Progression from mild cognitive impairment to Alzheimer's disease: effects of sex, butyrylcholinesterase genotype, and rivastigmine treatment.
OBJECTIVE
Evaluate the effect of sex and butyrylcholinesterase (BuChE) genotype on the incidence of Alzheimer's disease (AD), cognitive and functional decline, brain volume changes, and response to rivastigmine treatment in individuals with mild cognitive impairment (MCI).


METHODS
This retrospective exploratory analysis from a 3-4 year, randomized, placebo-controlled study of rivastigmine in MCI patients included participants who consented to pharmacogenetic testing.


RESULTS
Of a total of 1018 patients, 490 [253 (52%) female] were successfully genotyped for BuChE. In patients receiving placebo, the BuChE wt/wt genotype was associated with a statistically significant higher incidence of progression to AD and functional decline in women, compared with men with the BuChE wt/wt genotype. In patients with a BuChE-K allele receiving placebo, incidence of progression to AD and rate of functional decline were not significantly different by sex; however, cognitive decline was significantly faster in men. Statistically significant benefits of rivastigmine treatment on incident AD, functional decline, ventricular volume expansion, whole-brain atrophy, and white matter loss were evident in female BuChE wt/wt.


CONCLUSIONS
Sex and BuChE genotype seem to differentially influence the type of decline in MCI patients, with more rapid progression of cognitive decline in male BuChE-K, and more incident AD and functional decline in female BuChE wt/wt. Cognitive decline in male BuChE-K and functional decline and incident AD in female BuChE wt/wt were significantly attenuated by rivastigmine. Rivastigmine treatment also significantly reduced ventricular expansion, whole-brain atrophy rate, and white matter loss in female BuChE wt/wt, suggesting a possible disease-modifying effect.
Ferris
Steven
S
Alzheimer's Disease Center, Center of Excellence on Brain Aging, NYU Langone Medical Center, Orangeburg, New York, USA. steven.ferris@nyumc.org
Nordberg
Agneta
A
Soininen
Hilkka
H
Darreh-Shori
Taher
T
Lane
Roger
R
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000235:genetics*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition; D003072:Cognition Disorders / Q000175:diagnosis* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D010597:Pharmacogenetics / Q000379:methods; D048448:Phenylcarbamates / Q000494:pharmacology*; D010919:Placebos; D012189:Retrospective Studies; D000068836:Rivastigmine; D016896:Treatment Outcome
D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D010919:Placebos; D002091:Butyrylcholinesterase; D000068836:Rivastigmine