Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 607

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

Alzheimer’s disease hypothesis and related therapies

Open access
Du, Xiaoguang, Wang, Xinyi, Geng, Meiyu·2018·Translational Neurodegeneration
DOI 10.1186/s40035-018-0107-y
Open this paper in CoChat — free account

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in the extracellular spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, etc., and many anti-AD drugs based on these hypotheses have been developed. In this review, we will discuss the existing and emerging hypothesis and related therapies.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s40035-018-0107-y

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 37 references

Research works printed but not linked: 78

  1. Ali G-C, Guerchet M, Wu Y-T, Prince M, Prina M. Chapter 2: The global prevalence of dementia. In: Prince M, Guerchet M, Ali G-C, Wu Y-T, Prina M, editors. The Global Impact of Dementia. An analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International (ADI); 2015. p. 10–29.
  2. Vassar R, Citron M. Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron. 2000;27(3):419–22. · DOI · Paper page
  3. van Es JH, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435(7044):959–63. · DOI · Paper page
  4. Olry A, et al. Generation and characterization of mutant cell lines defective in gamma-secretase processing of notch and amyloid precursor protein. J Biol Chem. 2005;280(31):28564–71. · DOI
  5. Tarassishin L, et al. Processing of notch and amyloid precursor protein by gamma-secretase is spatially distinct. Proc Natl Acad Sci U S A. 2004;101(49):17050–5. · DOI
  6. Sastre M, et al. Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of notch. EMBO Rep. 2001;2(9):835–41. · DOI · Paper page
  7. Klaver DW, et al. Is BACE1 a suitable therapeutic target for the treatment of Alzheimer’s disease? Current strategies and future directions. Biol Chem. 2010;391(8):849–59. · DOI
  8. Abramov E, et al. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009;12(12):1567–76. · DOI · Paper page
  9. Laskowitz DT, Kolls BJ. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2010;74(24):2026. author reply 2026-7 · DOI
  10. Bouter Y, et al. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against Ntruncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol. 2015;130(5):713–29. · DOI
  11. Gandy S, Sano M. Alzheimer disease: Solanezumab-prospects for meaningful interventions in AD? Nat Rev Neurol. 2015;11(12):669–70. · DOI
  12. Landen JW, et al. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol. 2013;36(1):14–23. · DOI
  13. Burstein AH, et al. Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease. Clin Neuropharmacol. 2013;36(1):8–13. · DOI
  14. La Porte SL, et al. Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. J Mol Biol. 2012;421(4–5):525–36. · DOI
  15. Carlson C, et al. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimers Dement (Amst). 2016;2:75–85. · DOI
  16. Greenberg SM, et al. A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Alzheimer Dis Assoc Disord. 2006;20(4):269–74. · DOI
  17. Gervais F, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28(4):537–47. · DOI · Paper page
  18. Nie Q, Du XG, Geng MY. Small molecule inhibitors of amyloid beta peptide aggregation as a potential therapeutic strategy for Alzheimer's disease. Acta Pharmacol Sin. 2011;32(5):545–51. · DOI
  19. Patel KR. Biogen's aducanumab raises hope that Alzheimer's can be treated at its source. Manag Care. 2015;24(6):19.
  20. Karran E. Recent trial shows that solanezumab has disease modifying effects. BMJ. 2015;351:h4528. · doi:10.1136/bmj.h4528
  21. Siemers ER, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016;12(2):110–20. · DOI · Paper page
  22. Barrera-Ocampo A, Lopera F. Amyloid-beta immunotherapy: the hope for Alzheimer disease? Colomb Med (Cali). 2016;47(4):203–12. · DOI
  23. Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci. 2015;18(6):800–6. · DOI · Paper page
  24. Wang J, et al. A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain. Nat Rev Neurol. 2017;13(10):612–23. · DOI · Paper page
  25. Morris M, et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci. 2015;18(8):1183–9. · DOI · Paper page
  26. Novak P, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–34. · DOI · Paper page
  27. Bliss TV, Collingridge GL, Morris RG. Synaptic plasticity in health and disease: introduction and overview. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1633):20130129. · DOI
  28. Chen J, et al. Inhibition of AGEs/RAGE/rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-kappaB pathway. J Neuroimmunol. 2017;305:108–14. · DOI
  29. Hirbec H E, Noristani HN, Perrin FE. Microglia Responses in Acute and Chronic Neurological Diseases: What Microglia-Specific Transcriptomic Studies Taught (and did Not Teach) Us. Front Aging Neurosci. 2017;9:227. · DOI
  30. Saresella M, et al. A potential role for the PD1/PD-L1 pathway in the neuroinflammation of Alzheimer's disease. Neurobiol Aging. 2012;33(3):624 e11–22. · DOI
  31. Saresella M, et al. PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2010;21(3):927–38. · DOI
  32. Jevtic S, et al. The role of the immune system in Alzheimer disease: etiology and treatment. Ageing Res Rev. 2017;40:84–94. · DOI · Paper page
  33. McGeer PL, McGeer EG. Targeting microglia for the treatment of Alzheimer's disease. Expert Opin Ther Targets. 2015;19(4):497–506. · DOI
  34. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23(9):1018–27. · DOI · Paper page
  35. Hasselmo ME, Anderson BP, Bower JM. Cholinergic modulation of cortical associative memory function. J Neurophysiol. 1992;67(5):1230–46. · DOI · Paper page
  36. Fine A, et al. Learning impairments following injection of a selective cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of Meynert in monkeys. Neuroscience. 1997;81(2):331–43. · DOI
  37. Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1–2):28–46. · DOI · Paper page
  38. Miranda MI, Bermudez-Rattoni F. Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories. Proc Natl Acad Sci U S A. 1999;96(11):6478–82. · DOI
  39. Haam J, Yakel JL. Cholinergic modulation of the hippocampal region and memory function. J Neurochem. 2017;142(Suppl 2):111–21. · DOI · Paper page
  40. Brinkman SD, Gershon S. Measurement of cholinergic drug effects on memory in Alzheimer's disease. Neurobiol Aging. 1983;4(2):139–45. · DOI
  41. Summers WK, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med. 1986;315(20):1241–5. · DOI · Paper page
  42. Summers WK, et al. Use of THA in treatment of Alzheimer-like dementia: pilot study in twelve patients. Biol Psychiatry. 1981;16(2):145–53.
  43. Sultana R, Butterfield DA. Redox proteomics studies of in vivo amyloid beta-peptide animal models of Alzheimer's disease: insight into the role of oxidative stress. Proteomics Clin Appl. 2008;2(5):685–96. · DOI
  44. Butterfield DA, et al. Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med. 2007;43(5):658–77. · DOI · Paper page
  45. Mohmmad Abdul H, et al. Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease. J Neurochem. 2006;96(5):1322–35. · DOI
  46. Gibson GL, Allsop D, Austen BM. Induction of cellular oxidative stress by the beta-amyloid peptide involved in Alzheimer's disease. Protein Pept Lett. 2004;11(3):257–70. · DOI
  47. Butterfield DA, et al. Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists. J Alzheimers Dis. 2002;4(3):193–201. · DOI
  48. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med. 2002;32(11):1050–60. · DOI · Paper page
  49. Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer's disease: why did antioxidant therapy fail? Oxidative Med Cell Longev. 2014;2014:427318. · DOI · Paper page
  50. Teixeira J, et al. Alzheimer's disease and antioxidant therapy: how long how far? Curr Med Chem. 2013;20(24):2939–52. · DOI
  51. Caldwell CC, Yao J, Brinton RD. Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities. Neurotherapeutics. 2015;12(1):66–80. · DOI
  52. Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017;95(4):943–72. · DOI · Paper page
  53. Nasrallah I, Dubroff J. An overview of PET neuroimaging. Semin Nucl Med. 2013;43(6):449–61. · DOI
  54. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78. · DOI · Paper page
  55. Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89. · DOI · Paper page
  56. Erickson MA, Dohi K, Banks WA. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation. 2012;19(2):121–30. · DOI · Paper page
  57. Banks WA. The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Behav Immun. 2015;44:1–8. · DOI · Paper page
  58. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–12. · DOI · Paper page
  59. Bhattacharjee S, Lukiw WJ. Alzheimer's disease and the microbiome. Front Cell Neurosci. 2013;7:153. · DOI
  60. Tomkovich S, Jobin C. Microbiota and host immune responses: a love-hate relationship. Immunology. 2016;147(1):1–10. · DOI
  61. Agace WW, McCoy KD. Regionalized development and maintenance of the intestinal adaptive immune landscape. Immunity. 2017;46(4):532–48. · DOI
  62. Erny D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–77. · DOI · Paper page
  63. Ivanov II, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. · DOI · Paper page
  64. O'Mahony SM, et al. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015;277:32–48. · DOI · Paper page
  65. Praveen V, Praveen S. Microbiome-gut-brain Axis: a pathway for improving brainstem serotonin homeostasis and successful autoresuscitation in SIDS-A novel hypothesis. Front Pediatr. 2016;4:136.
  66. Jiang XG, et al. Research progress in anti-inflammation of vagus nerve and neurotransmitter ach. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2003;15(1):59–61.
  67. Das UN. Vagus nerve stimulation, depression, and inflammation. Neuropsychopharmacology. 2007;32(9):2053–4. · DOI
  68. de Haan JJ, et al. Exploring the link between inflammation and the vagus nerve. J Intern Med. 2010;267(1):130–1. · DOI
  69. Hoeger S, et al. Modulation of brain dead induced inflammation by vagus nerve stimulation. Am J Transplant. 2010;10(3):477–89. · DOI
  70. Gordon JI, et al. The human gut microbiota and undernutrition. Sci Transl Med. 2012;4(137):137ps12. · DOI
  71. Frost G, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611. · DOI · Paper page
  72. Zhao Y, Dua P, Lukiw WJ. Microbial sources of amyloid and relevance to Amyloidogenesis and Alzheimer's disease (AD). J Alzheimers Dis Parkinsonism. 2015;5(1):177.
  73. Schwartz K, Boles BR. Microbial amyloids--functions and interactions within the host. Curr Opin Microbiol. 2013;16(1):93–9. · DOI
  74. Hill JM, Lukiw WJ. Microbial-generated amyloids and Alzheimer's disease (AD). Front Aging Neurosci. 2015;7:9. · DOI
  75. Park AM, et al. Helicobacter pylori and gut microbiota in multiple sclerosis versus Alzheimer's disease: 10 pitfalls of microbiome studies. Clin Exp Neuroimmunol. 2017;8(3):215–32. · DOI
  76. Chen F, et al. Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs? J Ethnopharmacol. 2016;179:253–64. · DOI
  77. Zheng X, et al. Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way? Neuropharmacology. 2015;96(Pt A):94–104. · DOI
  78. Yang WT, et al. Chinese herbal medicine for Alzheimer's disease: clinical evidence and possible mechanism of neurogenesis. Biochem Pharmacol. 2017;141:143–55. · DOI

Cited by

See all 607

Metadata

Authors
Du, X., Wang, X., & Geng, M.
Venue
Translational Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2018-01-30
Volume
7
Issue
1
Pages
2-2
ISSN
2047-9158 (ISSN-L)
DOI
10.1186/s40035-018-0107-y
OpenAlex
W2796303051
Cited by
607
References
37
FWCI
32.96
Type
journal article
Language
en
Open access
gold
Funders
Personalized Medicines-Molecular Signature based Drug Discovery and Development, Strategic Priority Research program of Sciences (No.XDA12040101.)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Alzheimer’s disease hypothesis and related therapies. https://app.cochat.ai/papers/10.1186/s40035-018-0107-y
The paper
Du, X., Wang, X., & Geng, M. (2018). Alzheimer’s disease hypothesis and related therapies. Translational Neurodegeneration. https://doi.org/10.1186/s40035-018-0107-y

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.