Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study
Open accessAbstract
Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
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RELN is a candidate gene associated with Alzheimer's disease pathology in cognitively healthy individuals.
“others identified RELN as a candidate gene associated with AD pathology in cognitively healthy individuals28”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [28]
The RELN/DAB1 pathway is linked to Alzheimer's disease.
“further linking the RELN/DAB1 pathway to Alzheimer’s29.”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [28]
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Cites
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
The Clinical Dementia Rating (CDR): Current version and scoring rules
Morris, J. C. (1993) · Neurology · doi:10.1212/wnl.43.11.2412-a · Cited by 9,882 · see citing works
Self-citationRandomization, Bootstrap and Monte Carlo Methods in Biology
Manly, B. F. J. (2018) · Chapman & Hall/CRC eBooks · doi:10.1201/9781315273075 · Cited by 4,233 · see citing works
Alzheimer Disease in the US Population: Prevalence Estimates Using the 2000 Census
Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1119 · Cited by 2,168 · see citing works
Self-citationHYMAN, B. T., & TROJANOWSKI, J. Q. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199710000-00002 · Cited by 1,542 · see citing works
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., & Herz, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80782-5 · Cited by 1,261 · see citing works
Randomization, Bootstrap and Monte Carlo Methods in Biology
Robinson, A. P. (2007) · Journal of the Royal Statistical Society Series A (Statistics in Society) · doi:10.1111/j.1467-985x.2007.00485_5.x · Cited by 1,024 · see citing works
Consensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease
(1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00057-2 · Cited by 981 · see citing works
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., & Herz, J. (1999) · Neuron · doi:10.1016/s0896-6273(00)80861-2 · Cited by 916 · see citing works
Whitlock, M. C. (2005) · Journal of Evolutionary Biology · doi:10.1111/j.1420-9101.2005.00917.x · Cited by 758 · see citing works
Two independent alleles at 6q23 associated with risk of rheumatoid arthritis
Plenge, R. M., Cotsapas, C. J., Davies, L. R. L., Price, A. L., de Bakker, P. I. W., Maller, J., Pe’er, I., Burtt, N. P., Blumenstiel, B. S., DeFelice, M., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.27 · Cited by 550 · see citing works
Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions
Bennett, D. A., Schneider, J. A., Bienias, J. L., Evans, D. A., & Wilson, R. S. (2005) · Neurology · doi:10.1212/01.wnl.0000152982.47274.9e · Cited by 537 · see citing works
Self-citationGreen, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3203-08.2008 · Cited by 404 · see citing works
Histone acetylation and disease
Timmermann, S., Lehrmann, H., Polesskaya, A., & Harel‐Bellan, A. (2001) · Cellular and Molecular Life Sciences · doi:10.1007/pl00000896 · Cited by 341 · see citing works
Trimming, Weighting, and Grouping SNPs in Human Case-Control Association StudiesPreprint
Hoh, J. J., Wille, A., & Ott, J. (2001) · Genome Research · doi:10.1101/gr.204001 · Cited by 316 · see citing works
Self-citationDong, E., Agís‐Balboa, R. C., Simonini, M. V., Grayson, D. R., Costa, E., & Guidotti, A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505394102 · Cited by 198 · see citing works
Chin, J., Massaro, C. M., Palop, J. J., Thwin, M. T., Yu, G.-Q., Bien-Ly, N., Bender, A., & Mucke, L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3758-06.2007 · Cited by 188 · see citing works
Reelin signaling antagonizes β-amyloid at the synapse
Durakoglugil, M. S., Chen, Y., White, C. L., Kavalali, E. T., & Herz, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908176106 · Cited by 153 · see citing works
Factors associated with resistance to dementia despite high Alzheimer disease pathology
Erten‐Lyons, D., Woltjer, R. L., Dodge, H. H., Nixon, R. A., Vorobik, R., Calvert, J. F., Leahy, M., Montine, T. J., & Kaye, J. A. (2009) · Neurology · doi:10.1212/01.wnl.0000341273.18141.64 · Cited by 148 · see citing works
Self-citationOhkubo, N., Lee, Y., Morishima, A., Terashima, T., Kikkawa, S., Tohyama, M., Sakanaka, M., Tanaka, J., Maeda, N., Vitek, M. P., et al. (2002) · The FASEB Journal · doi:10.1096/fj.02-0434fje · Cited by 118 · see citing works
Reelin mouse mutants as models of cortical development disorders
D’Arcangelo, G. (2005) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2005.09.005 · Cited by 110 · see citing works
<i>APOE ε4 does not predict mortality, cognitive decline, or dementia in the oldest old</i>
Juva, K., Verkkoniemi, A., Viramo, P., Polvikoski, T., Kainulainen, K., Kontula, K., & Sulkava, R. (2000) · Neurology · doi:10.1212/wnl.54.2.412 · Cited by 108 · see citing works
Bar, I. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01675-1 · Cited by 101 · see citing works
The RELN Locus in Alzheimer's Disease
Seripa, D., Matera, M. G., Franceschi, M., Daniele, A., Bizzarro, A., Rinaldi, M., Panza, F., Fazio, V. M., Gravina, C., D’Onofrio, G., et al. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14308 · Cited by 68 · see citing works
Martínez‐Cerdeño, V. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.12.1298 · Cited by 64 · see citing works
Reelin in plaques of β-amyloid precursor protein and presenilin-1 double-transgenic mice
Wirths, O., Multhaup, G., Czech, C., Blanchard, V., Tremp, G. L., Pradier, L., Beyreuther, K. T., & Bayer, T. A. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)02399-0 · Cited by 60 · see citing works
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Sorted by citations
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
Jun, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.201 · Cited by 422 · see citing works
The involvement of Reelin in neurodevelopmental disorders
Folsom, T. D., & Fatemi, S. H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.015 · Cited by 275 · see citing works
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Lopera, F., Marino, C., Chandrahas, A. S., O’Hare, M., Villalba-Moreno, N. D., Aguillon, D., Baena, A., Sanchez, J. S., Vila-Castelar, C., Ramirez Gomez, L., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02318-3 · Cited by 192 · see citing works
Reelin and neuropsychiatric disorders
Ishii, K., Kubo, K.-I., & Nakajima, K. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00229 · Cited by 185 · see citing works
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · see citing works
“Some SNPs in the Reelin gene have been identified as being protective against AD and are hypothesized to increase Reelin levels in the presence of AD pathology [45]; however, definitive studies showing a protective effect of Reelin in humans are largely lacking.”
BackgroundMore than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
Neuroglialpharmacology: Myelination as a shared mechanism of action of psychotropic treatments
Bartzokis, G. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.015 · Cited by 142 · see citing works
Pujadas, L., Rossi, D., Andrés, R., Teixeira, C. M., Serra-Vidal, B., Parcerisas, A., Maldonado, R., Giralt, E., Carulla, N., & Soriano, E. (2014) · Nature Communications · doi:10.1038/ncomms4443 · Cited by 129 · see citing works
Reelin protects against amyloid β toxicity in vivo
Lane-Donovan, C., Philips, G. T., Wasser, C. R., Durakoglugil, M. S., Masiulis, I., Upadhaya, A., Pohlkamp, T., Coskun, C., Kotti, T., Steller, L., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aaa6674 · Cited by 96 · see citing works
Calcium channelopathies and Alzheimer's disease: Insight into therapeutic success and failures
Chakroborty, S., & Stutzmann, G. E. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.11.012 · Cited by 91 · see citing works
Ding, Y., Huang, L., Xian, X., Yuhanna, I. S., Wasser, C. R., Frotscher, M., Mineo, C., Shaul, P. W., & Herz, J. (2016) · Science Signaling · doi:10.1126/scisignal.aad5578 · Cited by 72 · see citing works
Elias-Sonnenschein, L. S., Helisalmi, S., Natunen, T., Hall, A., Paajanen, T., Herukka, S.-K., Laitinen, M., Remes, A. M., Koivisto, A. M., Mattila, K. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059676 · Cited by 70 · see citing works
Singh, A., Allen, D., Fracassi, A., Tumurbaatar, B., Natarajan, C., Scaduto, P., Woltjer, R., Kayed, R., Limon, A., Krishnan, B., et al. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-200716 · Cited by 56 · see citing works
Self-citationZolochevska, O., & Taglialatela, G. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160518142110 · Cited by 49 · see citing works
Reelin proteolysis affects signaling related to normal synapse function and neurodegeneration
Lussier, A. L., Weeber, E. J., & Rebeck, G. W. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00075 · Cited by 31 · see citing works
- Authors
- Kramer, P. L., Xu, H., Woltjer, R. L., Westaway, S. K., Clark, D., Erten-Lyons, D., Kaye, J. A., Welsh-Bohmer, K. A., Troncoso, J. C., Markesbery, W. R., Petersen, R. C., Turner, R. S., Kukull, W. A., Bennett, D. A., Galasko, D., Morris, J. C., & Ott, J.
- Affiliations
- Oregon Health & Science University (US)
- Rockefeller University (US)
- Duke University (US)
- Johns Hopkins University (US)
- University of Kentucky (US)
- Mayo Clinic (US)
- University of Michigan (US)
- National Alzheimer's Coordinating Center (US)
- Rush University Medical Center (US)
- University of California San Diego (US)
- Washington University in St. Louis (US)
- Corresponding author
- Kramer, Patricia L.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 32
- Issue
- 12
- Pages
- 2113-2122
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC2990809
- OpenAlex
- W1999608737
- Cited by
- 108
- References
- 29
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 8 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 13 · 2012: 16
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01-AG026916, P30-AG028377, P50-AG005146, P30-AG028383, P50-AG16574, U01-AG06786, P30-AG008017, P30-AG10161, R01-AG17917, P30-AG10129, P50-AG05131, P50-AG08671, P50-AG05681, P01-AG03991, U01-AG016976)
- 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, neurofibrillary tangles, non-demented elderly, RELN gene, reelin, tau phosphorylation, amyloid-beta, genetic susceptibility, neuropathology, cognitive health, compensatory response
- MeSH terms
- Reelin Protein, Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Health Status, Humans, Longitudinal Studies, Male, Nerve Tissue Proteins, Phosphorylation, Serine Endopeptidases, Cohort Studies, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Neurofibrillary Tangles, tau Proteins, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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