Alzheimer Disease: Meyer J

Lane R, Feldman HH, Meyer J, He Y, Ferris SH, Nordberg A, Darreh-Shori T, Soininen H, Pirttilä T, Farlow MR, Sfikas N, Ballard C, Greig NH. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA. · Pharmacogenet Genomics. · Pubmed #18334913 No free full text.

Abstract: OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, Rapatz G, Nagel J, Lane R. · Hospital Sta Creu i Sant Pau, Barcelona, Spain. · Pharmacogenet Genomics. · Pubmed #17047484 No free full text.

Abstract: A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.

Meyer J, Xu G, Thornby J, Chowdhury M, Quach M. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · J Neurol Sci. · Pubmed #12163189 No free full text.

Abstract: Research directed towards early diagnosis and therapy of dementia demands rapid identification of prodromal mild cognitive impairment (MCI). A longitudinal study was designed to clarify whether different domains of cognitive impairment, tested by Mini-Mental State Examination (MMSE), help predict dementia. After 3.74+/-2.94 years of follow-up among 291 cognitively normative volunteers, 73 developed MCI. During the next 3.88+/-3.01 years of MCI follow-up, 47.9% of MCI developed dementia of Alzheimer's type (DAT), 20.5% of MCI developed vascular dementia (VaD) and 31.5% maintained persistent MCI at the time of data analysis. Total MMSE and subtest scores analyzed at MCI onset showed significant differences for serial seven subtest scores between DAT and persistent MCI (P<0.05). Rates of change in subtests of orientation and memory and total MMSE scores predicted DAT (P<0.01). Decreasing orientation and total MMSE scores predicted VaD conversion rates of MCI to DAT at 2 years were 20.06% among single-domain MCI versus 41.7% for multi-domain MCI (P<0.05). Subjects with MCI often have impaired cognitive domains other than memory and show rapid deterioration, which predicts DAT. VaD sometimes mimics DAT with subtle cognitive impairment appearing before onset of dementia.