The discovery of Alzheimer‐causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”
Open accessAbstract
The cloning of APP and genetic analysis of families with Alzheimer's disease were both reported in 1987 and much present work on the disease is based upon the foundations laid at that time. Progress was not smooth, however, and many errors were made. In this memoir, I lay out both the progress and the errors.
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.
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
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Self-citationAlzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · see citing works
Self-citationThe amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Self-citationGlenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · see citing works
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659 · see citing works
Self-citationThe precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Amyloid plaque core protein in Alzheimer disease and Down syndrome.
Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.12.4245 · Cited by 4,431 · see citing works
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051 · see citing works
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708 · see citing works
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538 · see citing works
Self-citationA polymorphic DNA marker genetically linked to Huntington's disease
Gusella, J. F., Wexler, N. S., Conneally, P. M., Naylor, S. L., Anderson, M. A., Tanzi, R. E., Watkins, P. C., Ottina, K. A., Wallace, M. R., Sakaguchi, A. Y., et al. (1983) · Nature · doi:10.1038/306234a0 · Cited by 2,340 · see citing works
Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(84)91209-9 · Cited by 1,693 · see citing works
Amyloid β Protein Gene: cDNA, mRNA Distribution, and Genetic Linkage Near the Alzheimer Locus
Tanzi, R. E., Gusella, J. F., Watkins, P. C., Bruns, G. A. P., St George-Hyslop, P., Van Keuren, M. L., Patterson, D., Pagan, S., Kurnit, D. M., & Neve, R. L. (1987) · Science · doi:10.1126/science.2949367 · Cited by 1,611 · see citing works
Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch Type
Levy, E., Carman, M. D., Fernandez-Madrid, I. J., Power, M. D., Lieberburg, I. M., van Duinen, S. G., Bots, G. T. A. M., Luyendijk, W., & Frangione, B. (1990) · Science · doi:10.1126/science.2111584 · Cited by 1,380 · see citing works
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U., & Gajdusek, D. C. (1987) · Science · doi:10.1126/science.3810169 · Cited by 1,333 · see citing works
Rovelet‐Lecrux, A., Hannequin, D., Raux, G., Meur, N. L., Laquerrière, A., Vital, A., Dumanchin‐Njock, C., Feuillette, S., Brice, A., Vercelletto, M., et al. (2005) · Nature Genetics · doi:10.1038/ng1718 · Cited by 1,249 · see citing works
Chartier-Harlin, M.-C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J., et al. (1991) · Nature · doi:10.1038/353844a0 · Cited by 1,214 · see citing works
Self-citationThe Genetic Defect Causing Familial Alzheimer's Disease Maps on Chromosome 21
George‐Hyslop, P. S., Tanzi, R. E., Polinsky, R. J., Haines, J. L., Nee, L. E., Watkins, P. C., Myers, R. H., Feldman, R. G., Pollen, D. A., Drachman, D. A., et al. (1987) · Science · doi:10.1126/science.2880399 · Cited by 1,160 · see citing works
A mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease
Murrell, J. R., Farlow, M. R., Ghetti, B. F., & Benson, M. D. (1991) · Science · doi:10.1126/science.1925564 · Cited by 1,122 · see citing works
Robakis, N. K. R. K., Ramakrishna, N., Wolfe, G. C., & Wisniewski, H. M. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.12.4190 · Cited by 603 · see citing works
Amyloid β Protein Precursor Gene and Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch)
Broeckhoven, C. V., Haan, J., Bakker, E., Hardy, J., Hul, W. V., Wehnert, A., der Vlis, M. V.-V., & Roos, R. A. C. (1990) · Science · doi:10.1126/science.1971458 · Cited by 471 · see citing works
Self-citationRossor, M. N., Emson, P. C., Mountjoy, C. Q., Roth, M., & Iversen, L. L. (1980) · Neuroscience Letters · doi:10.1016/0304-3940(80)90177-9 · Cited by 433 · see citing works
Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder
George‐Hyslop, P. S., Haines, J. L., Farrer, L. A., Polinsky, R. J., Broeckhoven, C. V., Goate, A., McLachlan, D. R. C., Orr, H. T., Bruni, A. C., Sorbi, S., et al. (1990) · Nature · doi:10.1038/347194a0 · Cited by 392 · see citing works
Self-citationMurray, J., Davies, K. E., Harper, P. S., Meredith, L., Mueller, C. R., & Williamson, R. (1982) · Nature · doi:10.1038/300069a0 · Cited by 330 · see citing works
Transmitter deficits in Alzheimer's disease
Hardy, J., Adolfsson, R., Alafuzoff, I. I., Bucht, G., Marcusson, J. O., Nyberg, P., Perdahl, E., Wester, P. O., & Winblad, B. G. (1985) · Neurochemistry International · doi:10.1016/0197-0186(85)90050-6 · Cited by 329 · see citing works
Self-citationvan Duinen, S. G., Castaño, E. M., Prelli, F., Bots, G. T. A. M., Luyendijk, W., & Frangione, B. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.16.5991 · Cited by 309 · see citing works
PRESENILE DEMENTIA AND ALZHEIMER'S DISEASE IN MONGOLISM
Olson, M. I., & Shaw, C. (1969) · Brain · doi:10.1093/brain/92.1.147 · Cited by 290 · see citing works
Broeckhoven, C. V., Genthe, A. M., Vandenberghe, A., Horsthemke, B., Backhovens, H., Raeymaekers, P., Hul, W. V., Wehnert, A., Gheuens, J., Cras, P. P., et al. (1987) · Nature · doi:10.1038/329153a0 · Cited by 273 · see citing works
Self-citationPREDISPOSING LOCUS FOR ALZHEIMER'S DISEASE ON CHROMOSOME 21
Goate, A., Owen, M., James, L., Mullan, M., Rossor, M., Haynes, A., Farrall, M., Lai, L. C., Roques, P., Williamson, R., et al. (1989) · The Lancet · doi:10.1016/s0140-6736(89)91725-x · Cited by 270 · see citing works
Self-citationTanzi, R. E., George‐Hyslop, P. S., Haines, J. L., Polinsky, R. J., Nee, L. E., Foncin, J. F., Neve, R. L., McClatchey, A. I., Conneally, P. M., & Gusella, J. F. (1987) · Nature · doi:10.1038/329156a0 · Cited by 267 · see citing works
Absence of Linkage of Chromosome 21q21 Markers to Familial Alzheimer's Disease
Schellenberg, G. D., Bird, T. D., Wijsman, E. M., Moore, D. K., Boehnke, M., Bryant, E. M., Lampe, T. H., Nochlin, D., Sumi, S. M., Deeb, S. S., et al. (1988) · Science · doi:10.1126/science.3420406 · Cited by 242 · see citing works
β Amyloid Gene Duplication in Alzheimer's Disease and Karyotypically Normal Down Syndrome
Delabar, J. M., Goldgaber, D., Lamour, Y. A., Nicole, A., Huret, J. L., GROUCHY, J. D., Brown, P., Gajdusek, D. C., & Sinet, P. (1987) · Science · doi:10.1126/science.2950593 · Cited by 187 · see citing works
Region-specific loss of glutamate innervation in Alzheimer's disease
Hardy, J., Cowburn, R. F., BARTON, A. J. L., Reynolds, G. P., Lofdahl, E., O’Carroll, A., Wester, P. O., & Winblad, B. G. (1987) · Neuroscience Letters · doi:10.1016/0304-3940(87)90034-6 · Cited by 147 · see citing works
Self-citationAbsence of Duplication of Chromosome 21 Genes in Familial and Sporadic Alzheimer's Disease
George‐Hyslop, P. S., Tanzi, R. E., Polinsky, R. J., Neve, R. L., Pollen, D. A., Drachman, D. A., Growdon, J. H., Cupples, L. A., Nee, L. E., Myers, R. H., et al. (1987) · Science · doi:10.1126/science.2890206 · Cited by 142 · see citing works
Glenner, G. G. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.08.020 · Cited by 104 · see citing works
Perry, E. K., Atack, J. R., Perry, R. H., Hardy, J., Dodd, P. R., Edwardson, J. A., Blessed, G., Tomlinson, B. E., & FAIRBAIRN, A. F. (1984) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1984.tb02801.x · Cited by 92 · see citing works
Self-citationCamp, G. V., Hul, W. V., Backhovens, H., Stinissen, P., Wehnert, A., Patterson, D., Vandenberghe, A., & Broeckhoven, C. V. (1990) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01233360 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Role of mitochondrial <scp>ROS</scp> in the brain: from physiology to neurodegeneration
Angelova, P. R., & Abramov, A. Y. (2018) · FEBS Letters · doi:10.1002/1873-3468.12964 · Cited by 789 · see citing works
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793 · see citing works
Self-citationDementia in Down syndrome: unique insights for Alzheimer disease research
Lott, I. T., & Head, E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0132-6 · Cited by 383 · 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
Interaction of Mitochondrial Calcium and ROS in Neurodegeneration
Baev, A. Y., Vinokurov, A. Y., Novikova, I. N., Dremin, V. V., Potapova, E. V., & Abramov, A. Y. (2022) · Cells · doi:10.3390/cells11040706 · Cited by 162 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“V717L, V717I) influence the activity of g-secretase altering APP processing so that longer Aβ peptides more prone to aggregation are generated, including species 42–43 amino acids in length (Aβ1–42 and Aβ1–43) (Hardy, 2017).”
BackgroundAmyloid-β oligomers in cellular models of Alzheimer’s disease
Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O., Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15030 · Cited by 115 · see citing works
Alzheimer's disease in Down syndrome: an overlooked population for prevention trials
Strydom, A., Coppus, A., Blesa, R., Danek, A., Fortea, J., Hardy, J., Levin, J., Nuebling, G., Rebillat, A., Ritchie, C., et al. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.10.006 · Cited by 110 · see citing works
Self-citationThe role of PI3K signaling pathway in Alzheimer’s disease
Pan, J., Yao, Q., Wang, Y., Chang, S., Li, C., Wu, Y., Shen, J., & Yang, R. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1459025 · Cited by 89 · see citing works
Glycation affects fibril formation of Aβ peptides
Emendato, A., Milordini, G., Zacco, E., Sicorello, A., Dal Piaz, F., Guerrini, R., Thorogate, R., Picone, D., & Pastore, A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002275 · Cited by 65 · see citing works
Kim, W., Ma, L., Lomoio, S., Willen, R., Lombardo, S., Dong, J., Haydon, P. G., & Tesco, G. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0239-7 · Cited by 32 · see citing works
Beta-amyloid short- and long-term synaptic entanglement
Lanni, C., Fagiani, F., Racchi, M., Preda, S., Pascale, A., Grilli, M., Allegri, N., & Govoni, S. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2018.11.018 · Cited by 29 · see citing works
- Authors
- Hardy, J.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Hardy, John
- ORCID
- Hardy, John
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2017-04
- Volume
- 284
- Issue
- 7
- Pages
- 1040-1044
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W2569555624
- Cited by
- 153
- References
- 37
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 15 · 2023: 9 · 2022: 22 · 2021: 20 · 2020: 28 · 2019: 19 · 2018: 12 · 2017: 9 · 2016: 1
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Parkinson's UK (G-1307)
- Rosetrees Trust
- Medical Research Council (MR/K01417X/1, MR/L501542/1, MR/J004758/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurology and Historical Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, APP gene, amyloid hypothesis, APP mutations, gene cloning, amyloid-beta
- MeSH terms
- Alzheimer Disease, Chromosomes, Human, Pair 21, Down Syndrome, Genetic Markers, Humans, Gene Expression, Artifacts, Amyloid beta-Protein Precursor, Gene Duplication, History, 20th Century
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
