Introduction

Patients with Alzheimer's disease (AD) are currently treated with cholinesterase inhibitors, such as galantamine, without actual knowledge of its concentration in plasma. Our objective was to analyse potential relationships between galantamine concentration, galantamine dose, socio-demographic characteristics, body weight, body mass index (BMI), and treatment response.

Methods

Eighty-four patients with AD recruited from the Memory Clinic, Malmö, Sweden, and treated with galantamine were included in the study. Efficacy measures, including cognition (Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog)) and instrumental activities of daily living (IADL), were evaluated at baseline, 2 months after treatment initiation (MMSE only) and semi-annually over 3 years. At these assessments, blood samples were obtained for the analysis of the galantamine concentration, and body weight, BMI, drug dose and time from drug intake were recorded.

Results

All patients had a measurable concentration of galantamine at all assessments. The mean plasma concentration of the drug exhibited a positive linear association with dose (r = 0.513, P < 0.001). The dose did not differ between sexes. Negative linear associations between the galantamine plasma concentration and BMI (r = -0.454, P = 0.001) or body weight (r = -0.310, P = 0.034) were found exclusively in the male group. When mixed-effects models were used, the dose of galantamine (P < 0.001), time from drug intake (P < 0.001), and BMI (P = 0.021) or weight (P = 0.002) were factors that predicted the concentration, whereas sex, age, and cognitive and functional changes were not.

Conclusions

High compliance to galantamine treatment was found among all patients in this naturalistic AD study. The impact of BMI or body weight on the plasma concentration of galantamine was important only among males. No relationship was observed between concentration and short-term treatment response or progression rate in terms of cognitive and functional abilities.

In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.

Drug candidates targeting amyloid-β (Aβ) pathology in Alzheimer's disease are in different phases of clinical trials. These treatments will probably be most effective in the earlier stages of the disease, before neurodegeneration is too severe, but at the same time symptoms are vague and the clinical diagnosis is difficult. Recent research advances have resulted in promising biomarkers, including cerebrospinal fluid analyses for tau and Aβ, magnetic resonance imaging measurement of atrophy, and positron emission tomography imaging of glucose metabolism and Aβ pathology, which allow identification of prodromal Alzheimer's disease. More details are needed, however, on how these biomarkers can be standardized, to allow a general implementation in the clinical routine diagnostic work-up of patients with cognitive disturbances.

Introduction

LY450139 (semagacestat) inhibits γ-secretase, a key enzyme for generation of amyloid β (Aβ), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Aβ, but has no clear effect on Aβ1-40 or Aβ1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Aβ isoforms, such as Aβ1-16, that in experimental settings increase during γ-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Aβ isoforms may be biomarkers of γ-secretase inhibitor treatment in clinical trials.

Methods

In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Aβ isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry.

Results

The CSF levels of Aβ1-14, Aβ1-15, and Aβ1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Aβ1-40 and Aβ1-42 were unaffected by treatment.

Conclusions

CSF Aβ1-14, Aβ1-15, and Aβ1-16 increase during γ-secretase inhibitor treatment in AD, even at doses that do not affect Aβ1-42 or Aβ1-40, probably because of increased substrate availability of the C99 APP stub (APP β-CTF) induced by γ-secretase inhibition. These Aβ isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials.

Trial registration

Clinical Trials.gov NCT00244322