Effectiveness of rivastigmine in Alzheimer's disease

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
____________________________________________________
                            ApoE alleles
                        ____________________________

                         */3   */4
                        (*=2   (*=2,3
                        or 3)   or 4)  3/3    4/4
____________________________________________________
Responders (49)	        11	38	7	10
Non Responders (217)	75	142	68	36
____________________________________________________

*/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,
vice president,
Pharmacogenetics
Department, Novartis Pharmaceuticals Corporation, 59 Route 10, East
Hanover, NJ 07936

Kenneth W. Culver,
executive director,
Pharmacogenetics Department,
Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936

Fiona Crawford,
associate director,
Roskamp Institute, University of
South Florida, 3515 E. Fletcher Ave., Tampa, FL 33613

Michael Mullan,
director,
Roskamp Institute, University of South
Florida, 3515 E. Fletcher Ave., Tampa, FL 33613

Richard D. Hartman,
clinical research manager,
CNS Medical Affairs,
Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936

Ravi Anand,
executive director,
CNS Medical Affairs, Novartis
Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936

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.