Therapeutics of Alzheimer’s Disease

Abstract

Alzheimer disease (AD) is the commonest degenerative brain disease characterised by progressive cognitive decline, leading to impairment in self-care abilities. With the ageing of the Hong Kong population, the incidence of AD, which is age related, is expected to rise very significantly in the coming years. AD patients typically do not actively complain about dementia symptoms because of their insidious onset, the associated loss of insight and the common misconception that cognitive decline is normal in old age. On the other hand, the burden of the disease on families is severe, leading to physical and psychological morbidities and even increased mortality in family caregivers. AD is therefore a medical disease with major adverse social consequences. The prevailing theory about the cause of AD is the amyloid cascade hypothesis. Abnormal metabolism of amyloid precursor protein leads to increased production of amyloid beta protein which precipitates into amyloid plaques. Amyloid beta protein somehow leads to hyperphosphorylation of Tau protein, which impairs the stability of microtubules in axons, leading to neurofibrillary tangles and eventually neuronal death. But whether amyloid plaques and neurofibrillary tangles are the causes or the effects of AD remains to be determined. An earlier phase one trial of an active vaccine of amyloid beta protein was abandoned because of the complication of meningoencephalitis. The vaccinated subjects continued to have progressive dementia, despite evidence of clearing of amyloid plaques on subsequent post-mortem examinations. Since then, more active and passive immunotherapies have been investigated. The more promising one is bapineuzumab, which is a humanised anti-amyloid beta monoclonal antibody. In its phase two trial, study "completers" and APOE epsilon4 noncarriers showed treatment effects in cognition and functional status. Vasogenic oedema of the brain on MRI was noted in 10% of subjects, but the subjects were not significantly symptomatic. Its phase three trial is ongoing. It has been well known for several decades that loss of cholinergic activity is an early and prominent f e a t u r e o f A D b r a i n. B a s e d o n t h i s i m p o r t a n t finding, several cholinesterase inhibitors (CheI) were developed. Currently three of these drugs-Donepezil, Rivastigmine, Galantamine have been licensed for treatment in mild to moderate AD. They have been shown to have modest effects on cognition and behaviour in AD patients and are moderately well tolerated. There is no head to head to compare the efficacy or side effect incidence among the three drugs. Before starting these drugs, patients and families should be warned that the effect is modest, but they may stabilise cognitive decline. The drug effect tends to be more noticeable in moderate AD. Gastrointestinal side effects e.g. anorexia, abdominal pain, diarrhoea are quite common in Chinese patients, especially at high doses. These side effects may be avoided by stepping up the doses gradually and may lessen over time. The transdermal preparation of Rivastigmine has the advantage of having less GI side effects, but some patients complain of skin irritation from the patches. Apart from GI side effects, a meta-analysis of randomised trial data showed that syncope was more common with ChEI use. ChEI should therefore be used with caution in patients with cardiovascular disorders. Dizziness and frequency of urine may also be troublesome. The other class of drug licensed for use in moderate to severe AD is memantine. It is believed to work by partially inhibiting the N-methyl-d-aspartate (NMDA) receptors. This may protect the NMDA receptors from the neurotoxic effect of over-stimulation by glutamate. Randomised placebo controlled trials have demonstrated modest cognitive benefits in moderate and severe AD. Post hoc analysis showed significant reduction in agitation and aggression, which was not consistently shown in randomised trials of ChEI. The effect of memantine in agitated AD patients has however not been specifically examined. Memantine is generally well tolerated, though it may potentiate the effects of anti-parkinsonian drugs and warfarin. Memantine is therefore a good alternative of ChEI if there are GI side effects or when there is agitation or aggression in patients with moderate to severe AD. In a six-month randomised placebo controlled trial in moderate to severe AD patients, the addition of memantine to ChEI had a mild additive effect on cognition, behaviour and functional status and the combination was tolerated by patients. Whether this effect is sustained in the long term, and whether the ChEI and memantine combination is superior to memantine alone in moderate to severe AD warrant