Aβ-independent processes—rethinking preclinical AD
Open accessAbstract
The amyloid cascade hypothesis, which posits that amyloid-β accumulation is the key event in Alzheimer disease neurodegeneration, has dominated the field for 20 years. Recent findings, however, show that neuronal-injury biomarkers are independent of amyloid-β, calling for reconsideration of the pathological cascade and assessment of alternative therapeutic strategies.
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
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?
For many subjects with suspected AD or increased risk, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes.
“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [207]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155 · see citing works
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., & Trojanowski, J. Q. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70299-6 · Cited by 4,806 · see citing works
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1202753 · Cited by 3,814 · see citing works
Jack, C. R., Knopman, D. S., Weigand, S. D., Wiste, H. J., Vemuri, P., Lowe, V., Kantarci, K., Gunter, J. L., Senjem, M. L., Ivnik, R. J., et al. (2012) · Annals of Neurology · doi:10.1002/ana.22628 · Cited by 602 · see citing works
Reiman, E. M., Quiroz, Y. T., Fleisher, A. S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A. M., Shah, A. R., Alvarez, S., Arbelaez, A., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70228-4 · Cited by 541 · see citing works
La Joie, R., Perrotin, A., Barré, L., Hommet, C., Mézenge, F., Ibazizene, M., Camus, V., Abbas, A., Landeau, B., Guilloteau, D., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.2170-12.2012 · Cited by 374 · see citing works
Self-citationDirect voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer's disease
Chételat, G., Desgranges, B., Landeau, B., Mézenge, F., Poline, J.-B., Sayette, V. D. L., Viader, F., Eustache, F., & Baron, J. (2007) · Brain · doi:10.1093/brain/awm288 · Cited by 340 · see citing works
Self-citationShort-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease
Knopman, D. S., Jack, C. R., Wiste, H. J., Weigand, S. D., Vemuri, P., Lowe, V. J., Kantarci, K., Gunter, J. L., Senjem, M. L., Ivnik, R. J., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182563bbe · Cited by 243 · see citing works
Brain injury biomarkers are not dependent on β‐amyloid in normal elderly
Knopman, D. S., Jack, C. R., Wiste, H. J., Weigand, S. D., Vemuri, P., Lowe, V. J., Kantarci, K., Gunter, J. L., Senjem, M. L., Mielke, M. M., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23816 · Cited by 183 · see citing works
Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging
Jagust, W. J., Landau, S. M., & Initiative, F. T. A. D. N. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.3266-12.2012 · Cited by 162 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Feldman, H. H., Frisoni, G. B., Hampel, H., Jagust, W. J., Johnson, K. A., Knopman, D. S., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002923 · Cited by 1,864 · see citing works
Biomarker Modeling of Alzheimer’s Disease
Jack, C. R., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.12.003 · Cited by 1,002 · see citing works
A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease
Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0116-6 · Cited by 965 · see citing works
Spreading of pathology in neurodegenerative diseases: a focus on human studies
Brettschneider, J., Tredici, K. D., Lee, V. M.-Y., & Trojanowski, J. Q. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3887 · Cited by 790 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials
Sperling, R., Mormino, E., & Johnson, K. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.038 · Cited by 725 · see citing works
Molecular genetics of early-onset Alzheimer’s disease revisited
Cacace, R., Sleegers, K., & Van Broeckhoven, C. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.01.012 · Cited by 617 · see citing works
Alzheimer's Disease: Treatment Strategies and Their Limitations.
Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F. T., & Arab-Tehrany, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213954 · Cited by 592 · see citing works
“Indeed, amyloid pathology and tauopathy have been shown to appear independently under the influence of genetic and environmental factors [59,60].”
BackgroundChételat, G., Arbizu, J., Barthel, H., Garibotto, V., Law, I., Morbelli, S., van de Giessen, E., Agosta, F., Barkhof, F., Brooks, D. J., et al. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30314-8 · Cited by 526 · see citing works
Self-citationInconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease
Morris, G. P., Clark, I. A., & Vissel, B. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0135-5 · Cited by 522 · see citing works
Tau imaging: early progress and future directions
Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L., & Rowe, C. C. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70252-2 · Cited by 501 · see citing works
Mormino, E. C., Betensky, R. A., Hedden, T., Schultz, A. P., Amariglio, R. E., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2031 · Cited by 328 · see citing works
La Joie, R., Perrotin, A., de La Sayette, V., Egret, S., Doeuvre, L., Belliard, S., Eustache, F., Desgranges, B., & Chételat, G. (2013) · NeuroImage: Clinical · doi:10.1016/j.nicl.2013.08.007 · Cited by 290 · see citing works
Self-citationAmyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease
Pooler, A. M., Polydoro, M., Maury, E. A., Nicholls, S. B., Reddy, S. M., Wegmann, S., William, C., Saqran, L., Cagsal-Getkin, O., Pitstick, R., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0199-x · Cited by 236 · see citing works
Amyloid burden and neural function in people at risk for Alzheimer's Disease
Johnson, S. C., Christian, B. T., Okonkwo, O. C., Oh, J. M., Harding, S., Xu, G., Hillmer, A. T., Wooten, D. W., Murali, D., Barnhart, T. E., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.028 · Cited by 218 · see citing works
Morris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212 · see citing works
Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease
Kurochkin, I. V., Guarnera, E., & Berezovsky, I. N. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.10.008 · Cited by 185 · see citing works
Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?
Panza, F., Lozupone, M., Seripa, D., & Imbimbo, B. P. (2019) · Annals of Neurology · doi:10.1002/ana.25410 · Cited by 178 · see citing works
Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease
Iaccarino, L., Tammewar, G., Ayakta, N., Baker, S. L., Bejanin, A., Boxer, A. L., Gorno-Tempini, M. L., Janabi, M., Kramer, J. H., Lazaris, A., et al. (2018) · NeuroImage: Clinical · doi:10.1016/j.nicl.2017.09.016 · Cited by 165 · see citing works
Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
Leuzy, A., Smith, R., Cullen, N. C., Strandberg, O., Vogel, J. W., Binette, A. P., Borroni, E., Janelidze, S., Ohlsson, T., Jögi, J., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2021.4654 · Cited by 149 · see citing works
Besson, F. L., La Joie, R., Doeuvre, L., Gaubert, M., Mezenge, F., Egret, S., Landeau, B., Barre, L., Abbas, A., Ibazizene, M., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0150-15.2015 · Cited by 141 · see citing works
Mild cognitive impairment with suspected nonamyloid pathology (SNAP): Prediction of progression
Caroli, A., Prestia, A., Galluzzi, S., Ferrari, C., van der Flier, W. M., Ossenkoppele, R., Van Berckel, B., Barkhof, F., Teunissen, C., Wall, A. E., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001209 · Cited by 142 · see citing works
Fan, Z., Okello, A. A., Brooks, D. J., & Edison, P. (2015) · Brain · doi:10.1093/brain/awv288 · Cited by 135 · see citing works
Racine, A. M., Adluru, N., Alexander, A. L., Christian, B. T., Okonkwo, O. C., Oh, J., Cleary, C. A., Birdsill, A., Hillmer, A. T., Murali, D., et al. (2014) · NeuroImage: Clinical · doi:10.1016/j.nicl.2014.02.001 · Cited by 136 · see citing works
Gordon, B. A., Blazey, T., Su, Y., Fagan, A. M., Holtzman, D. M., Morris, J. C., & Benzinger, T. L. S. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.2642 · Cited by 105 · see citing works
La Barbera, L., Vedele, F., Nobili, A., Krashia, P., Spoleti, E., Latagliata, E. C., Cutuli, D., Cauzzi, E., Marino, R., Viscomi, M. T., et al. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102031 · Cited by 98 · see citing works
“…which states that the accumulation and deposition of oligomeric or fibrillar Aβ peptides are the primary cause of AD, has been the most widespread theory in the medical and scientific community for over 20 years (Chételat, 2013; Hardy and Selkoe, 2002; Herrup, 2015; Tanzi and Bertram, 2005).”
Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
Mroczko, B., Groblewska, M., Litman-Zawadzka, A., Kornhuber, J., & Lewczuk, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071884 · Cited by 97 · see citing works
Kantarci, K., Schwarz, C. G., Reid, R. I., Przybelski, S. A., Lesnick, T. G., Zuk, S. M., Senjem, M. L., Gunter, J. L., Lowe, V., Machulda, M. M., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1482 · Cited by 88 · see citing works
Dedifferentiation and neuronal repression define familial Alzheimer’s disease
Caldwell, A. B., Liu, Q., Schroth, G. P., Galasko, D. R., Yuan, S. H., Wagner, S. L., & Subramaniam, S. (2020) · Science Advances · doi:10.1126/sciadv.aba5933 · Cited by 69 · see citing works
Lista, S., Molinuevo, J. L., Cavedo, E., Rami, L., Amouyel, P., Teipel, S. J., Garaci, F., Toschi, N., Habert, M.-O., Blennow, K., et al. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150202 · Cited by 53 · see citing works
Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls
Mattsson, N., Insel, P. S., Donohue, M., Jagust, W., Sperling, R., Aisen, P., & Weiner, M. W. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.4530 · Cited by 45 · see citing works
When the infectious environment meets the AD brain
Ganz, T., Fainstein, N., & Ben-Hur, T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00559-3 · Cited by 39 · see citing works
Tracking the earliest pathologic changes in Alzheimer disease
Landau, S. M., & Frosch, M. P. (2014) · Neurology · doi:10.1212/wnl.0000000000000392 · Cited by 20 · see citing works
- Authors
- Chételat, G.
- Affiliations
- Inserm (FR)
- Corresponding author
- Chételat, Gaël
- ORCID
- Chételat, Gaël
- Venue
- Nature Reviews Neurology
- Published
- 2013-02-12
- Volume
- 9
- Issue
- 3
- Pages
- 123-124
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC3935395
- OpenAlex
- W2065174137
- Cited by
- 184
- References
- 10
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 9 · 2021: 17 · 2020: 16 · 2019: 10 · 2018: 24 · 2017: 18 · 2016: 17 · 2015: 22 · 2014: 20 · 2013: 11
- FWCI
- 16.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › 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-beta, amyloid hypothesis, preclinical Alzheimer's disease, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloidosis, Brain, Brain Injuries, Cognition Disorders, Humans, Amyloid beta-Peptides
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
