Quantitative assessment of cortical synaptic density in Alzheimer's disease
Abstract
Significant progress has been made over the last decade in delineating the neuropathological and neurochemical changes in the brains of patients with Alzheimer's disease (AD). Less well studied are the actual synaptic connections of affected areas of the brain, such as the cerebral cortex. Because the final common pathway for neurotransmission involves synaptic integrity, we quantitatively assessed synaptic number and synapse size in lamina III and V of human frontal cortex (Brodmann area 9) in patients with AD and age-matched controls. Samples were also matched for postmortem interval, and artifacts associated with postmortem change were eliminated. We found a significant decrease in synaptic number per unit volume in both lamina, more marked in lamina III (-42%) than V (-29%). In both normal controls and AD brains, there was a negative correlation between synapse number and synapse size as indexed by the length of the postsynaptic density (PSD); cortical samples with fewer synapses had larger synapse size. This appeared to be a compensatory response, rather than a selective loss of small synapses, since the total amount of synaptic contact area per unit volume did not decline in lamina V (despite a 29% loss of synapses); in lamina III it was reduced 11% despite a 42% loss of synapses. The loss of synapses in AD is widespread and significant in frontal cortex; there is observable compensation by enlargement of synaptic size. This compensatory effort is overcome by the continuing loss of synapses in areas most affected by the degeneration.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
In the absence of more definitive premortem cognitive status data, the present research focuses on synapse loss, a postmortem correlate of dementia, and not on dementia itself.
“Nonetheless, in the absence of more definitive premortem cognitive status data, the present research focuses on a correlate of dementia that is quantifiable postmortem, synapse loss, 11,12 and not on dementia itself.”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [11]
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Statistical principles in experimental design.
Winer, B. J. (1962) · McGraw-Hill Book Company · doi:10.1037/11774-000 · Cited by 27,137 · see citing works
Statistical Principles in Experimental Design
Myers, J. L., & Winer, B. J. (1964) · The American Journal of Psychology · doi:10.2307/1419292 · Cited by 8,111 · see citing works
The cholinergic hypothesis of geriatric memory dysfunction
Bartus, R. T., Dean, R. L., Beer, B., & Lippa, A. S. (1982) · Science · doi:10.1126/science.7046051 · Cited by 5,545 · see citing works
Alzheimer's Disease: A Disorder of Cortical Cholinergic Innervation
Coyle, J. T., Price, D. L., & DeLong, M. R. (1983) · Science · doi:10.1126/science.6338589 · Cited by 3,050 · see citing works
Synaptic density in human frontal cortex —Developmental changes and effects of aging
Peter R., H. (1979) · Brain Research · doi:10.1016/0006-8993(79)90349-4 · Cited by 2,645 · see citing works
Diagnosis of Alzheimer's Disease
Khachaturian, Z. S. (1985) · Archives of Neurology · doi:10.1001/archneur.1985.04060100083029 · Cited by 2,499 · see citing works
The Clinical Diagnosis of Alzheimer's Disease
Wade, J. P. H., Mirsen, T. R., Hachinski, V. C., Fisman, M., Lau, C. S., & Merskey, H. (1987) · Archives of Neurology · doi:10.1001/archneur.1987.00520130016010 · Cited by 1,416 · see citing works
Davies, P., Katzman, R., & Terry, R. D. (1980) · Nature · doi:10.1038/288279a0 · Cited by 882 · see citing works
Some morphometric aspects of the brain in senile dementia of the alzheimer type
Terry, R. D., Peck, A., DeTeresa, R., Schechter, R., & Horoupian, D. S. (1981) · Annals of Neurology · doi:10.1002/ana.410100209 · Cited by 801 · see citing works
Katzman, R. (1986) · New England Journal of Medicine · doi:10.1056/nejm198604103141506 · Cited by 801 · see citing works
Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease
Coleman, P. D., & Flood, D. G. (1987) · Neurobiology of Aging · doi:10.1016/0197-4580(87)90127-8 · Cited by 772 · see citing works
Davies, C. A., Mann, D. M. A., Sumpter, P. Q., & Yates, P. O. (1987) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(87)90057-8 · Cited by 628 · see citing works
Dendritic Growth in the Aged Human Brain and Failure of Growth in Senile Dementia
Buell, S. J., & Coleman, P. D. (1979) · Science · doi:10.1126/science.493989 · Cited by 475 · see citing works
Plasticity of Hippocampal Circuitry in Alzheimer's Disease
Geddes, J. W., Monaghan, D. T., Cotman, C. W., Lott, I. T., Kim, R. C., & Chui, H. C. (1985) · Science · doi:10.1126/science.4071042 · Cited by 461 · see citing works
Rossor, 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
Rogers, J., & Morrison, J. (1985) · Journal of Neuroscience · doi:10.1523/jneurosci.05-10-02801.1985 · Cited by 410 · see citing works
MILLER, A. K. H., Alston, R. L., & Corsellis, J. (1980) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1980.tb00283.x · Cited by 351 · see citing works
Cortical neuronal counts in normal elderly controls and demented patients
Mountjoy, C. Q., Roth, M., Evans, N. J. R., & Evans, H. M. (1983) · Neurobiology of Aging · doi:10.1016/0197-4580(83)90048-9 · Cited by 291 · see citing works
Alzheimer's disease: a correlative study.
Neary, D., Snowden, J. S., Mann, D. M. A., Bowen, D. M., Sims, N. R., Northen, B., Yates, P. O., & DAVISON, A. N. (1986) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.49.3.229 · Cited by 277 · see citing works
Mann, D. M. A., Yates, P. O., & Marcyniuk, B. (1985) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(85)90129-7 · Cited by 240 · see citing works
THE DENSITY OF SYNAPSES AND NEURONS IN NORMAL, MENTALLY DEFECTIVE AND AGEING HUMAN BRAINS
Cragg, B. G. (1975) · Brain · doi:10.1093/brain/98.1.81 · Cited by 225 · see citing works
A quantitative study of cerebral atrophy in old age and senile dementia
Hubbard, B. M., & Anderson, J. M. (1981) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(81)90048-4 · Cited by 223 · see citing works
Presynaptic Serotonergic Dysfunction in Patients with Alzheimer's Disease
Palmer, A. M., Francis, P. T., Benton, J. S., Sims, N. R., Mann, D. M. A., Neary, D., Snowden, J. S., & Bowen, D. M. (1987) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1987.tb13120.x · Cited by 214 · see citing works
Henke, H., & Lang, W. (1983) · Brain Research · doi:10.1016/0006-8993(83)90880-6 · Cited by 176 · see citing works
Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia
Flood, D. G., Buell, S. J., Horwitz, G. J., & Coleman, P. D. (1987) · Brain Research · doi:10.1016/0006-8993(87)90027-8 · Cited by 164 · see citing works
de Ruiter, J. P., & Uylings, H. B. M. (1987) · Brain Research · doi:10.1016/0006-8993(87)90028-x · Cited by 141 · see citing works
Colonnier, M., & Beaulieu, C. (1985) · The Journal of Comparative Neurology · doi:10.1002/cne.902310205 · Cited by 114 · 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
Gibson, P. H. (1983) · Acta Neuropathologica · doi:10.1007/bf00684929 · Cited by 79 · see citing works
DeKosky, S. T., Scheff, S. W., & Markesbery, W. R. (1985) · Neurology · doi:10.1212/wnl.35.10.1425 · Cited by 72 · see citing works
Adams, I. (1987) · Neurobiology of Aging · doi:10.1016/0197-4580(87)90003-0 · Cited by 71 · see citing works
Hubbard, B. M., & Anderson, J. M. (1985) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1985.tb00033.x · Cited by 61 · see citing works
Gibson, P. H. (1983) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1983.tb00123.x · Cited by 59 · see citing works
Is senile dementia of the Alzheimer type associated with hippocampal plasticity?
Represa, A., Duyckaerts, C. J., Tremblay, E. C., Hauw, J., & Ben‐Ari, Y. (1988) · Brain Research · doi:10.1016/0006-8993(88)90706-8 · Cited by 58 · see citing works
A quantitative electron microscopic study of the ageing human cerebral cortex
Rees, S. M. (1976) · Acta Neuropathologica · doi:10.1007/bf00699640 · Cited by 36 · see citing works
Paula-Barbosa, M. M., Saraiva, A., Tavares, M. A., Borges, M. M., & Verwer, R. W. H. (2009) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1986.tb03533.x · Cited by 24 · see citing works
Qualitative abnormalities of choline acetyltransferase in Alzheimer type dementia
Koshimura, K., Kato, T., Tohyama, I., Nakamura, S., & Kameyama, M. (1986) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(86)90164-4 · Cited by 22 · see citing works
Biochemistry of Senile Dementia
DeKosky, S. T., & Bass, N. H. (1985) · Springer eBooks · doi:10.1007/978-1-4757-0797-7_23 · Cited by 14 · see citing works
Gibson, P. H., & Tomlinson, B. E. (1979) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1979.tb00608.x · Cited by 9 · see citing works
Koshimura, K., Kato, T., Yohyama, I., Nakamura, S., & Kameyama, M. (1987) · Neuroscience Research · doi:10.1016/s0921-8696(87)80033-6 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neuropathological alterations in Alzheimer disease
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006189 · Cited by 3,345 · see citing works
Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity
DeKosky, S. T., & Scheff, S. W. (1990) · Annals of Neurology · doi:10.1002/ana.410270502 · Cited by 2,376 · see citing works
Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530 · see citing works
Dickerson, B. C., Bakkour, A., Salat, D. H., Feczko, E., Pacheco, J., Greve, D. N., Grodstein, F., Wright, C. I., Blacker, D., Rosas, H. D., et al. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhn113 · Cited by 1,153 · see citing works
Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment
Scheff, S. W., Price, D. A., Schmitt, F. A., & Mufson, E. J. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.012 · Cited by 1,017 · see citing works
Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders?
Fiala, J. C., Spacek, J., & Harris, K. M. (2002) · Brain Research Reviews · doi:10.1016/s0165-0173(02)00158-3 · Cited by 811 · see citing works
BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases
Lu, B., Nagappan, G., Guan, X.-M., Nathan, P. J., & Wren, P. B. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3505 · Cited by 747 · see citing works
Rajmohan, R., & Reddy, P. H. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160612 · Cited by 695 · see citing works
Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons
Um, J. W., Nygaard, H. B., Heiss, J. K., Kostylev, M. A., Stagi, M., Vortmeyer, A. O., Wısnıewskı, T., Gunther, E. C., & Strittmatter, S. M. (2012) · Nature Neuroscience · doi:10.1038/nn.3178 · Cited by 654 · see citing works
Butterfield, D. A., Reed, T., Newman, S. F., & Sultana, R. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.05.037 · Cited by 564 · see citing works
Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease
Roy, E. R., Wang, B., Wan, Y.-W., Chiu, G., Cole, A., Yin, Z., Propson, N. E., Xu, Y., Jankowsky, J. L., Liu, Z., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133737 · Cited by 563 · see citing works
Spires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · see citing works
“In AD, synapses and dendritic spines are lost in the cortex and the hippocampus (Davies et al., 1987; de Ruiter and Uylings, 1987; Catala et al., 1988; Scheff et al., 1990; Scheff et al., 1996), and decreased cortical synapse density correlates with cognitive decline in patients (Terry et al.”
BackgroundSynaptic degeneration in Alzheimer's disease
Arendt, T. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0536-x · Cited by 517 · see citing works
Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses
Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., & Slutsky, I. (2009) · Nature Neuroscience · doi:10.1038/nn.2433 · Cited by 499 · see citing works
Reduced IGF-1 signaling delays age-associated proteotoxicity in mice
Cohen, E., Paulsson, J. F., Blinder, P., Burstyn-Cohen, T., Du, D., Estepa, G., Adame, A., Pham, H. M., Holzenberger, M., Kelly, J. W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.11.014 · Cited by 488 · see citing works
Sultana, R., Perluigi, M., & Butterfield, D. A. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.09.027 · Cited by 478 · see citing works
Voytko, M. L., Olton, D. S., Richardson, R., Gorman, L. K., Tobin, J., & Price, D. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-01-00167.1994 · Cited by 482 · see citing works
Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein
Gimbel, D. A., Nygaard, H. B., Coffey, E. E., Gunther, E. C., Laurén, J., Gimbel, Z. A., & Strittmatter, S. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0395-10.2010 · Cited by 418 · see citing works
Correlations of synaptic and pathological markers with cognition of the elderly
Dickson, D. W., Crystal, H. A., Bevona, C., Honer, W., Vincent, I., & Davies, P. (1995) · Neurobiology of Aging · doi:10.1016/0197-4580(95)00013-5 · Cited by 410 · see citing works
Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders
DeKosky, S. T., & MAREK, K. L. (2003) · Science · doi:10.1126/science.1090349 · Cited by 403 · see citing works
Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies
Scheff, S. (2003) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.08.002 · Cited by 391 · see citing works
Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction
Reddy, P. H., Mani, G., Park, B. S., Jacques, J., MURDOCH, G. H., Whetsell, W. O., Kaye, J. A., & Mańczak, M. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7203 · Cited by 372 · see citing works
“Preclinical” AD revisited: Neuropathology of cognitively normal older adults
Schmitt, F. A., Davis, D. G., Wekstein, D. R., Smith, C. D., Ashford, J. W., & Markesbery, W. R. (2000) · Neurology · doi:10.1212/wnl.55.3.370 · Cited by 369 · see citing works
Synaptic slaughter in Alzheimer's disease
Coleman, P. (2003) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.09.001 · Cited by 351 · see citing works
Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348 · see citing works
Svennerholm, L. T., & Gottfries, C. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.62031039.x · Cited by 327 · see citing works
Category-Specific Semantic Deficits in Focal and Widespread Brain Damage: A Computational Account
Devlin, J. T., Gonnerman, L. M., Andersen, E. S., & Seidenberg, M. S. (1998) · Journal of Cognitive Neuroscience · doi:10.1162/089892998563798 · Cited by 327 · see citing works
Arendt, T., Schindler, C., Brückner, M. K., Eschrich, K., Bigl, V., Zedlick, D., & Marcova, L. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-02-00516.1997 · Cited by 319 · see citing works
A focus on the synapse for neuroprotection in Alzheimer disease and other dementias
Coleman, P., Federoff, H., & Kurlan, R. (2004) · Neurology · doi:10.1212/01.wnl.0000140626.48118.0a · Cited by 314 · see citing works
Law, A. (2001) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00051-5 · Cited by 312 · see citing works
Microtubule Reduction in Alzheimer's Disease and Aging Is Independent of τ Filament Formation
Cash, A., Aliev, G. M., Siedlak, S. L., Nunomura, A., Fujioka, H., Zhu, X., Raina, A. K., Vinters, H. V., Tabaton, M., Johnson, T., et al. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64296-4 · Cited by 309 · see citing works
In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET
Mecca, A. P., Chen, M., O'Dell, R. S., Naganawa, M., Toyonaga, T., Godek, T. A., Harris, J. E., Bartlett, H. H., Zhao, W., Nabulsi, N. B., et al. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12097 · Cited by 288 · see citing works
Patterns of Motor Impairment in Normal Aging, Mild Cognitive Decline, and Early Alzheimer' Disease
Kluger, A., Gianutsos, J. G., Golomb, J. B., Ferris, S. H., GEORGE, A. E., Franssen, E., & Reisberg, . (1997) · The Journals of Gerontology Series B · doi:10.1093/geronb/52b.1.p28 · Cited by 304 · see citing works
Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer's disease.
Masliah, E., Terry, R. D., Alford, M. F., DeTeresa, R. M., & Hansen, L. A. (1991) · PubMed Central · Cited by 296 · see citing works
Chen, X., & Mobley, W. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00659 · Cited by 291 · see citing works
Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus.
Scheff, S. W., & Price, D. A. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s312 · Cited by 284 · see citing works
Self-citationde Wilde, M. C., Overk, C., Sijben, J., & Masliah, E. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.12.005 · Cited by 273 · see citing works
Kanaan, N. M., Morfini, G. A., LaPointe, N. E., Pigino, G. F., Patterson, K. R., Song, Y., Andreadis, A., Fu, Y., Brady, S. T., & Binder, L. I. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0560-11.2011 · Cited by 273 · see citing works
Synapse loss in the temporal lobe in Alzheimer's disease
Scheff, S. W., & PRICE, D. A. (1993) · Annals of Neurology · doi:10.1002/ana.410330209 · Cited by 263 · see citing works
Nakamura, K., Greenwood, A., Binder, L. I., Bigio, E. H., Denial, S., Nicholson, L. K., Zhou, X. Z., & Lu, K. P. (2012) · Cell · doi:10.1016/j.cell.2012.02.016 · Cited by 255 · see citing works
Mild cognitive impairment: pathology and mechanisms
Mufson, E. J., Binder, L. I., Counts, S., DeKosky, S. T., deToledo‐Morrell, L., Ginsberg, S. D., Ikonomović, M. D., Perez, S. E., & Scheff, S. W. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0884-1 · Cited by 258 · see citing works
Patterns of aberrant sprouting in alzheimer's disease
Masliah, E., Mallory, M. E., Hansen, L. A., Alford, M. F., Albright, T., DeTeresa, R. M., Terry, R. D., Baudier, J., & Saitoh, T. (1991) · Neuron · doi:10.1016/0896-6273(91)90170-5 · Cited by 245 · see citing works
Calkins, M. J., & Reddy, P. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.01.007 · Cited by 244 · see citing works
Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease
Overk, C. R., & Masliah, E. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.015 · Cited by 242 · see citing works
Perluigi, M., Coccia, R., & Butterfield, D. A. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4406 · Cited by 229 · see citing works
Fagan, A. M., Bu, G., Sun, Y., Daugherty, A., & Holtzman, D. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.30121 · Cited by 226 · see citing works
Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study
Ferreri, F., Pauri, F., Pasqualetti, P., Fini, R., Forno, G. D., & Rossini, P. M. (2002) · Annals of Neurology · doi:10.1002/ana.10416 · Cited by 223 · see citing works
DeKosky, S. T., Harbaugh, R. E., Schmitt, F. A., Bakay, R. A. E., Chui, H. C., Knopman, D. S., Reeder, T. M., Shetter, A. G., Senter, H. J., Markesbery, W. R., et al. (1992) · Annals of Neurology · doi:10.1002/ana.410320505 · Cited by 222 · see citing works
Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan
Tay, T. L., Béchade, C., D’Andrea, I., St‐Pierre, M., Henry, M. S., Roumier, A., & Tremblay, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00421 · Cited by 211 · see citing works
Counts, S., Nadeem, M., Lad, S. P., Wuu, J., & Mufson, E. J. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-200606000-00007 · Cited by 211 · see citing works
The Eye As a Biomarker for Alzheimer's Disease
Lim, J. K. H., Li, Q.-X., He, Z., Vingrys, A. J., Wong, V. H. Y., Currier, N. V., Mullen, J., Bui, B. V., & Nguyen, C. T. O. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00536 · Cited by 211 · see citing works
Diffuse plaques do not accentuate synapse loss in Alzheimer's disease.
(1990) · Europe PMC (PubMed Central) · Cited by 209 · see citing works
A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment
Das, B., & Yan, R. (2019) · CNS Drugs · doi:10.1007/s40263-019-00613-7 · Cited by 169 · see citing works
Yao, P. J., Zhu, M., Pyun, E. I., Brooks, A. I., Therianos, S., Meyers, V. E., & Coleman, P. D. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(02)00009-8 · Cited by 205 · see citing works
Calcium/calmodulin-dependent kinase II and Alzheimer’s disease
Ghosh, A., & Giese, K. P. (2015) · Molecular Brain · doi:10.1186/s13041-015-0166-2 · Cited by 205 · see citing works
Fractionating verbal episodic memory in Alzheimer's disease
Wolk, D. A., & Dickerson, B. C. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.09.005 · Cited by 203 · see citing works
Colom‐Cadena, M., Davies, C., Sirisi, S., Lee, J., Simzer, E. M., Tzioras, M., Querol‐Vilaseca, M., Sánchez‐Aced, É., Chang, Y. Y., Holt, K., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.020 · Cited by 203 · see citing works
Synapse pathology in Alzheimer’s disease
Griffiths, J., & Grant, S. G. N. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.028 · Cited by 203 · see citing works
Meftah, S., & Gan, J. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2023.1129036 · Cited by 197 · see citing works
Arendt, T. (2003) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2003.09.007 · Cited by 188 · see citing works
Heat stress-induced memory impairment is associated with neuroinflammation in mice
Lee, W., Moon, M., Kim, H. G., Lee, T. H., & Oh, M. S. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0324-6 · Cited by 188 · see citing works
Neely, M. D., Sidell, K. R., Graham, D. G., & Montine, T. J. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0722323.x · Cited by 186 · see citing works
Geula, C. (1998) · Neurology · doi:10.1212/wnl.51.1_suppl_1.s18 · Cited by 184 · see citing works
Reimagining cholinergic therapy for Alzheimer’s disease
Giacobini, E., Cuello, A. C., & Fisher, A. (2022) · Brain · doi:10.1093/brain/awac096 · Cited by 187 · see citing works
LoPachin, R. M., Barber, D. S., & Gavin, T. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm301 · Cited by 182 · see citing works
Regional synaptic pathology in Alzheimer's disease
Honer, W. G., Dickson, D. W., Gleeson, J., & Davies, P. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90111-a · Cited by 179 · see citing works
Chen, X., & Mobley, W. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00446 · Cited by 174 · see citing works
Clare, R., King, V. G., Wirenfeldt, M., & Vinters, H. V. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22392 · Cited by 163 · see citing works
Immunoelectron microscopic study of synaptic pathology in Alzheimer's disease
Masliah, E., Hansen, L. A., Albright, T., Mallory, M. E., & Terry, R. D. (1991) · Acta Neuropathologica · doi:10.1007/bf00293464 · Cited by 174 · see citing works
Hippocampal plasticity during the progression of Alzheimer’s disease
Mufson, E. J., Mahady, L. J., Waters, D., Counts, S., Perez, S. E., DeKosky, S. T., Ginsberg, S. D., Ikonomović, M. D., Scheff, S. W., & Binder, L. I. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.03.006 · Cited by 172 · see citing works
Neuroplasticity in Alzheimer's disease
Teter, B., & Ashford, J. W. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10441 · Cited by 170 · see citing works
Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization
Arendt, T. (2001) · Neuroscience · doi:10.1016/s0306-4522(00)00516-9 · Cited by 168 · see citing works
(1994) · PubMed Central · Cited by 169 · see citing works
Masliah, E., Iwai, A., Mallory, M. E., Uéda, K., & Saitoh, T. (1996) · Europe PMC (PubMed Central) · Cited by 166 · see citing works
Lassmann, H., Weiler, R., Fischer, P. A., Bancher, C., Jellinger, K. A., Floor, E., Danielczyk, W., SEITELBERGER, F., & Winkler, H. J. S. (1992) · Neuroscience · doi:10.1016/0306-4522(92)90003-k · Cited by 160 · see citing works
Haas, L. T., Salazar, S. V., Kostylev, M. A., Um, J. W., Kaufman, A. C., & Strittmatter, S. M. (2015) · Brain · doi:10.1093/brain/awv356 · Cited by 140 · see citing works
D’Andrea, M. R., & Nagele, R. G. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206775474224 · Cited by 147 · see citing works
Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment
Bell, K. F. S., Bennett, D. A., & Cuello, A. C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3269-07.2007 · Cited by 145 · see citing works
The Role of Synaptic Proteins in the Pathogenesis of Disorders of the Central Nervous System
Masliah, E., & Terry, R. D. (1993) · Brain Pathology · doi:10.1111/j.1750-3639.1993.tb00728.x · Cited by 142 · see citing works
Duits, F. H., Brinkmalm, G., Teunissen, C. E., Brinkmalm, A., Scheltens, P., Van der Flier, W. M., Zetterberg, H., & Blennow, K. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0335-x · Cited by 137 · see citing works
The amyloid pathology progresses in a neurotransmitter-specific manner
Bell, K. F. S., Ducatenzeiler, A., Ribeiro‐da‐Silva, A., Duff, K., Bennett, D. A., & Cuello, A. C. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.034 · Cited by 134 · see citing works
Synaptic remodeling during aging and in Alzheimer's disease
Masliah, E., Crews, L., & Hansen, L. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s311 · Cited by 132 · see citing works
Synaptic phosphorylated α-synuclein in dementia with Lewy bodies
Colom‐Cadena, M., Pegueroles, J., Herrmann, A. G., Henstridge, C. M., Muñoz, L., Querol‐Vilaseca, M., Martín-Paniello, C. S., Luque-Cabecerans, J., Clarimón, J., Belbin, O., et al. (2017) · Brain · doi:10.1093/brain/awx275 · Cited by 123 · see citing works
β-Amyloid-induced Dynamin 1 Depletion in Hippocampal Neurons
Kelly, B. L., Vassar, R. J., & Ferreira, A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503259200 · Cited by 127 · see citing works
Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice
Kurt, M. A., Davies, D. C., Kidd, M., Dierssen, M., & Flórez, J. (2000) · Brain Research · doi:10.1016/s0006-8993(00)01984-3 · Cited by 127 · see citing works
Ayberk Kurt, M., Ilker Kafa, M., Dierssen, M., & Ceri Davies, D. (2004) · Brain Research · doi:10.1016/j.brainres.2004.06.075 · Cited by 126 · see citing works
ProNGF and Neurodegeneration in Alzheimer’s Disease
Fahnestock, M. L., & Shekari, A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00129 · Cited by 127 · see citing works
Alzheimer 100 – highlights in the history of Alzheimer research
Jellinger, K. A. (2006) · Journal of Neural Transmission · doi:10.1007/s00702-006-0578-3 · Cited by 124 · see citing works
Synaptic alterations in the rTg4510 mouse model of tauopathy
Kopeikina, K. J., Polydoro, M., Tai, H., Yaeger, E., Carlson, G. A., Pitstick, R., Hyman, B. T., & Spires‐Jones, T. L. (2012) · The Journal of Comparative Neurology · doi:10.1002/cne.23234 · Cited by 125 · see citing works
Chiang, M., Cheng, Y., Chen, S., Yen, C., & Huang, R. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.08.013 · Cited by 123 · see citing works
Alzheimer's disease and aging: Effects on perforant pathway perikarya and synapses
Lippa, C. F., Hamos, J. E., Pulaski-Salo, D., DeGennaro, L. J., & Drachman, D. A. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90115-e · Cited by 122 · see citing works
ADAM-10 over-expression increases cortical synaptogenesis
Bell, K. F. S., Zheng, L., Fahrenholz, F., & Cuello, A. C. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.11.004 · Cited by 120 · see citing works
Haas, L. T., Salazar, S. V., Smith, L. M., Zhao, H. R., Cox, T. O., Herber, C. S., Degnan, A. P., Balakrishnan, A., Macor, J. E., Albright, C. F., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.023 · Cited by 117 · see citing works
Is synaptic loss a unique hallmark of Alzheimer’s disease?
Scheff, S. W., Neltner, J. H., & Nelson, P. T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.028 · Cited by 118 · see citing works
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
Landfield, P. W., Thibault, O., Mazzanti, M. L., Porter, N. M., & Kerr, D. S. (1992) · Journal of Neurobiology · doi:10.1002/neu.480230914 · Cited by 118 · see citing works
Synaptic Dysfunction in Alzheimer’s Disease: Aβ, Tau, and Epigenetic Alterations
Li, K., Wei, Q., Liu, F., Hu, F., Xie, A., Zhu, L., & Liu, D. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0533-3 · Cited by 119 · see citing works
Kazim, S. F., & Iqbal, K. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0119-y · Cited by 118 · see citing works
Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα
Mockett, B. G., Richter, M., Abraham, W. C., & Müller, U. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00030 · Cited by 115 · see citing works
Synaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 113 · see citing works
- Authors
- Scheff, S. W., DeKosky, S. T., & Price, D. A.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Scheff, Stephen W.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 1990-01
- Volume
- 11
- Issue
- 1
- Pages
- 29-37
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2083752135
- Cited by
- 446
- References
- 41
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 14 · 2023: 19 · 2022: 16 · 2021: 14 · 2020: 19 · 2019: 14 · 2018: 15 · 2017: 12 · 2016: 17 · 2015: 21 · 2014: 13 · 2013: 16 · 2012: 16
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Kentucky
- National Institute on Aging (P50AG005144, AG-05144, P01AG005119, AG0 5119)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, synaptic density, synapse size, postsynaptic density, frontal cortex, Brodmann area 9, cortical layers, synaptic loss, postmortem interval, neuropathology
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cell Count, Cerebral Cortex, Female, Humans, Male, Middle Aged, Nerve Degeneration, Synapses, In Vitro Techniques
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