Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-058aPresent and Future Treatments ofAlzheimer’s DiseaseLawrence J. Whalley 1 and John M. Starr 21University of Aberdeen and 2 University of Edinburgh, UKModern theories of disease predict that, when valid diagnosticcriteria are available and causes can be confidently ascribed to adisease condition, then effective treatments will be developed 1 .Inclinical practice, the diagnosis of late-onset Alzheimer’s disease(AD) is not supported by definitive diagnostic findings and noconsensus exists on its causes. Currently, diagnosis depends on acluster of neuropsychological features combined with the absenceof other pathologies, identified clinically or by investigation. Inthose patients who present at a later stage, neuropsychologicaldeficits are so severe and global that differentiation from otheraetiologies is difficult. Moreover, the presence of other causes ofcognitive decline, such as stroke, does not exclude AD; indeed, theprevalence of AD is far more common in people with stroke thanwould be expected by chance alone.Observational longitudinal studies suggest that both geneticand environmental factors are important in early-onset AD 2 . Bestestimates in late-onset AD are that genetic and environmentalinfluences are approximately equal 3 . In early-onset AD geneticfactors seem more important but at present can account for fewerthan 10% of cases 4 . Known mutations that contribute to thecauses of late-onset AD appear so far to be relatively infrequent 2,5but genetic contributions to functional ability in late life are alsoestablished 6 . Genetic susceptibility factors are less well established;apolipoprotein E polymorphisms are best known and mayinfluence the timing of the onset of AD in almost 50% of cases 7 .For many commentators, these sparse facts encourage the searchfor environmental factors that certainly contribute to the onset ofdementia and, by extension, to the possible modification of thoseexposures. These interventions may slow or even prevent the onsetof dementia. So far, however, no single factor or group of factorshas been reliably confirmed as an environmental contributor tothe risk of dementia. This situation is similar to the problemsfaced by specialists in old age medicine about 30 years ago. Atthat time, there was some concern about the accumulation ofdisabilities in old age, so much so that population projectionspredicted increasing longevity and an increased burden posed bylarge numbers of disabled old people 8 . One of the great successesof modern geriatric medicine was the postponement of theexpected accumulation of disability into the final year of life.This in turn has reduced the period of dependency in old age,especially for men 9 . Prevention of disability was the key outcomeof the interdisciplinary research programme one ‘‘successfulageing’’ in the USA 10 . Compression of disability and morbidityhas been so great that the proportion of men aged 80 years inNorth America and Northern Europe with at least one disabilityhalved between 1975 and 1995 11 .These reductions were achieved by preventative measures todetect and reduce environmental exposures in old people knownto be at increased risk for vascular disease. Hypertension,smoking, diabetes, obesity and hyperlipidaemia proved susceptibleto such interventions. Likewise, smoking reduction andimprovements in air quality reduced the burden posed byrespiratory disease and cancer. Reduction of disease incidenceand subsequent improvements in well-being in old age haveprompted some researchers to speculate that much of what isregarded as ‘‘ageing’’ is made up of at least two processes 12 . Oneprocess comprises the accumulated effects of disease and theacquired handicaps and disabilities of old age. The other is madeup of at least one process, usually termed ‘‘intrinsic ageing’’. Thenature and cause of intrinsic ageing processes are currentlydescribed using terms such as ‘‘the oxidative stress model’’ or‘‘accumulated DNA damage’’ or ‘‘inefficient DNA repair’’. Theformation of advanced glycated end products, the consequencesof membrane lipid peroxidation and failure of immune surveillanceare all included in current hypotheses concerning intrinsicageing. However, given that the brain enjoys specific privileges,e.g. in terms of immuno-surveillance and neurons being naturallyin a post-mitotic state throughout most of the lifespan, whethersome general ‘‘intrinsic ageing’’ process applies to the centralnervous system or is the same as that for other organs isquestionable.From the standpoint of dementia prevention and/or treatment,brain ageing research is now of pivotal importance to futureprogress. The success of modern geriatric medicine has beenachieved largely by translation of epidemiological data into publichealth-based preventative programmes. This chapter first considerswhat is currently available to treat or prevent dementia.Second, it examines some of the potential for neuroprotection anddementia prevention and/or treatment provided by recentresearch findings in brain ageing. Third, lessons learnt fromgeneral medicine in the prevention of heart disease andcerebrovascular accidents will be considered. Fourth, futurestrategies proposed to slow or even prevent brain ageing andthe characteristic features of AD will be briefly summarized.CURRENT TREATMENTSWho is Eligible for Treatment?AD is the most frequent cause of late-onset cognitive impairmentin the UK and probably affects around 350 000 people. IncidencePrinciples and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd