J Neurol Neurosurg Psychiatry 1999;66:137-147 ( February )

Review

The cholinergic hypothesis of Alzheimer's disease: a review of progress Paul T Francis,^a Alan M Palmer,^b Michael Snape,^b Gordon K Wilcock^c

^a Dementia Research Laboratory, Neuroscience Research Centre, Guy's, King's and St Thomas' Schools of Biomedical Sciences, King's College, London, SE1 9RT, UK, ^b Cerebrus, Oakdene Court, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, UK, ^c Department of Care of the Elderly, Frenchay Hospital, Bristol, BS16 2EW, UK

Correspondence to: Dr Paul T Francis, Dementia Research Laboratory, Division of Biomolecular Sciences, Guy's, King's and St Thomas' Schools of Biomedical Sciences, King's College, St Thomas Street, London SE1 9RT, UK. Telephone 0044 171 955 2611; fax and answer phone 0044 171 955 2600; email p.francis{at}umds.ac.uk

Received 11 June and in revised form 20 October 1998; Accepted 30 October 1998

Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

---

© 1999 by Journal of Neurology, Neurosurgery, and Psychiatry
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Buckingham, S. D., Jones, A. K., Brown, L. A., Sattelle, D. B. (2009). Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection. Pharmacol. Rev. 61: 39-61 [Abstract] [Full Text]  
• Jalbert, J. J., Daiello, L. A., Lapane, K. L. (2008). Dementia of the Alzheimer Type. Epidemiol Rev 30: 15-34 [Abstract] [Full Text]  
• Bar, K.-J., Boettger, M. K., Seidler, N., Mentzel, H. J., Terborg, C., Sauer, H. (2007). Influence of Galantamine on Vasomotor Reactivity in Alzheimer's Disease and Vascular Dementia Due to Cerebral Microangiopathy. Stroke 38: 3186-3192 [Abstract] [Full Text]  
• Yesavage, J., Hoblyn, J., Friedman, L., Mumenthaler, M., Schneider, B., O'Hara, R. (2007). Should One Use Medications in Combination With Cognitive Training? If So, Which Ones?. Journals of Gerontology Series B: Psychological Sciences and Social Science 62: 11-18 [Abstract] [Full Text]  
• Rowland, J. P., Rigby, J., Harper, A. C., Rowland, R. (2007). Cardiovascular monitoring with acetylcholinesterase inhibitors: a clinical protocol. Adv. Psychiatr. Treat. 13: 178-184 [Abstract] [Full Text]  
• Ally, B. A., Jones, G. E., Cole, J. A., Budson, A. E. (2007). Sensory Gating in Patients With Alzheimer's Disease and Their Biological Children. AM J ALZHEIMERS DIS OTHER DEMEN 21: 439-447 [Abstract]  
• Yogev-Falach, M., Bar-Am, O., Amit, T., Weinreb, O., Youdim, M. B. H. (2006). A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing. FASEB J. 20: 2177-2179 [Abstract] [Full Text]  
• Farlow, M. R. (2006). Use of Antidementia Agents in Vascular Dementia: Beyond Alzheimer Disease. Mayo Clin Proc. 81: 1350-1358 [Abstract] [Full Text]  
• Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., Anandatheerthavarada, H. K. (2006). Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction.. J. Neurosci. 26: 9057-9068 [Abstract] [Full Text]  
• Jakubik, J., El-Fakahany, E. E., Dolezal, V. (2006). Differences in Kinetics of Xanomeline Binding and Selectivity of Activation of G Proteins at M1 and M2 Muscarinic Acetylcholine Receptors. Mol. Pharmacol. 70: 656-666 [Abstract] [Full Text]  
• Hawkes, C., Jhamandas, J. H., Harris, K. H., Fu, W., MacDonald, R. G., Kar, S. (2006). Single Transmembrane Domain Insulin-Like Growth Factor-II/Mannose-6-Phosphate Receptor Regulates Central Cholinergic Function by Activating a G-Protein-Sensitive, Protein Kinase C-Dependent Pathway. J. Neurosci. 26: 585-596 [Abstract] [Full Text]  
• Bocti, C., Swartz, R. H., Gao, F.-Q., Sahlas, D. J., Behl, P., Black, S. E. (2005). A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathways in Dementia. Stroke 36: 2126-2131 [Abstract] [Full Text]  
• Francis, P. T. (2005). Neuroanatomy/pathology and the interplay of neurotransmitters in moderate to severe Alzheimer disease. Neurology 65: S5-S9 [Full Text]  
• Di Lazzaro, V, Oliviero, A, Pilato, F, Saturno, E, Dileone, M, Marra, C, Ghirlanda, S, Ranieri, F, Gainotti, G, Tonali, P (2005). Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J. Neurol. Neurosurg. Psychiatry 76: 1064-1069 [Abstract] [Full Text]  
• Vandenberghe, R, Tournoy, J (2005). Cognitive aging and Alzheimer's disease. Postgrad. Med. J. 81: 343-352 [Abstract] [Full Text]  
• Yao, C., Raoufinia, A., Gold, M., Nye, J. S., Ramael, S., Padmanabhan, M., Walschap, Y., Verhaeghe, T., Zhao, Q. (2005). Steady-State Pharmacokinetics of Galantamine Are Not Affected by Addition of Memantine in Healthy Subjects. J Clin Pharmacol 45: 519-528 [Abstract] [Full Text]  
• Bayer, A. J., Bullock, R., Jones, R. W., Wilkinson, D., Paterson, K. R., Jenkins, L., Millais, S. B., Donoghue, S. (2005). Evaluation of the safety and immunogenicity of synthetic A{beta}42 (AN1792) in patients with AD. Neurology 64: 94-101 [Abstract] [Full Text]  
• Rockwood, K (2004). Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 75: 677-685 [Abstract] [Full Text]  
• Verbitsky, M., Yonan, A. L., Malleret, G., Kandel, E. R., Gilliam, T. C., Pavlidis, P. (2004). Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice. Learn. Mem. 11: 253-260 [Abstract] [Full Text]  
• Di Lazzaro, V, Oliviero, A, Pilato, F, Saturno, E, Dileone, M, Marra, C, Daniele, A, Ghirlanda, S, Gainotti, G, Tonali, P A (2004). Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 75: 555-559 [Abstract] [Full Text]  
• Adler, G, Brassen, S, Chwalek, K, Dieter, B, Teufel, M (2004). Prediction of treatment response to rivastigmine in Alzheimer's dementia. J. Neurol. Neurosurg. Psychiatry 75: 292-294 [Abstract] [Full Text]  
• Volpicelli-Daley, L. A., Hrabovska, A., Duysen, E. G., Ferguson, S. M., Blakely, R. D., Lockridge, O., Levey, A. I. (2003). Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice. Mol. Pharmacol. 64: 1309-1316 [Abstract] [Full Text]  
• Black, S., Roman, G. C., Geldmacher, D. S., Salloway, S., Hecker, J., Burns, A., Perdomo, C., Kumar, D., Pratt, R. (2003). Efficacy and Tolerability of Donepezil in Vascular Dementia: Positive Results of a 24-Week, Multicenter, International, Randomized, Placebo-Controlled Clinical Trial. Stroke 34: 2323-2330 [Abstract] [Full Text]  
• Lanctot, K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 169: 557-564 [Abstract] [Full Text]  
• Rosenthal, T. C., Khotianov, N. (2003). Managing Alzheimer Dementia Tomorrow. J Am Board Fam Med 16: 423-434 [Abstract] [Full Text]  
• Brangman, S. A. (2003). Long-term cholinesterase inhibitor therapy for Alzheimer's disease: Implications for long-term care. AM J ALZHEIMERS DIS OTHER DEMEN 18: 79-84 [Abstract]  
• Katada, E., Sato, K., Sawaki, A., Dohi, Y., Ueda, R., Ojika, K. (2003). Long-Term Effects of Donepezil on P300 Auditory Event-Related Potentials in Patients with Alzheimer's Disease. J Geriatr Psychiatry Neurol 16: 39-43 [Abstract]  
• Conroy, W. G., Liu, Q.-S., Nai, Q., Margiotta, J. F., Berg, D. K. (2003). Potentiation of alpha 7-Containing Nicotinic Acetylcholine Receptors by Select Albumins. Mol. Pharmacol. 63: 419-428 [Abstract] [Full Text]  
• Zhao, Q., Xie, C., Pesco-Koplowitz, L., Jia, X., Parier, J.-L. (2003). Pharmacokinetic and Safety Assessments of Concurrent Administration of Risperidone and Donepezil. J Clin Pharmacol 43: 180-186 [Abstract] [Full Text]  
• Rinne, J O, Kaasinen, V, Jarvenpaa, T, Nagren, K, Roivainen, A, Yu, M, Oikonen, V, Kurki, T (2003). Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 74: 113-115 [Abstract] [Full Text]  
• Okuda, T., Okamura, M., Kaitsuka, C., Haga, T., Gurwitz, D. (2002). Single Nucleotide Polymorphism of the Human High Affinity Choline Transporter Alters Transport Rate. J. Biol. Chem. 277: 45315-45322 [Abstract] [Full Text]  
• Rockwood, K, Graham, J E, Fay, S (2002). Goal setting and attainment in Alzheimer's disease patients treated with donepezil. J. Neurol. Neurosurg. Psychiatry 73: 500-507 [Abstract] [Full Text]  
• Fillit, H. M., Butler, R. N., O'Connell, A. W., Albert, M. S., Birren, J. E., Cotman, C. W., Greenough, W. T., Gold, P. E., Kramer, A. F., Kuller, L. H., Perls, T. T., Sahagan, B. G., Tully, T. (2002). Achieving and Maintaining Cognitive Vitality With Aging. Mayo Clin Proc. 77: 681-696 [Abstract]  
• Boyd, M. A. (2001). Behavioral Disturbances Associated with Dementia: Nursing Implications. J Am Psychiatr Nurses Assoc 7: S14-S22 [Abstract]  
• Rockwood, K, Mintzer, J, Truyen, L, Wessel, T, Wilkinson, D (2001). Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial. J. Neurol. Neurosurg. Psychiatry 71: 589-595 [Abstract] [Full Text]  
• P. Lai, M. K., Lai, O. -F., Keene, J., Esiri, M. M., Francis, P. T., Hope, T., Chen, C. P.L.-H. (2001). Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex. Neurology 57: 805-811 [Abstract] [Full Text]  
• Ros, E., Aleu, J., Gomez De Aranda, I., Canti, C., Pang, Y.-P., Marsal, J., Solsona, C. (2001). Effects of Bis(7)-Tacrine on Spontaneous Synaptic Activity and on the Nicotinic ACh Receptor of Torpedo Electric Organ. J. Neurophysiol. 86: 183-189 [Abstract] [Full Text]  
• Hodgkiss, J. P., Kelly, J. S. (2001). Effect of FK960, a Putative Cognitive Enhancer, on Synaptic Transmission in CA1 Neurons of Rat Hippocampus. J. Pharmacol. Exp. Ther. 297: 620-628 [Abstract] [Full Text]  
• Liu, Q.-s., Kawai, H., Berg, D. K. (2001). beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. USA 10.1073/pnas.081553598v1 [Abstract] [Full Text]  
• Wilcock, G. K, Lilienfeld, S., Gaens, E. (2000). Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. BMJ 321: 1445-1445 [Abstract] [Full Text]  
• Minger, S. L., Esiri, M. M., McDonald, B., Keene, J., Carter, J., Hope, T., Francis, P. T. (2000). Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 55: 1460-1467 [Abstract] [Full Text]  
• Buccafusco, J. J., Terry, A. V. Jr. (2000). Multiple Central Nervous System Targets for Eliciting Beneficial Effects on Memory and Cognition. J. Pharmacol. Exp. Ther. 295: 438-446 [Abstract] [Full Text]  
• Tariot, P. N., Solomon, P. R., Morris, J. C., Kershaw, P., Lilienfeld, S., Ding, C. (2000). A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 54: 2269-2276 [Abstract] [Full Text]  
• (2000). {blacktriangledown}Rivastigmine for Alzheimer's disease. DTB 38: 15-16 [Abstract] [Full Text]  
• Mayeux, R., Sano, M. (1999). Treatment of Alzheimer's Disease. NEJM 341: 1670-1679 [Full Text]  
• BABIC;, T, FRANCIS, P. T, PALMER, A. M, SNAPE, M., WILCOCK, G. K (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress. J. Neurol. Neurosurg. Psychiatry 67: 558-558 [Full Text]  
• Liu, Q.-s., Kawai, H., Berg, D. K. (2001). beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. USA 98: 4734-4739 [Abstract] [Full Text]  
• Pettit, D. L., Shao, Z., Yakel, J. L. (2001). {beta}-Amyloid1-42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice. J. Neurosci. 21: RC120-RC120 [Abstract] [Full Text]