The DOI matches its Crossref record; 472 of the 473 references it cites were found in a registry or an index.
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Open accessAbstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of patients. There are various descriptive hypotheses regarding the causes of AD, including the cholinergic hypothesis, amyloid hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, inflammatory hypothesis, metal ion hypothesis, and lymphatic system hypothesis. However, the ultimate etiology of AD remains obscure. In this review, we discuss the main hypotheses of AD and related clinical trials. Wealthy puzzles and lessons have made it possible to develop explanatory theories and identify potential strategies for therapeutic interventions for AD. The combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD. We further propose that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD.
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.
Integrity signals
Registry
Cites
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.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“AD can be categorized into two main types: familial (accounting for 1-5% of AD cases) and sporadic forms (over 95% of cases).76”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [76]
In the citing paper
“The most prevalent hypotheses are the Aβ cascade hypothesis, the inflammation hypothesis, the cholinergic hypothesis, the tau hypothesis, and the oxidative hypothesis [18,19,20].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [20]
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
Items 401–472 of 472
Neurexin controls plasticity of a mature, sexually dimorphic neuron
Hart, M. P., & Hobert, O. (2018) · Nature · doi:10.1038/nature25192 · Cited by 84
Moreira, P. I. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111127 · Cited by 83
Differential effects of age and history of hypertension on regional brain volumes and iron
Rodrigue, K. M., Haacke, E. M., & Raz, N. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.09.068 · Cited by 80
Chételat, G., Ossenkoppele, R., Villemagne, V. L., Perrotin, A., Landeau, B., Mézenge, F., Jagust, W. J., Dore, V., Miller, B. L., Egret, S., et al. (2016) · Brain · doi:10.1093/brain/aww159 · Cited by 80
Lunnon, K., & Mill, J. (2013) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32201 · Cited by 78
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD)
Silverman, J. M., Raiford, K., Edland, S. D., Fillenbaum, G. G., Morris, J. C., Clark, C. M., Kukull, W. A., & Heyman, A. (1994) · Neurology · doi:10.1212/wnl.44.7.1253 · Cited by 77
Levin‐Salomon, V., Bialik, S., & Kimchi, A. (2013) · APOPTOSIS · doi:10.1007/s10495-013-0918-3 · Cited by 76
Herpes and Alzheimer’s Disease: Subversion in the Central Nervous System and How It Might Be Halted
Itzhaki, R. F. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160607 · Cited by 76
MARCH5-FUNDC1 axis fine-tunes hypoxia-induced mitophagy
Chen, Z., Siraj, S., Liu, L., & Chen, Q. (2017) · Autophagy · doi:10.1080/15548627.2017.1310789 · Cited by 75
Wharton, W., Stein, J. H., Korcarz, C. E., Sachs, J., Olson, S. R., Zetterberg, H., Dowling, N. M., Ye, S., Gleason, C. E., Underbakke, G. L., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120763 · Cited by 73
Chapleau, M., Aldebert, J., Montembeault, M., & Brambati, S. M. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-160382 · Cited by 73
Fresh Evidence Points to an Old Suspect: Calcium
Marx, J. (2007) · Science · doi:10.1126/science.318.5849.384 · Cited by 71
MAPK, β-amyloid and synaptic dysfunction: the role of RAGE
Origlia, N., Arancio, O., Domenici, L., & Yan, S. S. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.107 · Cited by 71
Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease
Aboukhatwa, M. A., Dosanjh, L. E., & Luo, Y. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-10 · Cited by 70
Dynamic action of neurometals at the synapse
Tamano, H., & Takeda, A. (2011) · Metallomics · doi:10.1039/c1mt00008j · Cited by 68
Mastroeni, D., Nolz, J., Sekar, S., Delvaux, E., Serrano, G. E., Cuyugan, L., Liang, W. S., Beach, T. G., Rogers, J., & Coleman, P. D. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.10.019 · Cited by 67
Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration
McInnes, J. (2013) · Translational Neurodegeneration · doi:10.1186/2047-9158-2-12 · Cited by 65
Cholinesterase Inhibitor Discontinuation in Patients With Alzheimer’s Disease
O'Regan, J., Lanctôt, K. L., Mazereeuw, G., & Herrmann, N. (2015) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14r09237 · Cited by 64
Li, X., Lei, P., Tuo, Q., Ayton, S., Li, Q., Moon, S., Volitakis, I., Liu, R., Masters, C. L., Finkelstein, D. I., et al. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0378-2 · Cited by 63
Overview of Incidence Studies of Dementia Conducted in Europe
Launer, L. J. (1992) · Neuroepidemiology · doi:10.1159/000110954 · Cited by 61
A Community-Based Study of Dementia: The Rotterdam Elderly Study
Breteler, M. M. B., Ouweland, F. A. V. D., Grobbee, D. E., & Albert Hofman, D. (1992) · Neuroepidemiology · doi:10.1159/000110957 · Cited by 61
Delnomdedieu, M., Duvvuri, S., Li, D. J., Atassi, N., Lu, M., Brashear, H. R., Liu, E., Ness, S. L., & Kupiec, J. W. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0177-y · Cited by 61
High-sugar diets, type 2 diabetes and Alzheimerʼs disease
Moreira, P. I. (2013) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328361c7d1 · Cited by 59
Dong, X., Gao, W., Shao, T.-M., Hong-lin, X., Jiang-tao, B., Jing-yi, Z., & Xi-qing, C. (2014) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2014.11.009 · Cited by 59
Moonga, I., Niccolini, F., Wilson, H., Pagano, G., Politis, M., & Initiative, T. A. D. N. (2017) · European Journal of Neurology · doi:10.1111/ene.13374 · Cited by 59
Evidence of subnormal function of association cortex in presenile dementia
INGVAR, O. H., Risberg, J., & Schwartz, M. S. (1975) · Neurology · doi:10.1212/wnl.25.10.964 · Cited by 58
Hua, H., Munter, L. M., Harmeier, A., Georgiev, O., Multhaup, G., & Schaffner, W. (2011) · Biological Chemistry · doi:10.1515/bc.2011.084 · Cited by 58
Chronic Fluoxetine Increases Extra-Hippocampal Neurogenesis in Adult Mice
Sachs, B. D., & Caron, M. G. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu029 · Cited by 58
Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure
Wilkins, H., Koppel, S. J., Carl, S. M., Ramanujan, S., Weidling, I. W., Michaelis, M. L., Michaelis, E. K., & Swerdlow, R. H. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13545 · Cited by 55
Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians
Xiao, F.-H., Chen, X.-Q., Yu, Q., Ye, Y., Liu, Y.-W., Yan, D., Yang, L.-Q., Chen, G., Lin, R., Yang, L., et al. (2018) · Genome Research · doi:10.1101/gr.220780.117 · Cited by 55
Imoto, Y., Kira, T., Sukeno, M., Nishitani, N., Nagayasu, K., Nakagawa, T., Kaneko, S., Kobayashi, K., & Segi-Nishida, E. (2015) · Molecular Brain · doi:10.1186/s13041-015-0120-3 · Cited by 53
Qian, X., Hamad, B., & Dias-Lalcaca, G. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4749 · Cited by 52
HERPES-SIMPLEX VIRAL GENOME AND SENILE AND PRESENILE DEMENTIAS OF ALZHEIMER AND PICK
Middleton, P. J., Petrić, M., Kozak, M., Rewcastle, N. B., & McLachlan, D. R. C. (1980) · The Lancet · doi:10.1016/s0140-6736(80)91490-7 · Cited by 51
Evaluation of the cholinergic hypothesis in Alzheimer’s disease with neuropsychological methods
Fotiou, D. F., Καλτσάτου, Α., Tsiptsios, D., & Νάκου, Μ. (2015) · Aging Clinical and Experimental Research · doi:10.1007/s40520-015-0321-8 · Cited by 49
Micro-RNAs in cognition and cognitive disorders: Potential for novel biomarkers and therapeutics
Woldemichael, B. T., & Mansuy, I. M. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.11.021 · Cited by 49
Xie, Y., Liu, P.-P., Lian, Y.-J., Liu, H.-B., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0064-7 · Cited by 49
Self-citationLi, J., Gao, L., Sun, D., Wu, H., Wang, Q., Ke, D., Lei, H. C., Wang, J., & Liu, G. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9952-9 · Cited by 46
Zhuren, L., Zhuang, X., Kumar, D., Wu, X., Yue, C., Han, C., & Lv, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076203 · Cited by 45
Women’s issues in mood disorders
Goodnick, P. J., Chaudry, T., Artadi, J., & Arcey, S. (2000) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.1.5.903 · Cited by 45
Sala‐Llonch, R., Idland, A., Borza, T., Watne, L. O., Wyller, T. B., Brækhus, A., Zetterberg, H., Blennow, K., Walhovd, K. B., & Fjell, A. M. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161146 · Cited by 45
The Effects of Meditation on Grey Matter Atrophy and Neurodegeneration: A Systematic Review
Last, N., Tufts, E., & Auger, L. E. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160899 · Cited by 44
Metal Ions and Metal Complexes in Alzheimer's Disease
Spinello, A., Bonsignore, R., Barone, G., Keppler, B. K., & Terenzi, A. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160520115248 · Cited by 38
Feedback regulation between autophagy and PKA
Torres‐Quiroz, F., Filteau, M., & Landry, C. R. (2015) · Autophagy · doi:10.1080/15548627.2015.1055440 · Cited by 34
Tolerability and pharmacokinetics of oxaloacetate 100mg capsules in Alzheimer's subjects
Swerdlow, R. H., Bothwell, R. J., Hutfles, L. J., Burns, J. M., & Reed, G. A. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.03.005 · Cited by 33
Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults
Li, G., Mayer, C. L., Morelli, D., Millard, S., Raskind, W., Petrie, E., Cherrier, M., Fagan, A., Raskind, M., & Peskind, E. (2017) · Neurology · doi:10.1212/wnl.0000000000004392 · Cited by 33
Decreased HHV-6 IgG in Alzheimer’s Disease
Westman, G., Blomberg, J., Yun, Z., Lannfelt, L., Ingelsson, M., & Eriksson, B. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00040 · Cited by 32
Gibb, G., Pearce, J., Betts, J. C., Lovestone, S., Hoffmann, M. M., Maerz, W., Blackstock, W. P., & Anderton, B. H. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)02196-7 · Cited by 31
Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline
Risacher, S. L., Anderson, W. H., Charil, A., Castelluccio, P., Shcherbinin, S., Saykin, A. J., Schwarz, A. J., Stern, Y., & Initiative, A. D. N. (2022) · PMC · doi:10.7916/hhj9-0y94 · Cited by 30
Nicotra, A., Lupo, G., Giurdanella, G., Anfuso, C. D., Ragusa, N., Tirolo, C., Marchetti, B., & Alberghina, M. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2004.12.017 · Cited by 29
Mechanism of action of cholinesterase inhibitors in Alzheimer's disease
Håkansson, L. (2009) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1993.tb04245.x · Cited by 29
Zheng, J., Watanabe, H., Wines-Samuelson, M., Zhao, H., Gridley, T., Kopan, R., & Shen, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.349738 · Cited by 29
Mintzer, J. E., & Kershaw, P. R. (2003) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.826 · Cited by 28
Mitochondria as a target for neuroprotection: implications for Alzheimer´s disease
Cardoso, S., Seiça, R. M. F., & Moreira, P. I. (2016) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2016.1205488 · Cited by 27
Dementia is associated with iron-deficiency anemia in females: A population-based study
Chung, S., Sheu, J., Kao, L., Lin, H., & Kang, J. (2014) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2014.07.062 · Cited by 26
Self-citationGong, L., Tian, X.-Z., Zhou, J., Dong, Q., Tan, Y., Lü, Y., Wu, J., Zhao, Y., & Liu, X. (2019) · Cell Transplantation · doi:10.1177/0963689719831707 · Cited by 26
Marine glycan-derived therapeutics in China
Gao, Y., Zhang, L., & Jiao, W. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.02.006 · Cited by 23
Liu, Z.-D., Zhang, S., Jianjin, H., Xie, T., & Kang, J. (2016) · Protein & Cell · doi:10.1007/s13238-016-0301-6 · Cited by 19
Self-citationNativio, R., Donahue, G., Berson, A., Lan, Y., Amlie‐Wolf, A., Tüzer, F., Toledo, J. B., Gosai, S. J., Gregory, B. D., Torres, C. A., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0124-2 · Cited by 19
Xie, T., Liu, C.-F., & Kang, J. (2017) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2017.60 · Cited by 19
Self-citationNavigating patients and caregivers through the course of Alzheimer's disease.
Aupperle, P. M. (2006) · PubMed · Cited by 17
Soldán, M. M. P., Raman, M. R., Gamez, J. D., Lohrey, A. K., Chen, Y., Pirko, I., & Johnson, A. J. (2015) · Journal of Neuroimaging · doi:10.1111/jon.12250 · Cited by 17
Altered brain development in an early-onset murine model of Alzheimer's disease
Allemang-Grand, R., Scholz, J., Ellegood, J., Cahill, L. S., Laliberté, C. L., Fraser, P. E., Josselyn, S. A., Sled, J. G., & Lerch, J. P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.032 · Cited by 16
Navigating Patients and Caregivers Through the Course of Alzheimers Disease
Aupperle, P. M. (2006) · The Primary Care Companion to The Journal of Clinical Psychiatry · Cited by 16
Connections Between Herpes Simplex Virus Type 1 and Alzheimer's Disease Pathogenesis
McNamara, J., & Murray, T. A. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160314150136 · Cited by 16
Copper Status Abnormalities and How to Measure Them in Neurodegenerative Disorders
Siotto, M., Bucossi, S., & Squitti, R. (2010) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488910793362395 · Cited by 13
Drugs for Alzheimer's disease: best avoided. No therapeutic advantage.
(2012) · PubMed · Cited by 12
The cytoplasmic nuclear shuttling of Beclin 1 in neurons with Alzheimer’s disease-like injury
Wang, L., Xu, X.-B., You, W.-W., Lin, X., Li, C.-T., Qian, H., Zhang, L., & Yang, Y. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.09.055 · Cited by 11
FDA approves memantine drug for treating AD.
(2003) · PubMed · Cited by 11
Kong, L.-N., Geng, M., Mu, L., Xin, X., Yang, N., & Zuo, P.-P. (2005) · PubMed · Cited by 9
Micro-RNAs in transplant tolerance
Harden, J. T., & Krams, S. M. (2017) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000479 · Cited by 9
Mitobolites: The Elixir of Life
Katewa, S. D., Khanna, A., & Kapahi, P. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.06.013 · Cited by 8
Hampton, T. (2011) · JAMA · doi:10.1001/jama.2011.1086 · Cited by 1
Research works printed but not linked: 3
- Dementia – caring, ethics, ethnical and economical aspects: a systematic review. Stockholm: Swedish Council on Health Technology Assessment (SBU). SBU No. 172 (2008).
- Liu, B. et al. Preparation and identification of a series of mannose glucuronic acid oligosaccharides. Chem. J. Chin. Univ. 27, 485–487 (2006).
- M, G. GV-971, a new drug against Alzheimer’s disease. Chin. J. Pharmacol Toxicol. 31, 459–460 (2017).
Cited by
Sorted by citations
Mitochondrial dysfunction: mechanisms and advances in therapy
Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,382
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
“76 Familial AD (FAD) is predominantly characterized by autosomal dominant genetic mutations in amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes, typically manifesting between 30-65 years and progressing rapidly.”
BackgroundWightman, D. P., Jansen, I. E., Savage, J. E., Shadrin, A. A., Bahrami, S., Holland, D., Rongve, A., Børte, S., Winsvold, B. S., Drange, O. K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00921-z · Cited by 1,011
Lamptey, R. N. L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., & Singh, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031851 · Cited by 1,010
Metadata
- Authors
- Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S.
- Affiliations
- First Affiliated Hospital of Zhengzhou University (CN)
- Corresponding author
- Kang, Jian-Sheng
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2019-08-23
- Volume
- 4
- Issue
- 1
- Pages
- 29-29
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC6799833
- OpenAlex
- W2969562288
- Cited by
- 723
- References
- 473
- Citations by year
- 2026: 54 · 2025: 94 · 2024: 146 · 2023: 124 · 2022: 130 · 2021: 106 · 2020: 66 · 2019: 3
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-23)
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (31171369)
- the Chinese Academy of Sciences
- 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid hypothesis, cholinergic hypothesis, neuroinflammation, calcium homeostasis, brain hypometabolism, autophagy dysfunction, fluoxetine, selective serotonin reuptake inhibitors, clinical trials, therapeutic interventions
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