Alzheimer neuropathologic alterations in aged cognitively normal subjects
Abstract
The histopathologic changes distinguishing early Alzheimer disease (AD) from normal or pathologic aging are not clearly defined. This report describes the autopsy findings of 59 elderly, well-educated, volunteers. They were examined longitudinally with mental status testing, some for up to 8 years, as part of our normal aging study. This study reveals that (1) the brains of many subjects who did not show cognitive impairment on neuropsychologic testing contain abundant senile plaques (SP) and/or neurofibrillary tangles (NFT); (2) 29 subjects met Khachaturian criteria for AD, 15 met CERAD and 7 met National Institute on Aging-Reagan Institute guidelines; (3) Braak and Braak staging method included 9 in stage IV subjects, 4 in stage V, and 1 in stage VI; (4) there was a progression of NFT from entorhinal cortex to hippocampus and amygdala as a function of age; (5) 2 subjects met criteria for a diagnosis of dementia with Lewy bodies but were not demented; (6) cerebral amyloid angiopathy was present in leptomeningeal vessels in 75% of subjects and in parenchymal vessels in 62% of subjects; (7) only 10 of 59 subjects (17%) had no or few degenerative brain changes. Our study demonstrates that the brains of a large percentage of cognitively normal, relatively well-educated individuals contain numerous degenerative changes and only a small percentage are relatively free of these changes.
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A sizable percentage of non-demented elderly have plaques.
“Decades of clinical-pathological correlative studies, now corroborated by a decade of neuroimaging studies, also demonstrate a sizable percentage of the non-demented elderly have plaques [40, 51, 54, 55, 58–68].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [60]
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BackgroundPrimary age-related tauopathy (PART): a common pathology associated with human aging
Crary, J. F., Trojanowski, J. Q., Schneider, J. A., Abisambra, J. F., Abner, E. L., Alafuzoff, I., Arnold, S. E., Attems, J., Beach, T. G., Bigio, E. H., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1349-0 · Cited by 1,467 · see citing works
“Biomarker-based clinical research supports the claim, initially made based on the autopsy studies of putatively cognitively intact people [36, 88] and of persons with mild cognitive impairment (MCI) [83, 93, 113], that tauopathy in the absence of A β -type amyloidosis is common.”
ResultHolmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R. W., Bullock, R., Love, S., Neal, J. W., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61075-2 · Cited by 1,416 · see citing works
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PET Imaging of Tau Deposition in the Aging Human Brain
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“Neuropathological studies have repeatedly demonstrated that these aggregated proteins also accumulate in the brains of cognitively healthy older people (Bennett et al., 2006; Davis et al., 1999).”
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
Self-citationClassification and basic pathology of Alzheimer disease
Duyckaerts, C., Delatour, B., & Potier, M.-C. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0532-1 · Cited by 1,031 · see citing works
“The case–control type of study is difficult to apply to AD, since the control group, if matched for age, is invariably contaminated by pre-symptomatic cases [74].”
BackgroundThe neuropathology of probable Alzheimer disease and mild cognitive impairment
Schneider, J. A., Arvanitakis, Z., Leurgans, S. E., & Bennett, D. A. (2009) · Annals of Neurology · doi:10.1002/ana.21706 · Cited by 935 · see citing works
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Self-citationAlzheimer Disease as a Vascular Disorder
de la Torre, J. C. (2002) · Stroke · doi:10.1161/01.str.0000014421.15948.67 · Cited by 844 · see citing works
Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
Kametani, F., & Hasegawa, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00025 · Cited by 836 · see citing works
“Further, in the brain of elderly non-demented patients, the distribution of senile plaques is sometimes as extensive as that of dementia patients (Davis et al., 1999; Fagan et al., 2009; Price et al., 2009; Chetelat et al., 2013).”
BackgroundIs Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics
de la Torre, J. C. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00683-0 · Cited by 834 · see citing works
A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease
Swerdlow, R. H., & Khan, S. M. (2004) · Medical Hypotheses · doi:10.1016/j.mehy.2003.12.045 · Cited by 758 · see citing works
“Second, plaques are a relatively common finding in the non-demented elderly [20–22].”
BackgroundReview: Alzheimer's Amyloid β-Peptide-Associated Free Radical Oxidative Stress and Neurotoxicity
Varadarajan, S., Yatin, S., Aksenova, M., & Butterfield, D. A. (2000) · Journal of Structural Biology · doi:10.1006/jsbi.2000.4274 · Cited by 735 · see citing works
The overlap between vascular disease and Alzheimer’s disease - lessons from pathology
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“, small or large cerebral infarcts, lacunes, and WMLs, in up to 10% [10,165-167].”
BackgroundEpisodic memory loss is related to hippocampal-mediated -amyloid deposition in elderly subjects
Mormino, E. C., Kluth, J. T., Madison, C. M., Rabinovici, G. D., Baker, S. L., Miller, B. L., Koeppe, R. A., Mathis, C. A., Weiner, M. W., Jagust, W. J., et al. (2009) · Brain · doi:10.1093/brain/awn320 · Cited by 684 · see citing works
“pathology in normal elderly subjects (Tomlinson et al., 1968; Hulette et al., 1998; Davis et al., 1999; Price and Morris, 1999; Knopman et al., 2003; Bennett et al., 2006), and it has been”
BackgroundNeuropathology of Cognitively Normal Elderly
Knopman, D. S., Parisi, J. E., Salviati, A., Floriach-Robert, M., Boeve, B. F., Ivnik, R. J., Smith, G. E., Dickson, D. W., Johnson, K. A., Petersen, L. E., et al. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.11.1087 · Cited by 674 · see citing works
“In light of the pivotal importance of studies of wellcharacterized nondemented individuals, as well as the variability of AD pathology of normal subjects in the recent studies (7, 8), we analyzed the neuropathological features in prospectively recruited, prospectively diag-”
BackgroundNeuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship
Nelson, P. T., Braak, H., & Markesbery, W. R. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181919a48 · Cited by 643 · see citing works
“These data support the accuracy of the high likelihood NIARI criteria, but leave unanswered the important question: are there nondemented persons with truly end-stage AD-type pathology? We addressed this issue using data from the University of Kentucky Alzheimer’s Disease Center autopsy series (62, 63).”
MethodSelf-citationAntemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia
Jack, C. R., Dickson, D. W., Parisi, J. E., Xu, Y. C., Cha, R. H., O’Brien, P. C., Edland, S. D., Smith, G. E., Boeve, B. F., Tangalos, E. G., et al. (2002) · Neurology · doi:10.1212/wnl.58.5.750 · Cited by 610 · see citing works
Involvement of oxidative stress in Alzheimer disease
Nunomura, A., Castellani, R. J., Zhu, X., Moreira, P. I., Perry, G., & Smith, M. A. (2006) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/01.jnen.0000228136.58062.bf · Cited by 611 · see citing works
Sochocka, M., Donskow-Łysoniewska, K., Diniz, B. S., Kurpas, D., Brzozowska, E., & Leszek, J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1188-4 · Cited by 584 · see citing works
Neurofibrillary Tangles, Amyloid, and Memory in Aging and Mild Cognitive Impairment
Guillozet-Bongaarts, A. L., Weıntraub, S., Mash, D. C., & Mesulam, M. M. (2003) · Archives of Neurology · doi:10.1001/archneur.60.5.729 · Cited by 572 · see citing works
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“The idea of reserve against brain damage comes from the repeated observation [1-5] of individuals who manage to function clinically in the face of brain pathology.”
BackgroundCognitive status correlates with neuropathologic stage in Parkinson disease
Braak, H., Rüb, U., Steur, E. N. H. J., Tredici, K. D., & de Vos, R. A. I. (2005) · Neurology · doi:10.1212/01.wnl.0000158422.41380.82 · Cited by 555 · see citing works
Evidence of increased oxidative damage in subjects with mild cognitive impairment
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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
“In one study only 17% of cognitively normal elderly patients had few or no degenerative brain changes [79], and in neuroimaging amyloid-PET studies 10-30% of cognitively normal individuals have amyloidpositive scans [80].”
BackgroundEnvironmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Jankowsky, J. L., Melnikova, T., Fadale, D. J., Xu, G. M., Slunt, H. H., Gonzales, V., Younkin, L. H., Younkin, S. G., Borchelt, D. R., & Savonenko, A. V. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5080-04.2005 · Cited by 517 · see citing works
“Moreover, multiple studies from the clinical literature have documented patients with preserved cognitive function despite the presence of neuritic plaques and/or neurofibrillary tangles at levels normally diagnostic of Alzheimer’s disease (Katzman et al., 1988; Dickson et al., 1992; Sparks et al., 1993, 1995, and ref…”
BackgroundAlzheimer and frontotemporal pathology in subsets of primary progressive aphasia
Mesulam, M., Wicklund, A., Johnson, N., Rogalski, E., Léger, G. C., Rademaker, A., Weintraub, S., & Bigio, E. H. (2008) · Annals of Neurology · doi:10.1002/ana.21388 · Cited by 513 · see citing works
“The one significant correlate of AD pathology was age at death, an interesting relation in light of the correlation of autopsy age to NFT density, even in nondemented subjects.(42,43) The often-quoted statement that PPA can be caused by atypically distributed AD pathology may therefore need to be revised.”
BackgroundTDP-43 is a key player in the clinical features associated with Alzheimer’s disease
Josephs, K. A., Whitwell, J. L., Weigand, S. D., Murray, M. E., Tosakulwong, N., Liesinger, A. M., Petrucelli, L., Senjem, M. L., Knopman, D. S., Boeve, B. F., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1269-z · Cited by 481 · see citing works
The importance of neuritic plaques and tangles to the development and evolution of AD
Tiraboschi, P., Hansen, L. A., Thal, L. J., & Corey-Bloom, J. (2004) · Neurology · doi:10.1212/01.wnl.0000129697.01779.0a · Cited by 477 · see citing works
Cognitive reserve and the neurobiology of cognitive aging
Whalley, L. J., Deary, I. J., Appleton, C. L., & Starr, J. M. (2004) · Ageing Research Reviews · doi:10.1016/j.arr.2004.05.001 · Cited by 460 · see citing works
“Senile plaque density does not contribute reliably to the likelihood of a clinical dementia diagnosis and age-related neurodegenerative changes are commonplace with or without a dementia diagnosis (Davis et al., 1999; Morris and Price, 2001).”
BackgroundDiagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People
De Meyer, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.179 · Cited by 462 · see citing works
“This is not surprising because many neuropathological studies on cognitively normal elderly individuals reveal that a large portion of healthy elderly individuals exhibit amyloid-containing plaques and taucontaining neurofibrillary tangles in their brains.(21,22) Moreover, Pittsburgh Compound B positron emission tomog…”
Neuropathologic Substrate of Mild Cognitive Impairment
Markesbery, W. R., Schmitt, F. A., Kryscio, R. J., Davis, D. G., Smith, C. D., & Wekstein, D. R. (2006) · Archives of Neurology · doi:10.1001/archneur.63.1.38 · Cited by 460 · see citing works
Self-citationBacskai, B. J., Kajdasz, S. T., Christie, R. H., Carter, C., Games, D., Seubert, P. A., Schenk, D., & Hyman, B. T. (2001) · Nature Medicine · doi:10.1038/85525 · Cited by 445 · see citing works
Neuroplasticity Failure in Alzheimer's Disease
Mesulam, M.-M. (1999) · Neuron · doi:10.1016/s0896-6273(00)81109-5 · Cited by 449 · see citing works
Pathological correlates of dementia in a longitudinal, population‐based sample of aging
Sonnen, J. A., Larson, E. B., Crane, P. K., Haneuse, S., Li, G., Schellenberg, G. D., Craft, S., Leverenz, J. B., & Montine, T. J. (2007) · Annals of Neurology · doi:10.1002/ana.21208 · Cited by 432 · see citing works
“These values are in close agreement with ROS, HAAS, and normal elderly individuals observed longitudinally at the University of Kentucky.(5,20,35) Like neuritic plaques and neurofibrillary tangles, accumulation of LBs is an imperfect structural indicator of complex underlying biochemical processes that contribute to d…”
ResultClinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease
Harding, A. J., Stimson, E., Henderson, J. M., & Halliday, G. M. (2002) · Brain · doi:10.1093/brain/awf251 · Cited by 445 · see citing works
“The amygdala is a region in which age-related pathology is common (Iseki et al., 1996; Anderton, 1997; Davis et al., 1999), and the exclusion of cases with age- or dementia-related neuro®brillary tangles in this region signi®cantly restricted the number of Parkinson's disease cases that could be…”
BackgroundNeuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia
Jicha, G. A., Parisi, J. E., Dickson, D. W., Johnson, K., Cha, R., Ivnik, R. J., Tangalos, E. G., Boeve, B. F., Knopman, D. S., Braak, H., et al. (2006) · Archives of Neurology · doi:10.1001/archneur.63.5.674 · Cited by 399 · see citing works
“While neurofibrillary degeneration confined to limbic regions (Braak stages III-IV) can be seen in cognitively normal individuals, it is often associated with cognitive and functional impairment sufficient to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(24) criteria for dementia in others…”
BackgroundRiley, K. P., Snowdon, D. A., & Markesbery, W. R. (2002) · Annals of Neurology · doi:10.1002/ana.10161 · Cited by 392 · see citing works
“However, while the overall correlation was strong, there was a wide range of cognitive states within the Braak stages, consistent with previous reports.(24,28,32,33,37,39) In our study, Braak stages I and II showed the greatest variability, while in other reports stages III or IV seemed to be the most diverse in terms…”
ResultSelf-citationAstrocyte phenotype in relation to Alzheimer‐type pathology in the ageing brain
Simpson, J. E., Ince, P. G., Lace, G., Forster, G., Shaw, P. J., Matthews, F., Savva, G., Brayne, C., & Wharton, S. B. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.05.015 · Cited by 381 · 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
Self-citationDrake, J. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00225-7 · Cited by 371 · see citing works
“There are many observations that are inconsistent with the hypothesis that fibrils are necessary for A toxicity, i.e. amyloid deposits do not correlate with dementia [2] [5] [37] [38] [44]; non-demented individuals may exhibit plaques [10].”
ResultAge-related changes in the default mode network are more advanced in Alzheimer disease
Jones, D. T., Machulda, M. M., Vemuri, P., McDade, E. M., Zeng, G., Senjem, M. L., Gunter, J. L., Przybelski, S. A., Avula, R. T., Knopman, D. S., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e318233b33d · Cited by 370 · see citing works
Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?
Tomljenovic, L. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101494 · Cited by 371 · see citing works
“de at h [5 7, 24 8, 25 2, 29 2– 29 4] D ec lin e in m em or y, im pa ir ed”
BackgroundInfluentialThe Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease
Sabuncu, M. R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.167 · Cited by 360 · see citing works
Parkkinen, L., Pirttilä, T., & Alafuzoff, I. I. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0346-6 · Cited by 357 · see citing works
“Some authors have emphasized their key causative role [1, 18, 21, 26], whereas others have reported that there may be abundant cortical pathology in non-demented PD patients [8] as well as in neurologically unimpaired subjects [ 10 , 24, 32].”
BackgroundMormino, E. C., Smiljic, A., Hayenga, A. O., Onami, S. H., Greicius, M. D., Rabinovici, G. D., Janabi, M., Baker, S. L., Yen, I. V., Madison, C. M., et al. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr025 · Cited by 332 · see citing works
“…(Ab) plaques are a hallmark of Alzheimer’s disease (AD) (Walsh and Selkoe 2007), this pathology is frequently found in cognitively intact older people (Tomlinson et al. 1968; Hulette et al. 1998; Davis et al. 1999; Price and Morris 1999; Knopman et al. 2003; Bennett et al. 2006; Savva et al. 2009).”
BackgroundInfluentialJantzen, P. T., Connor, K. E., DiCarlo, G., Wenk, G. L., Wallace, J. L., Rojiani, A. M., Coppola, D., Morgan, D., & Gordon, M. N. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02246.2002 · Cited by 337 · see citing works
“At autopsy, a significant fraction of cognitively normal aged individuals present densities of amyloid plaques and neurofibrillary tangles consistent with a diagnosis of AD (Crystal et al., 1988; Davis et al., 1999).”
Backgroundα‐Synuclein pathology does not predict extrapyramidal symptoms or dementia
Parkkinen, L., Kauppinen, T., Pirttilä, T., Autere, J. M., & Alafuzoff, I. I. (2004) · Annals of Neurology · doi:10.1002/ana.20321 · Cited by 315 · see citing works
“disease or development of a nonspecific “senile degenerative” change similar to the AD-related pathology seen in a proportion of the nondemented elderly population.(6,16,18,22,23) An important issue with respect to pathogenesis is not only to understand how the pathological process develops but also where it first app…”
BackgroundLoss of motor function in preclinical Alzheimer's disease
Buchman, A. S., & Bennett, D. A. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.11.57 · Cited by 311 · see citing works
Brain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · see citing works
“Decades of clinical-pathological correlative studies, now corroborated by a decade of neuroimaging studies, also demonstrate a sizable percentage of the non-demented elderly have plaques [40, 51, 54, 55, 58–68].”
ResultSynaptic Loss in the Inferior Temporal Gyrus in Mild Cognitive Impairment and Alzheimer's Disease
Scheff, S. W., PRICE, D. A., Schmitt, F. A., Scheff, M. A., & Mufson, E. J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101782 · Cited by 301 · see citing works
“8 years; range 75 to 99 years; Table 1) who were participants in either the Religious Orders Study (ROS), a longitudinal clinical-pathologic study of aging and Alzheimer’s disease composed of older Catholic nuns, priests, and brothers [20–22], or the University of Kentucky Alzheimer’s Disease Center (UKADC) normal agi…”
Self-citationMeasuring cognitive reserve based on the decomposition of episodic memory variance
Reed, B. R., Mungas, D., Farias, S. T., Harvey, D., Beckett, L., Widaman, K., Hinton, L., & DeCarli, C. (2010) · Brain · doi:10.1093/brain/awq154 · Cited by 271 · see citing works
“…of old people who are cognitively normal and stable prior to death will be found to have sufficient Alzheimer’s disease path- ology post-mortem to meet neuropathological criteria for Alzheimer’s disease (Davis et al., 1999; Schmitt et al., 2000; Bennett et al., 2006; Driscoll et al., 2006).”
BackgroundThe gut microbiome in Alzheimer’s disease: what we know and what remains to be explored
Chandra, S., Sisodia, S. S., & Vassar, R. J. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00595-7 · Cited by 278 · see citing works
“Moreover, Aβ plaques can be present in cognitively normal individuals [68].”
BackgroundHippocampal sclerosis in advanced age: clinical and pathological features
Nelson, P. T., Schmitt, F. A., Lin, Y., Abner, E. L., Jicha, G. A., Patel, E., Thomason, P. C., Neltner, J. H., Smith, C. D., Santacruz, K. S., et al. (2011) · Brain · doi:10.1093/brain/awr053 · Cited by 279 · see citing works
“Pathological assessments were performed at the University of Kentucky on all the cases, and the methodology has been described in detail (Davis et al., 1999; Wolf et al., 1999; Riley et al., 2002; Nelson et al., 2007, 2009).”
MethodSelf-citationInterface between tauopathies and synucleinopathies: A tale of two proteins
Galpern, W. R., & Lang, A. E. (2006) · Annals of Neurology · doi:10.1002/ana.20819 · Cited by 262 · see citing works
“With respect to the overlap of tau and AS, analysis of brains from patients with PD shows that 30 to 43% fulfil Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria for a pathological diagnosis of AD(40,41) compared with 18 to 25% of cognitively normal elderly persons.(35,42,43) This pathologica…”
BackgroundWang, L., Swank, J. S., Glick, I. E., Gado, M. H., Miller, M. I., Morris, J. C., & Csernansky, J. G. (2003) · NeuroImage · doi:10.1016/s1053-8119(03)00361-6 · Cited by 263 · see citing works
Aging‐dependent changes of microglial cells and their relevance for neurodegenerative disorders
Von Bernhardi, R., Tichauer, J. E., & Eugenín, J. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06537.x · Cited by 258 · see citing works
Early-Life Risk Factors for Alzheimer Disease
Borenstein, A. R., Copenhaver, C. I., & Mortimer, J. A. (2006) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000201854.62116.d7 · Cited by 259 · see citing works
Bates, K. A., Verdile, G., Li, Q.-X., Ames, D., Hudson, P., Masters, C. L., & Martins, R. N. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.96 · Cited by 247 · see citing works
Vascular pathologies and cognition in a population-based cohort of elderly people
Fernando, M. S., & Ince, P. G. (2004) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.09.004 · Cited by 239 · see citing works
“An autopsy cohort of elderly people prospectively assessed at 6-month intervals up to death showed a similar proportion with a high density of neocortical neuritic plaques in nondemented elderly people [10].”
BackgroundCognitive Reserve and Alzheimer’s Disease
Xu, W., Yu, J., Tan, M., & Tan, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8720-y · Cited by 240 · see citing works
“Scarmeas N , Albert SM , Manly JJ , Stern Y ( 2006 ) Education and rates of cognitive decline in incident Alzheimer ' s disease .”
BackgroundVascular Basis of Alzheimer's Pathogenesis
de la Torre, J. C. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04817.x · Cited by 236 · see citing works
Aging of the brain, entropy, and Alzheimer disease
Drachman, D. A. (2006) · Neurology · doi:10.1212/01.wnl.0000240127.89601.83 · Cited by 230 · see citing works
A critical reappraisal of current staging of Lewy-related pathology in human brain
Jellinger, K. A. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0406-y · Cited by 229 · see citing works
“demonstrated that some subjects may tolerate substantial amounts of both AS and tau pathology without deWnite clinical manifestation, suggesting considerable compensatory mechanisms even of the aging brain [35, 95, 129, 146, 147].”
BackgroundA critical evaluation of current staging of α-synuclein pathology in Lewy body disorders
Jellinger, K. A. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.07.006 · Cited by 229 · see citing works
AD lesions and infarcts in demented and non‐demented Japanese‐American men
Petrovitch, H., Ross, G. W., Steinhorn, S. C., Abbott, R. D., Markesbery, W., Davis, D., Nelson, J., Hardman, J., Masaki, K., Vogt, M. R., et al. (2005) · Annals of Neurology · doi:10.1002/ana.20318 · Cited by 230 · see citing works
Self-citationKelleher, R. J., & Soiza, R. L. (2013) · Europe PMC (PubMed Central) · Cited by 225 · see citing works
Drachman, D. A. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.11.003 · Cited by 224 · see citing works
“[34] Davis DG, Schmitt FA, Wekstein DR, Markesbery WR.”
Backgroundβ‐amyloid burden is not associated with rates of brain atrophy
Josephs, K. A., Whitwell, J. L., Ahmed, Z., Shiung, M. M., Weigand, S. D., Knopman, D. S., Boeve, B. F., Parisi, J. E., Petersen, R. C., Dickson, D. W., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21223 · Cited by 224 · see citing works
The enigma of vascular cognitive disorder and vascular dementia
Jellinger, K. A. (2007) · Acta Neuropathologica · doi:10.1007/s00401-006-0185-2 · Cited by 221 · see citing works
“Periventricular WMLs predict the rate of cognitive decline [102], and they are often”
BackgroundVascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.
Román, G. C., & Kalaria, R. N. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.10.004 · Cited by 213 · see citing works
“[34] Davis DG, Schmitt FA, Wekstein DR, Markesbery WR.”
BackgroundVAN HOESEN, G. W., AUGUSTINACK, J. C., DIERKING, J., REDMAN, S. J., & THANGAVEL, R. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06731.x · Cited by 211 · see citing works
Lewy Body Pathology in Normal Elderly Subjects
Markesbery, W. R., Jicha, G. A., Liu, H., & Schmitt, F. A. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181ac10a7 · Cited by 210 · see citing works
“The subjects studied in this report were from the University of Kentucky Alzheimer’s Disease Center normal volunteer control group (17, 18).”
Self-citationCognitive decline correlates with neuropathological stage in Parkinson's disease
Braak, H., Rüb, U., & Tredici, K. D. (2006) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2006.05.011 · Cited by 210 · see citing works
Alzheimer’s Disease And Inflammation: A Review Of Cellular And Therapeutic Mechanisms
Halliday, G. M., Robinson, S. R., Shepherd, C. E., & Kril, J. J. (2000) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2000.03200.x · Cited by 206 · see citing works
“In almost every published prospective postmortem study of normal ageing, extensive b-amyloid deposits have been found in the cerebral cortices of cognitively intact elderly people.(2,4) It is now thought that deposition of b-amyloid in the brain is an inevitable consequence of ageing.”
BackgroundAltered Proteins in the Aging Brain
Elobeid, A., Libard, S., Leino, M., Popova, S. N., & Alafuzoff, I. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw002 · Cited by 202 · see citing works
“This significant difference is probably due to the number of sections assessed: 1 by us and 4 by Davis et al (17).”
Attems, J., Jellinger, K. A., & Lintner, F. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1064-y · Cited by 188 · see citing works
“It is a common finding in the brains of elderly demented and non-demented individuals, its incidence and severity increase with age [10, 12, 18, 23, 39, 40, 41, 52, 61], and the severity is associated with cerebral hemorrhages, infarctions, and white matter lesions [6, 18, 31, 32, 33, 3, 39, 40, 41, 49, 52] (for revie…”
BackgroundAltered brain activation in cognitively intact individuals at high risk for Alzheimer’s disease
Smith, C. D., Andersen, A. H., Kryscio, R. J., Schmitt, F. A., Kindy, M. S., Blonder, L. X., & Avison, M. J. (1999) · Neurology · doi:10.1212/wnl.53.7.1391 · Cited by 194 · see citing works
Self-citationSimpson, J. E., Ince, P. G., Shaw, P. J., Heath, P. R., Raman, R., Garwood, C. J., Gelsthorpe, C., Baxter, L., Forster, G., Matthews, F. E., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.04.013 · Cited by 188 · see citing works
Age‐related differences in the medial temporal lobe responses to emotional faces as revealed by fMRI
Iidaka, T., Okada, T., Murata, T., Omori, M., Kosaka, H., Sadato, N., & Yonekura, Y. (2002) · Hippocampus · doi:10.1002/hipo.1113 · Cited by 191 · see citing works
“It is well-established that structures in the medial temporal lobe are particularly vulnerable to aging, as confirmed by neuropathological (Giannakopoulos et al., 1997; Davis et al., 1999) and MRI volumetric (Jack et al.”
Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging
Silverberg, G. D., Messier, A. A., Miller, M. C., Machan, J. T., Majmudar, S. S., Stopa, E. G., Donahue, J. E., & Johanson, C. E. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181f46e25 · Cited by 191 · see citing works
“Pathological studies have, however, also shown that amyloid plaques and neurofibrillary tangles occur in the brains of aging subjects without dementia (44, 45).”
BackgroundSchmitt, F. A., Nelson, P. T., Abner, E. L., Scheff, S. W., Jicha, G. A., Smith, C. D., Cooper, G. E., Mendiondo, M. S., Danner, D. D., Eldik, L. J. V., et al. (2012) · Current Alzheimer Research · doi:10.2174/156720512801322591 · Cited by 184 · see citing works
“It was later recognized (in 1999 [19]) that moderate neuropathological changes along the AD spectrum may be seen in some individuals who evidenced little change on standard clinical assessments [19].”
BackgroundMethodSelf-citationNatural animal models of human psychiatric conditions: assessment of mechanism and validity
Overall, K. L. (2000) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(00)00104-4 · Cited by 190 · see citing works
Hamilton, R. H., Patel, S. V., Lee, E. B., Jackson, E. M., Lopinto, J., Arnold, S. E., Clark, C. M., Basil, A. K., Shaw, L. M. J., Xie, S. X., et al. (2010) · Annals of Neurology · doi:10.1002/ana.22015 · Cited by 187 · see citing works
Amyloid-β and τ serve antioxidant functions in the aging and Alzheimer brain
Smith, M. A., Casadesús, G., Joseph, J. A., & Perry, G. L. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01021-3 · Cited by 189 · see citing works
Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review
Keage, H. A. D., Carare, R. O., Friedland, R. P., Ince, P. G., Love, S., Nicoll, J. A. R., Wharton, S. B., Weller, R. O., & Brayne, C. (2009) · BMC Neurology · doi:10.1186/1471-2377-9-3 · Cited by 181 · see citing works
Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology?a pilot study
Attems, J., & Jellinger, K. A. (2004) · Acta Neuropathologica · doi:10.1007/s00401-003-0796-9 · Cited by 179 · see citing works
“Its incidence and severity increase with age [ 6 , 9, 12, 18, 29, 30, 31, 37, 45], and it is frequent and severe in a variety of familial disorders associated with mutations of the amyloid precursor protein [10, 17, 22, 29, 30, 31].”
BackgroundIron toxicity in neurodegeneration
Núñez, M. T., Urrutia, P. J., Mena, N. P., Aguirre, P., Tapia, V., & Salazar, J. (2012) · BioMetals · doi:10.1007/s10534-012-9523-0 · Cited by 181 · see citing works
“The finding that Ab-derived diffusible ligands promote tau phosphorylation suggests that tau pathology is secondary (Davis et al. 1999).”
BackgroundLee, H., Casadesús, G., Zhu, X., Takeda, A., Perry, G. L., & Smith, M. A. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1297.001 · Cited by 180 · see citing works
Age-related neuropathology, cognitive decline, and Alzheimer's disease.
Keller, J. (2006) · Ageing Research Reviews · doi:10.1016/j.arr.2005.06.002 · Cited by 188 · see citing works
Disturbance of Endogenous Circadian Rhythm in Aging and Alzheimer Disease
Harper, D. G., Volicer, L., Stopa, E. G., McKee, A. C., Nitta, M., & Satlin, A. (2005) · American Journal of Geriatric Psychiatry · doi:10.1176/appi.ajgp.13.5.359 · Cited by 199 · see citing works
Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid
Teunissen, C. E., de Vente, J., Steinbusch, H. W. M., & Bruijn, C. D. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00328-1 · Cited by 167 · see citing works
Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
(2024) · aging and disease · doi:10.14336/ad.2023.0608 · Cited by 183 · see citing works
“Additionally, it has been observed that up to 40% of elderly individuals without any signs of cognitive impairment can still exhibit some degree of neuropathological features typically associated with AD [37].”
BackgroundSynaptic Change in the Posterior Cingulate Gyrus in the Progression of Alzheimer's Disease
Scheff, S. W., PRICE, D. A., Ansari, M. A., Roberts, K. N., Schmitt, F. A., Ikonomović, M. D., & Mufson, E. J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141518 · Cited by 163 · see citing works
“9 years; range 67 to 97 years; Table 1) who were participants in either the University of Kentucky Alzheimer’s Disease Center (UKADC) [37], or the Rush Religious Orders Study (RROS), a longitudinal clinical-pathologic study of aging and AD composed of older Catholic nuns, priests, and brothers [38–40].”
Self-citationBlass, J. P. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.10087 · Cited by 162 · see citing works
“Accumulating data from a number of sources indicate that the accumulation of amyloid is not, by itself, adequate to cause dementia (Snowden, 1997; Davis et al., 1999; Wolf et al., 1999).”
BackgroundZeineh, M. M., Chen, Y., Kitzler, H. H., Hammond, R., Vogel, H., & Rutt, B. K. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.05.022 · Cited by 151 · see citing works
“…AD (Tanzi, 2012), themechanism of plaque-mediated neurodegeneration is unclear because of the presence of plaques in healthy elderly controls (Arnold et al., 2013; Davis et al., 1999) and the lack of a strong correlation between plaque deposition and the severity of dementia (Terry et al., 1991).”
The Vascular Hypothesis of Alzheimer’s Disease: Bench to Bedside and Beyond
de la Torre, J. C. (2010) · Neurodegenerative Diseases · doi:10.1159/000285520 · Cited by 159 · see citing works
- Authors
- Davis, D. G., Schmitt, F. A., Wekstein, D. R., & Markesbery, W. R.
- Affiliations
- University of Kentucky HealthCare (US)
- Corresponding author
- Davis, D G
- ORCID
- Schmitt, F A
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-04
- Volume
- 58
- Issue
- 4
- Pages
- 376-388
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W2009882167
- Cited by
- 516
- References
- 0
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 13 · 2020: 14 · 2019: 16 · 2018: 22 · 2017: 16 · 2016: 26 · 2015: 18 · 2014: 30 · 2013: 25 · 2012: 19
- FWCI
- 15.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG005144, P50-AGO5144, 1PO1-AGO51195)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, normal aging, amyloid plaques, neurofibrillary tangles, Braak staging, dementia with Lewy bodies, cerebral amyloid angiopathy, entorhinal cortex, hippocampus, amygdala, neuropathology
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloidosis, Apolipoproteins E, Brain, Cerebral Infarction, Chronic Disease, Cognition, Female, Genotype, Craniocerebral Trauma, Humans, Male, Mental Status Schedule, Middle Aged, Dementia, Vascular, Silver Staining, Lewy Bodies, Neurofibrillary Tangles
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