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No Association between ApoE4 Carrier Status and Response to Rivastigmine in Alzheimer's Disease
- Mihael H Polymeropoulos (19 June 2000)
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Cholinesterase inhibitors - further evidence for the benefits of rivastigmine
- Fraser Inglis (21 July 2000)
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BED BLOCKING AND CHOLINESTERASE INHIBITORS
- Fraser G Inglis (21 August 2000)
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Mihael H Polymeropoulos
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EDITOR- Polymorphisms in the apolipoprotein E gene have been associated with a diverse set of human disorders ranging from atherosclerosis to Alzheimer's disease. In Alzheimer's disease, it has been established that carriers of the ApoE4 allele are at increased risk for developing the illness compared to the general population.1 Additionally, it appears that the ApoE4 allele acts as a modifier of the age of onset. Individuals who carry the ApoE4 allele and are affected with Alzheimer's disease tend to have an onset of the illness earlier than non-carriers.1 While ApoE4 carrier status moderately increases the risk for Alzheimer's disease, other genetic alterations are also known to contribute to the aetiology of the illness. Mutations in the amyloid precursor protein (APP), presenilin (PS) 1, and 2 genes significantly increase the risk for the disease. Families, in which mutations in the APP and PS genes are observed, are at high risk for the development of early onset Alzheimer's disease. Most recently, a polymorphism in the alpha2 macroglobulin gene has also been noted to increase the risk for Alzheimer's disease.2 It has been suggested that the apolipoprotein status may predict the cognitive response to cholinesterase inhibitor therapy in AD patients.3 We investigated this relationship in AD patients participating in clinical trials with rivastigmine (Exelon®). While inhibition of neuronal acetylcholinesterase has been shown to have beneficial effects in patients with Alzheimer's disease, the pathophysiological connection between the acetylcholine system and the diverse genetic aetiologic factors for Alzheimer's disease remains unknown. The beneficial response seen with treatment with cholinesterase inhibitors including rivastigmine could suggest action of the acetylcholine system in Alzheimer's disease in a pathway upstream, downstream or parallel to the known aetiologic pathways. Participants, methods, and results We have investigated the segregation of the ApoE4 allele in Alzheimer's disease patients treated with rivastigmine in prospective, randomised double blind, multicentre, double blind, placebo controlled, parallel group clinical trials. Response to rivastigmine was measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog) and the results have been published.4 In a total of 262 patients ranging in age from 45-90 years of age with mild to moderately severe Alzheimer's disease treated with rivastigmine, 49 showed improvement of >4 points in the ADAS-cog. No significant association was observed between the ApoE4 carrier status and response rate to rivastigmine as shown in the table. Additional analyses for associations between homozygous or heterozygous carriers for the ApoE3 or ApoE4 alleles similarly revealed no significant association. Comment Clinical response to rivastigmine occurs in Alzheimer's disease patients regardless of their ApoE genotype. These results are in agreement with recent reports of non association of ApoE4 carrier status and treatment response with acetylcholinesterase inhibitors.5 However, these results contrast with an initial report of a negative correlation between tacrine and ApoE4 carrier status.3 The reported negative response to tacrine (Cognex®) in ApoE4 carriers may be due to a small number of individuals in that study or it could point to individual differences between members of the class of compounds. In conclusion, our genotype analysis of the ApoE gene in Alzheimer's disease patients treated with rivastigmine suggests no significant association between treatment response and ApoE4 carrier status. These results suggest that an equal response rate is expected between ApoE4 carriers and non-carriers.
Genotypes in the ApoE gene in Alzheimer's patients treated with
rivastigmine in placebo controlled phase III trials
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ApoE alleles
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*/3 */4
(*=2 (*=2,3
or 3) or 4) 3/3 4/4
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Responders (49) 11 38 7 10
Non Responders (217) 75 142 68 36
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*/3 vs. response (chi square=1.086 p=0.297)
*/4 vs. response (chi square=0.338 p=0.561)
3/3 vs. response (chi square=2.889 p=0.089)
4/4 vs. response (chi square=0.107 p=0.744)
Authors: Mihael H. Polymeropoulos, Kenneth W. Culver, Fiona Crawford, Michael Mullan, Richard D. Hartman, Ravi Anand, Correspondence to: mihael.polymeropoulos@pharma.novartis.com References 1. Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, Wasco W. The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis 1996;3:159-68 2. Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998;19:357-60 3. Farlow MR, Lahiri DK, Poirier J, Davignon J, Hui S. Apolipoprotein E genotype and gender influence response to tacrine therapy. Neurology 1998;50:669-77. 4. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;318:633-8 5. Poirier J, Delisle MC, Quirion R, Aubert I, Farlow M, Lahiri D, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995;92:12260-4 Contributors: RDH and RA participated in the design and execution of the study. FC and MM conducted the ApoE4 genotyping assays. MHP and KWC performed the data analysis and were the primary writers of the manuscript. MHP will act as the guarantor. Funding: This study was supported by funding from Novartis Pharmaceuticals Corporation Competing interests: MHP, KWC, RDH, and RA are employees of Novartis. |
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Fraser Inglis
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Editor - In a recent article on the cholinesterase inhibitor rivastigmine in Alzheimer's disease (AD)1, clinical benefits were reported for cognition and activities of daily living (ADL). We would like to present some additional evidence of improvements in AD observed with this agent. A retrospective analysis of patient records, collected from three different centres, has revealed that rivastigmine can provide clinically relevant benefits in certain behavioural and psychopathological abnormalities associated with this disease. All patients included in the analysis were diagnosed with mild-to-moderately severe AD and administered rivastigmine for a minimum of 6 months (13% on 12 mg/day rivastigmine at endpoint). Benefits were observed with three different instruments used at separate centres: the Neuropsychiatric Inventory2 (NPI), the Behavioural Pathology in Alzheimer's Disease rating scale3 (BEHAVE-AD) and the Mini Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD)4. Responders and non-responders to treatment were identified. In all instruments specific behavioural and psychopathological symptoms improved with rivastigmine therapy, particularly a resolution of apathy, hallucinations and activity disturbances. Cognition also improved significantly with rivastigmine treatment - assessed using the Mini-Mental State Examination (MMSE) (Table). Although not complete, these naturalistic data provide additional supportive evidence for the potential benefits of rivastigmine in AD. However, no specific claims can be made as we recognise the limitations of our analysis and that the results are not obtained from a controlled clinical trial. There is evidence that certain behavioural or psychopathological symptoms will respond to cholinesterase inhibitors5 and it may be helpful if we could identify individuals who are likely to benefit prior to treatment. In our view, assessing behaviour is a clinically relevant measurement of efficacy for cholinesterase inhibitors that can help in the decision to continue treatment.
Fraser Inglis, Consultant Geriatrician
Evelyn Russell, Consultant in Old Age Psychiatry
Alasdair Sim, Consultant in Old Age Psychiatry
Sean Page, Clinical Nurse Specialist
Acknowledgement: We would like to thank Dr C.D. Andrews (Novartis, UK) for his statistical analysis. Competing interests: The authors have conducted research on behalf of pharmaceutical companies, received remuneration for consultancy and lecturing. None of the authors has affiliation with any one pharmaceutical company. 1. Rösler M et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: results of an international, 26 week, multicentre, randomised, placebo-controlled trial. BMJ 1999; 318: 633-638. 2. Cummings JL et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308-2314. 3. Reisberg B et al. Behavioural symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987; 48: 9-15. 4. Allen NHP et al. Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD). B J Psych 1996; 169:293-307. 5. Mega M et al. The spectrum of behavioural responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol 1999; 56: 1388-1393. |
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Fraser G Inglis, CONSULTANT GERIATRICIAN CROSSHOUSE HOSPITAL, KILMARNOCK
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EDITOR - The benefits of cholinesterase inhibitors and their place in the management of patients with Alzheimer's disease is questioned by Bentham et al.Their call is for support for AD 2000 and this indeed may enhance our understanding of the benefits of these agents. As a clinician involved in the day to day management of patients with Alzheimer's disease I have been witness to the benefits that treatment can offer individual patients and their families. Current practice centres around patients usually still living at home with family support. We know that throughout the country large numbers of NHS beds are blocked by patients waiting for nursing home placement and undergoing community care assessment. In my own experience a significant number of the patients suffer from Alzheimer's disease. It would be very interesting to see if patients with Alzheimer's disease, blocking NHS beds could benefit from treatment with cholinesterase inhibitor therpy and be successfully returned to live in the community. This question could be addressed immediately and may provide further evidence of the benefits of these agents. 1. Bentham P, Gray R, Sellwood S, Raferty J. Effectiveness of Rivastigmine in Alzheimer's disease. BMJ 1999;319:640. |
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