Skip to main content
Log in

The Cognitive Psychopharmacology of Alzheimer's Disease: Focus on Cholinergic Systems

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Selkoe, D. J. 1997. Alzheimer's disease: genotypes, phenotype, and treatment. Science 275:630–631.

    Google Scholar 

  2. Robbins, T. W., Elliott, R., and Sahakian, B. J. 1996. Neuropsychology—dementia and affective disorders. British Medical Bulletin 52:627–643.

    Google Scholar 

  3. Hodges, J. R., and Patterson, K. 1995. Is semantic memory consistently impaired early in the course of Alzheimer's disease? neuroanatomical and diagnostic implications. Neuropsychologia 33:441–459.

    Google Scholar 

  4. Zec, R. F. 1993. Neuropsychological functioning in Alzheimer's disease. Pages 3–80 in Parks, R. W., Zec, R. F., Wilson, R. S. (eds), Neuropsychology of Alzheimer's Disease and Other Dementias, Oxford UP, New York.

    Google Scholar 

  5. Parasuraman, R., and Haxby, J. V. 1993. Attention and brain function in Alzheimer's disease: a review. Neuropsychology 7:242–272.

    Google Scholar 

  6. Sahakian, B. J., Jones, G. M. M., Levy, R., Gray, J. A., and Warburton, D. M. 1989. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer's type. British Journal of Psychiatry 154:797–800.

    Google Scholar 

  7. Brazzelli, M., Cocchini, G., Della Salla, S., and Spinnler, H. 1994. Alzheimer patients show a sensitivity decrement over time on a tonic alertness task. Journal of Clinical and Experimental Neuropsychology 16:851–860.

    Google Scholar 

  8. Parasuraman, R., Greenwood, P. M., Haxby, J. V., and Grady, C. L. 1992. Visuospatial attention in dementia of the Alzheimer type. Brain 115:711–733.

    Google Scholar 

  9. Oken, B. S., Kishiyama, M. A., Kaye, J. A., and Howieson, D. B. 1994. Attention deficit in Alzheimer's disease is not simulated by an anticholinergic/antihistaminergic drug and is distinct from deficits in healthy aging. Neurology 44:657–662.

    Google Scholar 

  10. Parasuraman, R., Greenwood, P. M., and Alexander, G. E. 1995. Selective impairment of spatial attention during visual search in Alzheimer's disease. Neuroreport 6:1861–1864.

    Google Scholar 

  11. Maruff, P., Malone, V., and Currie, J. 1995. Asymmetries in the cover orienting of visual spatial attention to spatial and nonspatial cues in Alzheimer's disease. Brain 118:1421–1435.

    Google Scholar 

  12. Scinto, L. F. M., Daffner, K. R., Castro, L., Weintrub, S., Vavrik, M., and Mesulam, M. M. 1994. Impairment of spatially directed attention in patients with probable Alzheimer's disease as measured by eye movements. Archives of Neurology 51:682–688.

    Google Scholar 

  13. Sahakian, B. J., Downes, J. J., Eagger, S., Evenden, J. L., Levy, R., Philpot, M. P., Roberts, A. C., and Robbins, T. W. 1990. Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type. Neuropsychologia 28:1197–1213.

    Google Scholar 

  14. Lawrence, A. D., and Sahakian, B. J. 1995. Alzheimer disease, attention and the cholinergic system. Alzheimer Disease and Associated Disorders 2:s43-s49.

    Google Scholar 

  15. Greenwood, P. M., Parasuraman, R., and Alexander, G. E. 1997. Controlling the focus of spatial attention during visual search: effects of advanced aging and Alzheimer disease. Neuropsychology 11:3–12.

    Google Scholar 

  16. Mesulam, M. M. 1996. The systems-level organization of cholinergic innervation in the human cerebral cortex and its alterations in Alzheimer's disease. Progress in Brain Research 109:285–297.

    Google Scholar 

  17. Everitt, B. J., Sirkia, T. J., Roberts, A. C., Jones, G. H., and Robbins, T. W. 1988. Distribution and some projections of cholinergic neurones in the brain of the common marmoset. Journal of Comparative Neurology 271:533–558.

    Google Scholar 

  18. Geula, C., and Mesulam, M. M. 1996. Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer's disease. Cerebral Cortex 6:165–177.

    Google Scholar 

  19. Wurtman, R. J., Blusztajn, J. K., and Ulus, I. H. 1990. Choline metabolism in cholinergic neurons: implications for the pathogenesis of neurodegenerative diseases. Papges 117–125 in Wurtman, R. J., Corkin, S., Growdon, J. H., Ritter-Walker, E. (eds.), Advances in Neurology. Alzheimer's disease, Raven Press, New York.

    Google Scholar 

  20. Bartus, R. T., Dean, R. C., Pontecorvo, M. J., and Flicker, C. 1985. The cholinergic hypothesis: a historical review, current perspectives and future directions. Annals of the New York Academy of Sciences 444:332–358.

    Google Scholar 

  21. Perry, E. K., Tomlinson, B. E., Blessed, G., Bergman, K., Gibson, P. H., and Perry, R. H. 1978. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. British Medical Journal 2:1457–1459.

    Google Scholar 

  22. Wilcock, G. K., Esiri, M. M., Bowen, D. M., and Smith, C. C. T. 1982. Alzheimer's disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. Journal of the Neurological Sciences 57:407–417.

    Google Scholar 

  23. Palmer, A. M., Francis, P. T., Bowen, D. M., Benton, J. S., Neary, D., Mann, D. M. A., and Snowden, J. S. 1987. Catecholaminergic neurons assessed antemortem in Alzheimer's disease. Brain Research 414:365–375.

    Google Scholar 

  24. Lehericy, S., Hirsch, E. C., Cervera-Pierot, P., Hersh, L. B., Bakchine, S., Piette, F., Duyckaerts, C., Hauw, J-J., Javoy-Agid, F., and Agid, Y. 1993. Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease. Journal of Comparative Neurology 330:15–31.

    Google Scholar 

  25. Drachman, D. A., and Sahakian, B. J. 1979. Effects of cholinergic agents on human learning and memory. Pages 351–366 in Barbeau, A., Growden, J. H., Wurtman, R. J. (eds.), Nutrition and the Brain: volume 5, Raven Press, New York:351–366.

    Google Scholar 

  26. Sahakian, B. J. 1988. Cholinergic drugs and human cognitive performance. Pages 393–424 in Iversen, L. L., Iversen, S. D., Snyder, S. H. (eds.), Handbook of Psychopharmacology Volume 20, Plenum, New York:393–424.

    Google Scholar 

  27. Sahakian, B. J., and Jones, G. M. M. 1991. Cholinergic drugs and human cognitive performance. pages 65–86 in Weinman, J., Hunter, J. (eds.), Memory: Neurochemical and Abnormal Perspectives, Harwood, London:65–86.

    Google Scholar 

  28. Aarsland, D., Larsen, J. P., Reinvang, I., and Aasland, A. M. 1994. Effects of cholinergic blockade on language in healthy young women: implications for the cholinergic hypothesis in dementia of the Alzheimer type. Brain 117:1377–1384.

    Google Scholar 

  29. Dunnett, S. B., Everitt, B. J., and Robbins, T. W. 1991. The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions. Trends in Neurosciences 14:494–501.

    Google Scholar 

  30. Robbins, T. W., McAlonan, G., Muir, J. L., and Everitt, B. J. 1997. Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease. Behavioural Brain Research 83:15–23.

    Google Scholar 

  31. Voytko, M. L. 1996. Cognitive functions of the basal forebrain cholinergic system in monkeys: memory or attention? Behavioural Brain Research 75:13–25.

    Google Scholar 

  32. Torres, E. M., Perry, T. A., Blokland, A., Wilkinson, L. S., Wiley, R. G., Lapp, D. A., and Dunnett, S. B. 1994. Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system. Neuroscience 63:95–122.

    Google Scholar 

  33. Wenk, G. L., Stoehr, J. D., Quintana, G., Mobley, S., and Wiley, R. G. 1994. Behavioral, biochemical, histological, and electrophysiological effects of 192 IgG-Saporin injections into the basal forebrain of rats. Journal of Neuroscience 14:5986–5995.

    Google Scholar 

  34. Voytko, M. L., Olton, D. S., Richardson, R. T., Gorman, L. K., Tobin, J. R., and Price, D. L. 1994. Basal forebrain lesions in monkeys disrupt attention but not learning and memory. Journal of Neuroscience 14:167–186.

    Google Scholar 

  35. Drachman, D. A., and Sahakian, B. J. 1980. Memory, aging and pharmacosystems. Pages 347–368 in Stein, D. (ed.). The Psychobiology of Aging: Problems and Perspectives, Elsevier, Amsterdam.

    Google Scholar 

  36. Richardson, R. T., and Delong, M. R. 1991. Functional implications of tonic and phasic activity changes in nucleus basalis neurons. Pages 135–166 in Richardson, R. T. (ed.). Activation to acquisition. Functional aspects of the basal forebrain cholinergic system, Birkhauser, Boston.

    Google Scholar 

  37. Robbins, T. W., and Everitt, B. J. 1995. Arousal systems and attention. Pages 703–720 in Gazzaniga, M. S. (ed.) The cognitive neuroscience, MIT Press, Massachusetts.

    Google Scholar 

  38. Thal, L. J. 1991. Physostigmine in Alzheimer's disease. Pages 209–215 in Becker, R., Giacobini, E., (eds.) Cholinergic basis for Alzheimer therapy, Birkhauser, Boston.

    Google Scholar 

  39. Muramoto, O., Sugishita, M., and Ando, K. 1984. Cholinergic system and constructional praxis: a further study of physostigmine in Alzheimer's disease. Journal of Neurology, Neurosurgery and Psychiatry 47:485–491.

    Google Scholar 

  40. Sahakian, B. J., Joyce, E. M., and Lishman, W. A. 1987. Cholinergic effects on constructional abilities and on mnemonic processes: a case report. Psychological Medicine 17:329–333.

    Google Scholar 

  41. Jacobs, D. H., Shuren, J., Gold, M., Adair, J. C., Bowers, D., Williamson, D. J. G., and Heilman, K. M. 1996. Physostigmine pharmacotherapy for anomia. Neurocase 2:83–91.

    Google Scholar 

  42. Thal, L. J. 1996. Cholinomimetic treatment of Alzheimer's disease. Progress in Brain Research 109:299–309.

    Google Scholar 

  43. Lawrence, A. D., and Sahakian, B. J. 1996. The neuropsychology of frontostriatal dementias. Pages 243–265 in Woods, R. T. (ed.). Handbook of the clinical psychology of ageing, Chichester, Wiley.

    Google Scholar 

  44. Robbins, T. W., James, M., Owen, A. M., Sahakian, B. J., McInnes, L., and Rabbitt, P. 1994. Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5:266–281.

    Google Scholar 

  45. Roberts, A. C., and Sahakian, B. J. 1993. Comparable tests of cognitive function in monkey and man. Pages 165–184 in Sahgal, A. (ed.) Behavioural neuroscience: a practical approach, IRL Press, Oxford.

    Google Scholar 

  46. Sahakian, B. J., Owen, A. M., Morant, N. J., Eagger, S. A., Boddington, S., Crayton, L., Crockford, H. A., Crooks, M., Hill, K., and Levy, R. 1993. Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer's disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology 110:395–401.

    Google Scholar 

  47. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., and Stadlan, E. M. 1985. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34:939–944.

    Google Scholar 

  48. Perry, E. K., Morris, C. M., Court, J. A., Cheng, A., Fairburn, A. F., McKeith, I. G., Irving, D., Brown, A., and Perry, R. H. 1995. Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology. Neuroscience 64:385–395.

    Google Scholar 

  49. Nordberg, A. 1996. Pharmacological treatment of cognitive dysfunction in dementia disorders. Acta Neurologica Scandinavia 168:s87-s92.

    Google Scholar 

  50. Rowell, P., and Winkler, D. L. 1984. Nicotinic stimulation of 3H-acetylcholine release from mouse cerebral cortical synaptosomes. Journal of Neurochemistry 43:1593–1598.

    Google Scholar 

  51. Heishman, S. J., Taylor, R. C., and Henningfield, J. E. 1994. Nicotine and smoking: a review of effects on human performance. Experimental and Clinical Psychopharmacology 2:345–395.

    Google Scholar 

  52. Jones, G. M. M., Sahakian, B. J., Levy, R., Warburton, D. M., and Gray, J. A. 1992. Effects of subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease. Psychopharmacology 108:485–494.

    Google Scholar 

  53. Snaedal, J., Johannesson, T., Jonsson, J. E., and Gylfadottir, G. 1996. The effects of nicotine in dermal plaster on cognitive functions in patients with Alzheimer's disease. Dementia 7:47–52.

    Google Scholar 

  54. Wilson, A. L., Langley, L. K., Monley, J., Bauer, T., Rottunda, S., McFalls, E., Kovera, C., and McCarten, J. R. 1995. Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacology, Biochemistry, and Behaviour 51:509–514.

    Google Scholar 

  55. Newhouse, P., Potter, A., and Corwin, J. 1996. Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer's and Parkinson's disease. Drug Development Research 38:278–289.

    Google Scholar 

  56. Parks, R. W., Becker, R. E., Rippey, R. F., Gilbert, D. G., et al. 1996. Increased regional cerebral glucose metabolism and semantic memory performance in Alzheimer's disease: a pilot double blind transdermal nicotine PET study. Neuropsychology Review 6:61–79.

    Google Scholar 

  57. Murray, E. A. 1996. What have ablation studies told us about the neural substrates of stimulus memory? Seminars in the Neurosciences 8:13–22.

    Google Scholar 

  58. Posner, M. I., and Dehaene, S. 1994. Attentional networks. Trends in Neurosciences 17:75–79.

    Google Scholar 

  59. Sarter, M., and Bruno, J. P. 1997. Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers. Behavioural Brain Research 83:7–14.

    Google Scholar 

  60. Cummings, J. L., and Kaufer, D. 1996. Neuropsychiatric aspects of Alzheimer's disease: the cholinergic hypothesis revisited. Neurology 47:876–883.

    Google Scholar 

  61. Chu, C.-C., Tranel, D., Damasio, A. R., and Van Hoesen, G. W. 1997. The autonomic-related cortex: pathology in Alzheimer's disease. Cerebral Cortex 7:86–95.

    Google Scholar 

  62. Aggleton, J. P. 1993. The amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss, New York.

    Google Scholar 

  63. Perry, E. K., Tomlinson, B. E., Blessed, G., Perry, R. H., Cross, A. J., and Crow, T. J. 1981. Neuropathological and biochemical observations on the noradrenergic system in Alzheimer's disease. Journal of the Neurological Sciences 51:279–287.

    Google Scholar 

  64. Arnsten, A. F. T., Steere, J. C., and Hunt, R. D. 1996. The contribution of alpha2-noradrenergic mechanisms to prefrontal cortical cognitive function. Archives of General Psychiatry 53:448–455.

    Google Scholar 

  65. Bierer, L. M., Aisen, P. S., Davidson, M., Ryan, T. M., Stern, R. G., Schmeidler, J., and Davis, K. L. 1993. A pilot study of oral physostigmine plus yohimbine in patients with Alzheimer's disease. Alzheimer Disease and Associated Disorders 7:98–104.

    Google Scholar 

  66. Bierer, L. M., Aisen, P. S., Davidson, M., Ryan, T. M., Schmeidler, J., and Davis, K. L. 1994. A pilot study of clonidine plus physostigmine in Alzheimer's disease. Dementia 5:243–246.

    Google Scholar 

  67. Mohr, E., Schlegel, J., Fabbrini, G., Williams, J., Mouradian, M., Mann, U. M., Claus, J. J., Fedio, P., and Chase, T. N. 1989. Clonidine treatment of Alzheimer's disease. Archives of Neurology 46:376–378.

    Google Scholar 

  68. Schlegel, J., Mohr, E., Williams, J., Mann, U., Gearing, M., and Chase, T. N. 1989. Guanfacine treatment of Alzheimer's disease. Clinical Neuropharmacology 12:124–128.

    Google Scholar 

  69. Coull, J. T., Sahakian, B. J., and Hodges, J. R. 1996. The alpha2 antagonist, idazoxan, remediates certain attentional and and executive dysfunction in patients with dementia of frontal type. Psychopharmacology 3:209–249.

    Google Scholar 

  70. Nitsch, R. M., Slack, B. E., Wurtman, R. J., and Growdon, J. H. 1992. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Nature 258:304–307.

    Google Scholar 

  71. Soininen, H., Kosunen, O., Helisalmi, S., Mannermaa, A., Paljarvi, L., Talasniemi, S., Ryynanen, M., and Riekkinen, P. 1995. A severe loss of choline-acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon-4 allele. Neuroscience Letters 187:79–82.

    Google Scholar 

  72. Riekkinen, P., Soininen, H., Partanen, J., Paakkonen, A., Helisalmi, S., and Riekkinen, P. 1997. The ability of THA treatment to increase cortical alpha waves is related to apolipoprotein E genotype of Alzheimer disease patients. Psychopharmacology 129:285–288.

    Google Scholar 

  73. Van Duijin, C. M., and Hofman, A. 1991. Relationship between nicotine intake and Alzheimer's disease. British Medical Journal 302:1491–1494.

    Google Scholar 

  74. Perry, E. K., Haroutunian, V., Davis, K. L. et al. 1994. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease. Neuroreport 5:747–749.

    Google Scholar 

  75. Levy, R., Eagger, S., Griffiths, M., Perry, E. K., Honavar, M., Dean, A., and Lantos, P. 1994 Lewy bodies and response to tacrine in Alzheimer's disease. Lancet 343:176.

    Google Scholar 

  76. Fagerstrom, K. O., Pomerleau, O., Giordani, B., and Stelson, F. 1994. Nicotine may relieve symptoms of Parkinson's disease. Psychopharmacology 166:117–119.

    Google Scholar 

  77. Levin, E. D., Connors, C. K., Sparrow, E., Hinton, S. C., Erhardt, D., Meck, W. H., Rose, J. E., and March, J. 1996. Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD). Psychopharmacology 123:55–63.

    Google Scholar 

  78. Freedman, R., Adler, L. E., Bickford, P., Byerley, W., Coon, H., Cullum, C. M., Griffith, J. M., Harris, J. G., Leonard, S., Miller, C., Myles-Worsley, M., Nagatomo, H. T., Rose, G., and Waldo, M. 1994. Schizophrenia and nicotinic receptors. Harvard Review of Psychiatry 2:179–192.

    Google Scholar 

  79. Dursun, S. M., Revely, M. A., Bird, R., and Stirton, F. 1994. Longlasting improvement of Tourette's syndrome with transdermal nicotine. Lancet 337:989–992.

    Google Scholar 

  80. Bryson, H. M., and Benfield, P. 1997. Donepezil. Drugs & Aging 10:234–239.

    Google Scholar 

  81. Rogers, S. L., and Friedhoff, L. T., Donepezil Study Group. 1996. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia 7:293–303.

    Google Scholar 

  82. Arendt, T., Schindler, C., Bruckner, M. K., Eschrich, K., Bigl, V., Zedlick, D., Marcova, L. 1997. Plastic neuronal remodelling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele. Journal of Neuroscience 17:516–529.

    Google Scholar 

  83. Poirer, J., Delisle, M. C., Quirion, R., Aubert, I., Farlow, M., Lahiri, D., Hui, S., Bertrand, P., Nalbantoglu, J., Gilfix, B. M., and Gauthier, S. 1995. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer's disease. Proceedings of the National Academy of Sciences, USA 92:12260–12264.

    Google Scholar 

  84. Pedersen, W. A., Kloczewiak, M. A., and Blusztajn, J. K. 1996. Amyloid beta-protein reduces acetylcholine synthesis in a cell-line derived from cholinergic neurons of the basal forebrain. Proceedings of the National Academy of Sciences, USA 93:8068–8071.

    Google Scholar 

  85. Kar, S., Seto, D., Gaudreau, P., and Quirion, R. 1996. Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine-release from rat hippocampal slices. Journal of Neurosciences 16:1034–1040.

    Google Scholar 

  86. Alhainen, K., and Riekkinen, P. J. 1993. Discrimination of Alzheimer patients responding to cholinesterase inhibitor therapy. Acta Neurological Scandinavica 88:s16-s21.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lawrence, A.D., Sahakian, B.J. The Cognitive Psychopharmacology of Alzheimer's Disease: Focus on Cholinergic Systems. Neurochem Res 23, 787–794 (1998). https://doi.org/10.1023/A:1022419712453

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022419712453

Navigation