Effects of Food and Drug Administration-approved medications for Alzheimer's disease on clinical progression.
BACKGROUND
Observational studies suggest that cholinesterase inhibitors and/or memantine may delay clinical progression of Alzheimer's disease (AD) in 40% of individuals taking the medications. Given this response and existence of side effects, we sought to quantify medication use and benefits in a population-based study of incident AD cases.


METHODS
The Cache County Dementia Progression Study enrolled and followed a cohort of 327 incident AD cases for a maximum of 9 years. Drug exposure was expressed using a persistency index (PI), calculated as total years of drug use divided by total years of observation. Linear mixed-effects models examined PI, and interactions with sex and apolipoprotein E (APOE) as predictors of clinical progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes.


RESULTS
A total of 69 participants (21.1%) reported having ever used cholinesterase inhibitors or memantine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI (i.e., greater duration of use) of cholinesterase inhibitors was associated with slower progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes, particularly among those with an APOE ɛ4 allele. In contrast, higher PI was associated with faster progression in males.


CONCLUSIONS
A low percentage of individuals with AD in the community are taking cholinesterase inhibitors or memantine. This study suggests that women, particularly those with an APOE ɛ4 allele, may benefit the most from these medications. With the newly approved increased dose of donepezil, it will be imperative to determine whether a higher dose is needed in men or whether other factors warrant consideration.
Department of Psychiatry, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mmielke1@jhmi.edu
Michelle M
MM
Mielke
Jeannie-Marie
JM
Leoutsakos
Chris D
CD
Corcoran
Robert C
RC
Green
Maria C
MC
Norton
Kathleen A
KA
Welsh-Bohmer
JoAnn T
JT
Tschanz
Constantine G
CG
Lyketsos
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D015331:Cohort Studies; D018672:Community Health Planning; D003430:Cross-Sectional Studies; D018450:Disease Progression; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D019370:Observation; D011569:Psychiatric Status Rating Scales; D014481:United States; D014486:United States Food and Drug Administration
D053327:Apolipoprotein E4; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine