Mohammed T. Abou-Saleh

326 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYPerhaps the most surprising and exciting development suggeststhat a vaccine is a therapeutic possibility for AD 14 . Amyloidpeptide was used to inoculate transgenic animals overexpressingthe amyloid precursor protein gene. In these animals, amyloidinoculation reduced amyloid deposition in the brain without anyapparent adverse effects on the animals. It remains to be seenwhether this is true in other animal models and whether cognitivedeficits are also prevented. More importantly, it will be necessaryto be very sure that there are no adverse consequences in man.The brain is supposedly (but probably not entirely) immunologicallysacrosanct, and injecting a normal brain protein andstimulating an immune reaction has the very real potential ofinducing auto-immune damage. Toxicity studies are under waythat will address this concern.TOWARDS DISEASE MODIFICATION—A TIME SCALEThe time scale of science is not linear; progress comes quickerthese days and the only reliable prediction regarding the future isthat predictions will continue to be usually wrong. However,disease-modifying treatments are already in clinical trials, andstrategies such as HRT, anti-inflammatories and vitamin E are inuse in other contexts. Another potential disease-modifyingapproach is to use the cholinergic therapies that are already inuse for palliation. It should be known within the first few years ofthe new millennium whether any of these approaches have a truebenefit for patients in modifying disease and, if so, given thatexperience in using these compounds in other contexts isextensive, then approval for use in secondary prevention may berapid. Other approaches modifying amyloid and tau will takelonger, not least because the time taken for novel drugs to travelfrom laboratory to clinic is best measured in decades.REFERENCES1. Braak E, Braak H, Mandelkow E-M. A sequence of cytoskeletonchanges related to the formation of neurofibrillary tangles and neuropilthreads. Acta Neuropathol 1994; 87: 554–67.2. Small GW, Mazziotta JC, Collins MT et al. Apolipoprotein E type 4allele and cerebral glucose metabolism in relatives at risk for familialAlzheimer disease. J Am Med Assoc 1995; 273: 942–7.3. Ott A, Stolk RP, Hofman A et al. Association of diabetes mellitusand dementia: the Rotterdam Study. Diabetologia 1996; 39(11): 1392–7.4. Breitner JC, Welsh KA, Helms MJ et al. Delayed onset ofAlzheimer’s disease with nonsteroidal anti-inflammatory andhistamine H 2 blocking drugs. Neurobiol Aging 1995; 16: 523–30.5. Sano M, Ernesto C, Thomas RG et al. A controlled trial of selegiline,a-tocopherol, or both as treatment for Alzheimer’s disease. N Engl JMed 1997; 336: 1216–22.6. Nitsch RM, Slack BE, Farber SA et al. Regulation of proteolyticprocessing of the amyloid b-protein precursor of Alzheimer’s diseasein transfected cell lines and in brain slices. J Neural Transm 1994; 44(suppl): 21–7.7. Spillantini MG, Goedert M. Tau protein pathology inneurodegenerative diseases. Trends Neurosci 1998; 21: 428–33.8. Lovestone S, Hartley CL, Pearce J, Anderton BH. Phosphorylationof tau by glycogen synthase kinase-3b in intact mammalian cells: theeffects on organisation and stability of microtubules. Neuroscience1996; 73(4): 1145–57.9. Lovestone S, Reynolds CH. The phosphorylation of tau: a criticalstage in neurodevelopmental and neurodegenerative processes.Neuroscience 1997; 78(2): 309–24.10. Lovestone S, Davis DR, Webster M-T et al. Lithium reduces tauphosphorylation—effects in living cells and in neurons at therapeuticconcentrations. Biol Psychiat 1999; 45(8): 995–1003.11. Muñoz-Montaño JR, Moreno FJ, Avila J, Dı´az-Nido J. Lithiuminhibits Alzheimer’s disease-like tau protein phosphorylation inneurons. FEBS Lett 1997; 411: 183–8.12. Sadot E, Gurwitz D, Barg J et al. Activation of m1 muscarinicacetylcholine receptor regulates tau phosphorylation in transfectedPC12 cells. J Neurochem 1996; 66: 877–80.13. Lovestone S. Muscarinic therapies in Alzheimer’s disease: frompalliative therapies to disease modification. Int J Psychiat Clin Pract1997; 1(1): 15–20.14. Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-battenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature 1999; 400(6740): 173–7.