Anatomy of Pathological Alterations in Alzheimer’s Disease

  • Bradley T. Hyman
Part of the Contemporary Neuroscience book series (CNEURO)


Even by inspection of the gross brain, it is evident that Alzheimer’s disease (AD) neuropathological changes do not occur randomly or uniformly, but instead target the medial temporal lobe and association cortices of the temporal and parietal areas (1–3). It might be expected, given the complex topography of brain architecture, that on finer examination, this distribution would show a pattern of vulnerability definable at the level of neural systems, cytoarchitectural fields, and even specific lamina within cytoarchitectural fields. Our anatomical studies of AD neuropathology have shown that this is indeed the case. Neurofibrillary tangles (NFT), senile plaques (SP), and neuronal loss affect individual cytoarchitectural areas and laminae in an extraordinarily specific and selective manner. Based on application of neuroanatomical principles and extrapolation of connectional data from the nonhuman primate experimental system, we have suggested that these lesions destroy major feed-forward and feedback projections, leading to disruption of neural systems related to memory and cognition (4). In this chapter, I will briefly review the major themes of the anatomical alterations in AD from the perspective of the studies we have carried out over the last decade.


Down Syndrome Entorhinal Cortex Neurofibrillary Tangle Senile Plaque Association Cortex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brun, A. and Gustafson, L. (1976) Distribution of cerebral degeneration in Alzheimer’s disease, Arch. Psychiatr. Nervenk 223, 15–33.CrossRefGoogle Scholar
  2. 2.
    Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., and Van Hoesen, G. W. (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in cerebral cortex of patients with Alzheimer’s disease, Cerebral Cortex 1, 103–116.PubMedCrossRefGoogle Scholar
  3. 3.
    Braak, H. and Braak, E. (1991) Neuropathological stageing of Alzheimer related changes, Acta Neuropathol. 82, 239–259.PubMedCrossRefGoogle Scholar
  4. 4.
    Hyman, B. T., Van Hoesen, G. W., and Damasio, A. R. (1990) Memory-related neural systems in Alzheimer’s disease: An anatomical study, Neurology 40, 1721–1730.PubMedCrossRefGoogle Scholar
  5. 5.
    Arnold, S. E., Hyman, B. T., and Van Hoesen, G. W. (1994) Neuropathological changes of the temporal pole in Alzheimer’s disease and Pick’s disease, Arch. Neurol. in press.Google Scholar
  6. 6.
    Arriagada, P. V., Louis, D. N., Hedley-Whyte, E. T., and Hyman, B. T. (1991) Neurofibrillary tangles and olfactory dysgenesis: a test of the olfactory hypothesis of neurofibrillary tangle formation, Lancet 337, 559.PubMedCrossRefGoogle Scholar
  7. 7.
    Arriagada, P. V., Marzloff, K., and Hyman, B. T. (1992) Distribution of Alzheimer-type pathological changes in nondemented elderly matches the pattern in Alzheimer’s disease, Neurology 42, 1681–1688.PubMedCrossRefGoogle Scholar
  8. 8.
    Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., and Hyman, B. T. (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer disease, Neurology 42, 631–639.PubMedCrossRefGoogle Scholar
  9. 9.
    Hyman, B. T. and Van Hoesen, G. W. (1989) Hippocampal and entorhinal cortex cellular pathology in Alzheimer’s disease, in The Hippocampus, New Vistas ( Chan-Palay, V. and Köhler, C., eds.), Liss, New York, pp. 499–512.Google Scholar
  10. 10.
    Hyman, B. T., Arriagada, P. V., and Van Hoesen, G. W. (1991) Pathological changes in the olfactory system in aging and Alzheimer’s disease, in Aging and Alzheimer ‘s Disease ( Wurtman, R., Corkin, S., and Growdon, J. H., eds.), NewYorkAcadeety of Science, New York, pp. 14–19.Google Scholar
  11. 11.
    Hyman, B. T. (1992) Down syndrome and Alzheimer’s disease. Down Syndrome and Alzheimer Disease, in Prog. Clin. Biol. Res., vol. 379 ( Nadel, L. and Epstein, C. W., eds.), Wiley-Liss, New York, pp. 123–142.Google Scholar
  12. 12.
    Hyman, B. T., Arriagada, P. V., Van Hoesen, G. W., and Damasio, A. R. (1993) Memory impairment in Alzheimer’s disease: An anatomical perspective, in Neuropsychology of Alzheimer ‘s Disease and other Dementias ( Parks, R. W., Zec, R. F., and Wilson, R. S., eds.), Oxford, New York, pp. 135–150.Google Scholar
  13. 13.
    Kromer-Vogt, L. J., Hyman, B. T., Van Hoesen, G. W., and Damasio, A. R. (1990) Pathological alterations in the amygdala in Alzheimer’s disease, Neuroscience 37, 377–385.PubMedCrossRefGoogle Scholar
  14. 14.
    Rebeck, G. W. and Hyman, B. T. (1993) Neuroanatomical connections and specific regional vulnerability in Alzheimer’s disease, Neurobiol. Aging 14, 45–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Simonian, N. A., Rebeck, G. W., and Hyman, B. T. (1994) Functional integrity of neural systems related to memory in Alzheimer disease, in Progress in Brain Research ( Bloom, F., ed.), Elsevier, Amsterdam, pp. 245–254.Google Scholar
  16. 16.
    Van Hoesen, G. W., Hyman, B. T., and Damasio, A. R. (1991) Entorhinal cortex pathology in Alzheimer’s disease, Hippocampus 1, 1–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Hyman, B T., Arriagada, P. V., McKee, A., Ghika, J., Corkin, S., and Growdon, J. H. (1991) The earliest symptoms of Alzheimer disease: Anatomic correlates, Soc. Neurosci. 371 Google Scholar
  18. 18.
    Hyman, B. T., Marzloff, K., and Arriagada, P. V. (1993) The lack of accumulation of senile plaques or amyloid burden in Alzheimer’s disease suggests a dynamic balance between amyloid deposition and resolution, J. Neuropathol. Exp. Neurol. 52, 594–600.PubMedCrossRefGoogle Scholar
  19. 19.
    Hyman, B. T. and Tanzi, R. E. (1992) Amyloid, dementia and Alzheimer’s disease, Curr. Opinion Neurol. Neurosurg. 5, 88–93.Google Scholar
  20. 20.
    Hof, P. R., Cox, K., and Morrison, J. H. (1990) Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease: I. Superior frontal and inferior temporal cortex, J. Comp. Neurol. 301, 44–54.PubMedCrossRefGoogle Scholar
  21. 21.
    Hof, P. R., Cox, K., and Morrison, J. H. (1988) Quantitative analysis of non-phosphorylated neurofilament protein (NPNFP)-immunoreactive neurons in normal and Alzheimer’s disease brain, Soc. Neurosci. 14, 1086.Google Scholar
  22. 22.
    Hyman, B. T., Marzloff, K. M., Wenniger, J. J., Dawson, T. M., Bredt, D. S., and Snyder, S. H. (1992) Relative sparing of nitric oxide synthase containing neurons in the hippocampal formation in Alzheimer’s disease, Ann. Neurol. 32, 818–821.PubMedCrossRefGoogle Scholar
  23. 23.
    Vickers, J. C., Delacourte, A., and Morrison, J. H. (1993) Progressive transformation of the cytoskeleton associated with normal aging and Alzheimer’s disease, Brain Res. 594, 273–278.CrossRefGoogle Scholar
  24. 24.
    Hyman, B. T., Van Hoesen, G. W., Kromer, L. J., and Damasio, A. R. (1986) Perforant pathway changes and the memory impairment of Alzheimer’s disease, Ann. Neurol. 20, 473–482.CrossRefGoogle Scholar
  25. 25.
    Hyman, B. T. and Mann, D. M. A. (1991) Alzheimer type pathological changes in Down’s syndrome individuals of various ages, in Alzheimer ‘s Disease: Basic Mechanisms, Diagnosis, and Therapeutic Strategies ( Iqbal, K., Mortimer, J., Winbld, B., and Wisniewski, H., eds.), Wiley, New York. pp. 105–113.Google Scholar
  26. 26.
    Bouras, C., Hof, P. R., and Morrison, J. H. (1993) Neurofibrillary tangle densities in the hippocampal formation in a nondemented population define subgroups of patients with differential early pathological changes, Neurosci. Lett. 153, 131–135.PubMedCrossRefGoogle Scholar
  27. 27.
    Price, D. L., Davis, R B., Morris, J. C., and White, D. L. (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease, Neurobiol. Aging 12, 295–312.PubMedCrossRefGoogle Scholar
  28. 27a.
    Gomez-Igla, T., Price, J. L., McKeel, D. W., Morris, J. C., Growdon, J. J., and Hyman, B. T. (1996) Profound loss of layer II of entorhinal cortex neurons occurs in very mild Alzheimer’s disease, J. Neurosci. 16, 4491–4500.Google Scholar
  29. 28.
    Hyman, B. T., Kromer, L. J., and Van Hoesen, G. W. (1987) Reinnervation of the hippocampal perforant pathway zone in Alzheimer’s disease, Ann. Neurol. 21, 259–267.PubMedCrossRefGoogle Scholar
  30. 29.
    Gertz, H. J., Cervos-Navarro, J., and Ewald, V. (1987) The septo-hippocampal pathway in patients suffering from senile dementia of Alzheimer’s type. Evidence for neuronal plasticity? Neurosci. Lett. 76, 228–232.PubMedCrossRefGoogle Scholar
  31. 30.
    Geddes, J. W., Monaghan, D. T., Cotman, C. W., Lott, I. T., Kim, R. C., and Chui, H. C. (1985) Plasticity of hippocampal circuitry in Alzheimer’s disease, Science 230, 1179–1181.PubMedCrossRefGoogle Scholar
  32. 31.
    Jaarsma, D., Sebens, J. B., and Korf, J. (1991) Reduction of adenosine Al-receptors in the perforant pathway terminal zone in Alzheimer hippocampus, Neurosci. Lett. 121, 111–114.PubMedCrossRefGoogle Scholar
  33. 32.
    Rebeck, G. W., Marzloff, K. M., and Hyman, B. T. (1993) The pattern of NADPH-diaphorase staining, a marker of nitric oxide synthase activity, is altered in the perforant pathway terminal zone in Alzheimer’s disease, Neurosci. Lett. 152, 165–168.PubMedCrossRefGoogle Scholar
  34. 33.
    Harr, S., Simonian, N., and Hyman, B. T. (1995) Functional alterations in Alzheimer’s disease: Decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone, I Neuropath. Exp. Neurol. 54, 38–41.CrossRefGoogle Scholar
  35. 34.
    Hyman, B. T., Van Hoesen, G. W., and Damasio, A. R. (1987) Alzheimer’s disease: Glutamate depletion in perforant pathway terminals, Ann. Neurol. 22, 37–40.PubMedCrossRefGoogle Scholar
  36. 35.
    Cabalka, L. M., Hyman, B. T., Goodlett, C. R., Ritchie, T. C., and Van Hoesen, G. W. (1992) Alteration in the pattern of nerve terminal protein immunoreactivity in the perforant pathway in Alzheimer’s disease and in rats after entorhinal lesions, Neurobiol. Aging 13, 283–291.PubMedCrossRefGoogle Scholar
  37. 36.
    Masliah, E., Terry, R. D., Alford, M., DeTeresa, R., and Hansen, L. A. (1991) Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease, Am. J. Pathol. 138, 235–246.PubMedGoogle Scholar
  38. 37.
    Terry, R. D., Masliah, E., and Salmon, D. P. (1991) Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment, Ann. Neurol. 41, 572–580.CrossRefGoogle Scholar
  39. 38.
    De Kosky, S. T. and Scheff, S. W. (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity, Ann. Neurol. 27, 457–464.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Bradley T. Hyman

There are no affiliations available

Personalised recommendations