Response to cholinesterase inhibitors affects lifespan in Alzheimer's disease

Abstract

Background: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer's disease (AD). Whether the individual-specific response, specific ChEI agent or dose affects mortality is unclear. We aimed to examine the relationship between the 6-month response to ChEI and lifespan.

Methods: Six hundred and eighty-one deceased patients with a clinical AD diagnosis and a Mini-Mental State Examination (MMSE) score of 10-26 at the start of ChEI therapy (baseline) were included in a prospective, observational, multicentre study in clinical practice. At baseline and after 6 months of treatment, the participants were assessed using the MMSE, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change (CIBIC), the Instrumental Activities of Daily Living (IADL) scale, and the Physical Self-Maintenance Scale (PSMS). The individuals' socio-demographic characteristics, ChEI dose, and date of death were recorded. Responses to ChEI and the association of possible risk factors with survival were analysed using general linear models.

Results: A longer lifespan (mean of 0.5 years) was observed among the improved/unchanged patients, as measured by MMSE or CIBIC score, but not by ADAS-cog score, after 6 months of ChEI therapy. In the multivariate models, increased survival time was independently related to a better 6-month response in MMSE, CIBIC, IADL, and PSMS scores, female sex, no antihypertensive/cardiac or antidiabetic therapy, younger age, lower education, milder disease stage at baseline, and higher ChEI dose. Apolipoprotein E genotype did not affect mortality significantly. The patients who received a higher ChEI dose during the first 6 months had a mean lifespan after baseline that was 15 months longer than that of those who received a lower dose.

Conclusions: A better short-term response to ChEI might prolong survival in naturalistic AD patients. In individuals who received and tolerated higher ChEI doses, a longer lifespan can be expected.

Figure 1

Time to death according to response in MMSE score. Kaplan–Meier graph of the distribution of time from the start of cholinesterase inhibitor treatment to death for the variable “improved/unchanged (≥0 point change) vs deteriorated (<0 point change)” based on the Mini-Mental State Examination (MMSE) score after 6 months. A log-rank test showed a significant difference between the two groups (P = 0.013).

Figure 2

Time to death according to ChEI dose. Kaplan–Meier graph of the distribution of time from the start of cholinesterase inhibitor (ChEI) treatment to death for the variable “ChEI dose”. A log-rank test showed a significant difference between high vs low doses during the first 6 months of therapy (P < 0.001). The cutoff median values for the drug doses were 5.0 mg for donepezil, 5.0 mg for rivastigmine, and 13.3 mg for galantamine.