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 0-470-84641-058bPossible Future Treatments and PreventativeStrategies for Alzheimer’s DiseaseSimon LovestoneInstitute of Psychiatry, London, UKPREVENTION OR CURE?It is a truism that prevention is better than cure, althoughhistorically both are usually preceded by palliation. Whilst thisseems to be true also for Alzheimer’s disease (AD), in that drugsfor symptomatic treatment have preceded other approaches, thesituation is complicated, both because these drugs may themselvesalter the disease process and because prevention and cure (in thesense of reversing or modifying the disease pathogenesis) may beinseparable. The confusion largely results from the timing of theonset of AD. At the point of diagnosis, disease has already beenestablished, probably for many decades. Careful pathologicalstudies have demonstrated that a marker of neuronal damage inAD—highly phosphorylated tau—accumulates in neurons incertain cortical areas in mid-life and progresses to frankneurofibrillary tangle formation and neuronal death in theseareas before the onset of clinical dementia 1 . Neuroimaging studiesshow that those with genetic risk factors for AD have evidence offunctional damage decades before onset 2 . Truly preventativestrategies, therefore, preventing even the onset of AD pathology,are probably not realistic. Rather, prevention will be secondary—preventing the disease process progressing to the point where itbecomes clinically manifest. This approach (prevention) differsfrom approaches designed to slow the progression of disease oncestarted (treatment) only in timing. It is best perhaps to think onlyof disease modification; either late, in which case it looks likeslowing of disease, or early, in which case it looks like prevention.From the biological point of view, both are the same.DISEASE MODIFICATION—DIRECTIONS FROMEPIDEMIOLOGYIdentification of risk factors for AD, such as vascular factors ordiabetes, points the way towards obvious potential interventionsto slow disease progression. It would be hoped that reducinghypertension and head injury, improving cardiovascular healthand controlling diabetes well would all reduce the conversion ofearly pathology to clinical dementia. Time will tell whether this isthe case. Worrying for this long-term strategy is the observationthat treatment with insulin carries a higher risk than diabetesalone 3 . This may be a surrogate for disease severity but it doeshighlight that the route between epidemiology and public healthmay not always be obstacle-free.Other population-based studies have suggested interventionalpossibilities for disease modification. Most promising at present isevidence suggesting that non-steroidal anti-inflammatory drugsmay delay progression or prevent the appearance of symptoms 4 .Similarly, there is evidence linking oxidative damage to pathologyand antioxidants to protection, and there may be an importantrole for vitamin E or some other antioxidant therapy in diseasemodification in the near to middle future 5 . The evidence linkinghormone replacement and protection has a more limitedpotential, if only by virtue of gender. Studies are currently inprogress that will determine whether any of these threeapproaches will have a clinical role in modifying the pathogenesisof AD.DISEASE MODIFICATION—DIRECTIONS FROMMOLECULAR BIOLOGYThe advances in understanding the molecular biology of AD havebeen rapid and profound. It is clear already that this work willyield compounds designed to modify disease, although whetherthese compounds make the difficult passage between laboratoryand clinic is a different matter. Preventing amyloid formation isthe most obvious drug target and compounds designed to do thisby inhibiting g-secretase are in the late stages of development.Another, complementary approach is to increase the activity of a-secretase (thus hopefully reducing amyloidogenic metabolism).Interestingly, all cholinomimetic therapies should increase theactivity of a-secretase indirectly, and this has been shown to be thecase for M1 agonists 6 .The other pathology of AD, tangles, is a harder target as it isnot yet clear why tau aggregates. However the importance of tauaggregation as a target is emphasized by the fact that this occursin many neurodegenerative conditions 7 , correlates with cognitiveimpairment and has functional consequences for neurons. Tauphosphorylation precedes aggregation and may cause aggregationin AD; certainly it inhibits tau function 8 . In neurons, tau isphosphorylated by an enzyme, glycogen synthase kinase-3b(GSK-3b), and inhibition of this would be expected to preventtau phosphorylation 9 . Lithium inhibits GSK-3b and, as predicted,reduces tau phosphorylation 10,11 . Might lithium modify diseaseprogression? Other GSK-3b inhibitors are in development. GSK-3b is also inhibited through the same signal transduction route asthat induced by muscarinic agonists, and in line with this is thefinding that muscarinic agonists reduce tau phosphorylation incellular models 12 . It is possible that cholinomimetic therapies(including the cholinesterase inhibitors) will have some diseasemodifyingeffect as well as a palliative effect 13 .Principles 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