In a cell model of APP metabolism, silencing of Rab10 expression leads to a significant decrease in Aβ42 and the Aβ42/40 ratio, consistent with prior reports.10,36”
The paper relies on this without support.
RAB10 can be therapeutically inhibited in humans without unacceptable toxicity.
“While small GTPases like RAB10 present significant challenges for therapeutic development, recent work in small molecules, antibodies, and antisense oligonucleotides suggests that success can be achieved.”
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Metadata
- Authors
- Tavana, J., Rosene, M., Jensen, N., Ridge, P. G., Kauwe, J. S. K., & Karch, C. M.
- Affiliations
- Brigham Young University (US)
- Washington University in St. Louis (US)
- Corresponding author
- Karch, Celeste M.
- Venue
- Clinical Interventions in Aging
- Publisher
- Informa UK Limited
- Published
- 2018-12
- Volume
- Volume 14
- Pages
- 73-79
- ISSN
- 1176-9092 (ISSN-L)
- 1178-1998
- PMC
- PMC6312396
- OpenAlex
- W2907234207
- Semantic Scholar
- 94cc3d552e2dc73dcc41517a2933f08376f90b93
- Cited by
- 62
- References
- 84
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 1
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Clinical Interventions in Aging (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Aging (RF1AG054052, K01AG046374, U01AG052411, R01AG062359)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Alzheimer's disease, Rab10, retromer complex, APP, genetic resilience, protective genetic variants, 3' untranslated region, GTPase, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Humans, 3' Untranslated Regions, rab GTP-Binding Proteins, Drug Discovery, Protective Factors
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