Mild Cognitive Impairment and Asymptomatic Alzheimer Disease Subjects: Equivalent β-Amyloid and Tau Loads With Divergent Cognitive Outcomes
Open accessAbstract
Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed "asymptomatic AD subjects" (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma.
“However, an increasingly growing body of evidence has demonstrated that AD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma.”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [5]
The Discussion reports divergent cognitive outcomes despite comparable insoluble Aβ and tau loads in the studied groups, and suggests that other protective or compensatory factors may contribute. This supports a narrower point about variation in cognitive outcomes, but does not demonstrate that AD itself is caused by various pathophysiologic mechanisms. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany individuals diagnosed with AD at postmortem biopsy do not show cognitive impairment.
“while many of those diagnosed with AD at postmortem biopsy do not show cognitive impairment (5)”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [5]
The Introduction and Methods (Definition of the Study Groups; page not provided) describe cognitively intact people with substantial AD pathology at autopsy, including 15 classified as asymptomatic AD. The paper does not establish that many people diagnosed with AD at autopsy are unimpaired: the groups were selected for comparison, and its criteria distinguish asymptomatic AD from definite AD. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCognitive impairment is neither dependent on nor fully assured by high levels of Aβ and tau accumulation.
“These findings are consistent with previous studies that have shown that cognitive impairment is neither dependent on nor fully assured by high levels of Aβ and tau accumulation (4, 5).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [5]
The Discussion reports comparable insoluble Aβ and tau loads in cognitively intact ASYMAD subjects and subjects with MCI, supporting the claim that high loads do not assure impairment. But the study’s cognitively impaired groups had AD pathology; it does not show impairment occurring without high Aβ and tau accumulation, so the ‘neither dependent on’ part is not established. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThere is now evidence showing that equivalent loads of AD-consistent pathology in different cases can be associated with various cognitive outcomes.
“There is now evidence showing that equivalent loads of AD-consistent pathology in different cases can be associated with various cognitive outcomes [63].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [63]
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
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
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Mild cognitive impairment as a diagnostic entity
Petersen, R. C. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2004.01388.x · Cited by 7,864 · see citing works
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · see citing works
Self-citationSoluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Montine, T. J., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., Mirra, S. S., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0910-3 · Cited by 2,992 · cited 2× · see citing works
“Table 2 shows the ‘‘ABC’’ scores and levels of AD neuropathologic changes for each subject as proposed by the National Institute on Aging-Alzheimer’s Association recommendations for pathologic criteria (14).”
Observations on the brains of demented old people
Tomlinson, B. E., Blessed, G., & Roth, M. (1970) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(70)90063-8 · Cited by 2,084 · see citing works
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · cited 3× · see citing works
“Tau immunoreactivity was measured using 2 different markers: one to measure tau immunoreactivity associated with tangles (tau-NFTs) and another to measure tau immunoreactivity associated with neuropil threads (tau-th) (Fig.”
Self-citationMemory and Executive Function in Aging and AD
Buckner, R. L. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.006 · Cited by 1,508 · see citing works
Neuropathology of older persons without cognitive impairment from two community-based studies
Bennett, D. A., Schneider, J. A., Arvanitakis, Z., Kelly, J. F., Aggarwal, N. T., Shah, R. C., & Wilson, R. S. (2006) · Neurology · doi:10.1212/01.wnl.0000219668.47116.e6 · Cited by 1,336 · see citing works
Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., Fuld, P., Renbing, X., & Peck, A. (1988) · Annals of Neurology · doi:10.1002/ana.410230206 · Cited by 1,225 · see citing works
Unbiased Stereology: Three-Dimensional Measurement in Microscopy
Howard, C. V., & Reed, M. (1998) · Cited by 1,149 · see citing works
Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R. (2003) · Neurology · doi:10.1212/01.wnl.0000063311.58879.01 · Cited by 1,118 · see citing works
Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD
Dickerson, B. C., Salat, D. H., Greve, D. N., Chua, E. F., Rand-Giovannetti, E., Rentz, D. M., Bertram, L., Mullin, K., Tanzi, R. E., Blacker, D., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000171450.97464.49 · Cited by 910 · see citing works
Normal Human Aging: The Baltimore Longitudinal Study on Aging
Shock, N. W., Greulich, R. C., Costa, P. T., Andres, R., Lakatta, E. G., Arenberg, D., & Tobin, J. D. (1984) · University Libraries (University of Maryland) · doi:10.13016/sclw-iccq · Cited by 757 · see citing works
Observations on the brains of non-demented old people
Tomlinson, B. E., Blessed, G., & Roth, M. (1968) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(68)90154-8 · Cited by 681 · see citing works
Neuropathology 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
Crystal, H., Dickson, D., Fuld, P., Masur, D., Scott, R., Mehler, M., Masdeu, J., Kawas, C., Aronson, M., & Wolfson, L. (1988) · Neurology · doi:10.1212/wnl.38.11.1682 · Cited by 586 · see citing works
Evidence from Functional Neuroimaging of a Compensatory Prefrontal Network in Alzheimer's Disease
Grady, C. L., McIntosh, A. R., Beig, S., Keightley, M., Burian, H., & Black, S. E. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-03-00986.2003 · Cited by 504 · see citing works
Brain reserve hypothesis in dementia
Fratiglioni, L., & Wang, H.-X. (2007) · Journal of Alzheimer's Disease · doi:10.3233/jad-2007-12103 · Cited by 499 · see citing works
Age-specific incidence rates of Alzheimer’s disease: The Baltimore Longitudinal Study of Aging
Kawas, C., Gray, S., Brookmeyer, R., Fozard, J., & Zonderman, A. (2000) · Neurology · doi:10.1212/wnl.54.11.2072 · Cited by 472 · see citing works
Self-citationThe Concept of Cognitive Reserve: A Catalyst for Research
Stern, Y. (2003) · Journal of Clinical and Experimental Neuropsychology · doi:10.1076/jcen.25.5.589.14571 · Cited by 410 · see citing works
Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology
Perez-Nievas, B. G., Stein, T. D., Tai, H.-C., Dols-Icardo, O., Scotton, T. C., Barroeta-Espar, I., Fernandez-Carballo, L., de Munain, E. L., Perez, J., Marquie, M., et al. (2013) · Brain · doi:10.1093/brain/awt171 · Cited by 387 · see citing works
Aging and Alzheimer's Disease: Lessons From the Nun Study
Snowdon, D. A. (1997) · The Gerontologist · doi:10.1093/geront/37.2.150 · Cited by 367 · see citing works
Yamamoto, T., & Hirano, A. (1986) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1986.tb00677.x · Cited by 330 · see citing works
Diagnostic and statistical manual of mental disorders, third edition, revised (DSM-III-R)
Berner, P., Gabriel, E., Katschnig, H., Kieffer, W., Koehler, K., & Lenz, G. (1992) · Cambridge University Press eBooks · doi:10.1017/cbo9780511663208.013 · Cited by 291 · see citing works
The Development of Amyloid β Protein Deposits in the Aged Brain
Thal, D. R., Capetillo-Zarate, E., Del Tredici, K., & Braak, H. (2006) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2006.6.re1 · Cited by 234 · see citing works
Effect of infarcts on dementia in the Baltimore longitudinal study of aging
Troncoso, J. C., Zonderman, A. B., Resnick, S. M., Crain, B., Pletnikova, O., & O'Brien, R. J. (2008) · Annals of Neurology · doi:10.1002/ana.21413 · Cited by 219 · see citing works
Self-citationNeuronal Hypertrophy in Asymptomatic Alzheimer Disease
Iacono, D., O'Brien, R., Resnick, S. M., Zonderman, A. B., Pletnikova, O., Rudow, G., An, Y., West, M. J., Crain, B., & Troncoso, J. C. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181772794 · Cited by 188 · see citing works
Self-citationParadoxical 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
Synaptic proteins, neuropathology and cognitive status in the oldest-old
Head, E., Corrada, M. M., Kahle-Wrobleski, K., Kim, R. C., Sarsoza, F., Goodus, M., & Kawas, C. H. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.10.001 · Cited by 145 · see citing works
Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging
Troncoso, J. C., Martin, L. J., Dal Forno, G., & Kawas, C. H. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00028-0 · Cited by 138 · see citing works
Self-citationAsymptomatic Alzheimers Disease: A Prodrome or a State of Resilience?
Driscoll, I., & Troncoso, J. (2011) · Current Alzheimer Research · doi:10.2174/156720511795745348 · Cited by 130 · see citing works
Self-citationSojkova, J., Driscoll, I. F., Iacono, D., Zhou, Y., Codispoti, K.-E., Kraut, M. A., Ferrucci, L., Pletniková, O., Mathis, C. A., Klunk, W. E., et al. (2011) · Archives of Neurology · doi:10.1001/archneurol.2010.357 · Cited by 112 · see citing works
Self-citationWoodard, J. L., Grafton, S. T., Votaw, J. R., Green, R. C., Dobraski, M. E., & Hoffman, J. M. (1998) · Neuropsychology · doi:10.1037/0894-4105.12.4.491 · Cited by 108 · see citing works
Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons
Riudavets, M. A., Iacono, D., Resnick, S. M., O’Brien, R., Zonderman, A. B., Martin, L. J., Rudow, G., Pletnikova, O., & Troncoso, J. C. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.05.005 · Cited by 106 · see citing works
Self-citationFunctional activation imaging in aging and dementia
Prvulovic, D., van de Ven, V. G., Sack, A. T., Maurer, K., & Linden, D. E. J. (2005) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2005.06.006 · Cited by 103 · see citing works
Effect of a clinical stroke on the risk of dementia in a prospective cohort
Gamaldo, A. A., Moghekar, A., Kilada, S., Resnick, S. M., Zonderman, A. B., & O’Brien, R. (2006) · Neurology · doi:10.1212/01.wnl.0000240285.89067.3f · Cited by 94 · see citing works
Self-citationHu, N., Smith, I. M., Walsh, D. M., & Rowan, M. J. (2008) · Brain · doi:10.1093/brain/awn174 · Cited by 84 · see citing works
Differential association of [ 11 C]PIB and [ 18 F]FDDNP binding with cognitive impairment
Tolboom, N., van der Flier, W. M., Yaqub, M. M., Koene, T., Boellaard, R., Windhorst, A. D., Scheltens, P., Lammertsma, A. A., & van Berckel, B. N. M. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c679cc · Cited by 44 · see citing works
Longitudinal brain activity changes in asymptomatic Alzheimer disease
Codispoti, K.-E., Beason‐Held, L. L., Kraut, M. A., O’Brien, R., Rudow, G. L., Pletniková, O., Crain, B. J., Troncoso, J. C., & Resnick, S. M. (2012) · Brain and Behavior · doi:10.1002/brb3.47 · Cited by 14 · see citing works
Self-citationThe Interface Between Alzheimers Disease, Normal Aging, and Related Disorders
Armstrong, R. A. (2008) · Current Aging Science · doi:10.2174/1874609810801020122 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
Tönnies, E., & Trushina, E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161088 · Cited by 1,750 · see citing works
Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group
Dubois, B., Villain, N., Frisoni, G. B., Rabinovici, G. D., Sabbagh, M., Cappa, S., Bejanin, A., Bombois, S., Epelbaum, S., Teichmann, M., et al. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00066-1 · Cited by 1,051 · see citing works
Snowden, S. G., Ebshiana, A. A., Hye, A., An, Y., Pletnikova, O., O’Brien, R., Troncoso, J., Legido-Quigley, C., & Thambisetty, M. (2017) · PLOS Medicine · doi:10.1371/journal.pmed.1002266 · Cited by 309 · see citing works
Self-citationNeff, R. A., Wang, M., Vatansever, S., Guo, L., Ming, C., Wang, Q., Wang, E., Horgusluoglu-Moloch, E., Song, W.-M., Li, A., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb5398 · Cited by 306 · 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
Varma, V. R., Büşra Lüleci, H., Oommen, A. M., Varma, S., Blackshear, C. T., Griswold, M. E., An, Y., Roberts, J. A., O’Brien, R., Pletnikova, O., et al. (2021) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-021-00064-9 · Cited by 153 · see citing works
Self-citationA critical review of chronic traumatic encephalopathy
Iverson, G. L., Gardner, A. J., McCrory, P., Zafonte, R., & Castellani, R. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.05.008 · Cited by 103 · see citing works
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
Eteleeb, A. M., Novotny, B. C., Tarraga, C. S., Sohn, C., Dhungel, E., Brase, L., Nallapu, A., Buss, J., Farias, F., Bergmann, K., et al. (2024) · PLOS Biology · doi:10.1371/journal.pbio.3002607 · Cited by 64 · see citing works
DNA repair deficiency and senescence in concussed professional athletes involved in contact sports
Schwab, N., Grenier, K., & Hazrati, L.-N. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0822-3 · Cited by 47 · see citing works
Sekiya, M., Wang, M., Fujisaki, N., Sakakibara, Y., Quan, X., Ehrlich, M. E., De Jager, P. L., Bennett, D. A., Schadt, E. E., Gandy, S., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0530-9 · Cited by 38 · see citing works
Jury-Garfe, N., Redding-Ochoa, J., You, Y., Martínez, P., Karahan, H., Chimal-Juárez, E., Johnson, T. S., Zhang, J., Resnick, S., Kim, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02775-1 · Cited by 22 · see citing works
“The postmortem brains were classified into aged-matched controls individuals, AsymAD cases, and AD cases as described in previously clinical and neuropathological studies [41–43,”
ResultSelf-citation
- Authors
- Iacono, D., Resnick, S. M., O’Brien, R., Zonderman, A. B., An, Y., Pletnikova, O., Rudow, G., Crain, B., & Troncoso, J. C.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Corresponding author
- Iacono, Diego
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04
- Volume
- 73
- Issue
- 4
- Pages
- 295-304
- ISSN
- 0022-3069 (ISSN-L)
- PMC
- PMC4062187
- OpenAlex
- W1966645427
- Cited by
- 73
- References
- 42
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 7 · 2014: 2
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P50AG005146, AG 05146)
- 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
- mild cognitive impairment, Alzheimer disease pathology, amyloid-beta, phosphorylated tau, neuronal hypertrophy, hippocampal CA1, anterior cingulate cortex, posterior cingulate cortex, primary visual cortex, stereology, cognitive impairment, Baltimore Longitudinal Study of Aging
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Autopsy, Brain, Female, Humans, Male, Neuropsychological Tests, Postmortem Changes, Stereotaxic Techniques, Amyloid beta-Peptides, tau Proteins, Cognitive Dysfunction
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
