CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Farmacogenetics of Alzheimer's disease

Background

In Alzheimer's disease (AD) a disease-modifying therapy is not available yet, and the target of drug therapy is temporary improvement, stabilization, and retardation of cognitive decline and improvement of behavioural symptoms. According to the "cholinergic hypothesis" of AD, several Acetylcholinesterase inhibitors (AChEIs), such as donepezil, galantamine and rivastigmine have been used for the treatment of patients with AD. Donepezil has been found to improve cognition and preserves function in mild to moderate patients with AD as well as in individuals with severe AD; Rivastigmine significantly benefited cognitive function and global performances in patients with AD; Galantamine demonstrated significant benefits in cognition and global function in patients with AD. On the whole, the efficacy of AChEIs, i.e. how they act in randomised control trials, on mild to moderate patients with AD is widely accepted, even if a recent meta-analysis drew a different conclusion, the effectiveness of AChEIs i.e. how they behave in the real world, is still controversial.

Few studies have been conducted in order to compare the effects of these three drugs. These studies differ in the number of patients included (less than 300 subjects in most of the studies), geographical origin, length of the follow-up and study design (randomised control trials or naturalistic studies). As far as we know, no clear difference have been reported among the treatments with donepezil, galantamine or rivastigmine apart from a study in which donepezil showed significantly greater improvements in cognition compared with galantamine. Indeed, a comparison among studies is hampered by a variety of factors including differences in patient baseline characteristics and methods used to asses efficacy, effectiveness and safety.

Aims

  1. To compare the effects of three AChEIs, donepezil, galantamine and rivastigmine, in a representative real world clinical practice.
  2. To determine if the Apolipoprotein E (APOE) genotypes might influence the response to the AchEIs and the creation of a biological database.

Methodology

The observational prospective study included 938 mild to moderate patients with AD, participating to the Cronos Project, started by the Ministry of Health in order to establish over the entire national territory the Unit di Valutazione Alzheimer. The patients were collected from October 2000 to December 2001 by 10 UVAs located in several Italian regions: Lombardia, Veneto, Toscana, Marche, Abruzzo, Campania, Calabria, Sicilia; have received AChEIs target daily doses according to the recommendations of manufacturer (5-10 mg for donepezil, 3-12 mg for rivastigmine and 8-16 mg for galantamine) and were followed for 36 weeks by measuring:

  1. function, using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales;
  2. cognition, using the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), which also allowed us to classify the patients as responders and non responders;
  3. behaviour, using the Neuropsychiatric Inventory (NPI) and the Clinical Dementia Rating (CDR).

Moreover, all patients were genotyped for APOE genetic variants.

Two classifications of responders/non responders were made upon the MMSE

  • Stable: subjects whose MMSE difference score lied within a standard deviation
  • Improved: subjects whose MMSE difference score was greater than 1 standard deviations;
  • Worsened: subjects whose MMSE difference score was lower than one standard deviations;
  • Stable/improved: subjects whose MMSE difference score (t36 t0) is equal or greater than zero.
  • Worsened: subjects whose MMSE difference score (t36 t0) was less than -1.

A classification of responders/non responders was made on the basis of the ADAS-Cog

  • No change or improvement (change from baseline ≤ 0).
  • Improvement of at least 4 points (change from baseline ≤ -4).
  • Improvement of at least 7 points (change from baseline ≤ -7).

Results

No statistical improvements on the outcome measures (MMSE and ADAS-Cog) from baseline to week 36 were found by drug therapy.

Among the secondary outcome measures (ADL, IADL, NPI), only the galantamine group worsened by losing, on average, about one IADL function from week 12 to week 36, with respect to the other two groups.

At week 36 all groups declined losing, on average, one point on the MMSE and gaining between two and three points on the ADAS-Cog scale.

No association was found by drug therapy with categories of responders, based either on the MMSE or on the ADAS-Cog. APOE e4 allele does not influence the effect of drug therapy.

 

Conclusions

Our data showed a short-term moderate cognitive benefit of AChEIs in mild to moderate AD for donepezil and rivastigmine groups, but not for galantamine. Globally, no statistical improvements on MMSE and ADAS-Cog from baseline to week 36 were found by drug therapy. Although the overall cognitive symptoms worsened by 12 and 36 weeks of evaluation, this impairment was lower than that attributed to the free-living people. In the absence of a cure for AD, a less than expected decline of cognitive symptoms is remarkable, given the cost implications of a delay in progression.

Publications

  • Bellelli G, Lucchi E, Minicuci N, Rozzini L, Bianchetti A, Padovani A, Trabucchi M (2005) Results of a multi-level therapeutic approach for Alzheimer's disease subjects in the "real world" (CRONOS project): a 36-week follow-up study. 17:54-61.

Grants

Ministry of Health: health targeted projects

Collaborations

  • C. Franceschi, University of Bologna, Italy.

 

PI photo

Nadia Minicuci

Contact information

email  E-mail

email  049 8211226

Participating staff

P. Siviero