ABSTRACT
To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Transcription Factors/genetics , Follow-Up Studies , Genetic Loci/genetics , Humans , Polymorphism, Single Nucleotide/genetics , SpainABSTRACT
OBJECTIVE: To review systematically the methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease (AD). METHODS: Trials included were those conducted on AD patients, aged 40 years or over, assigned to tacrine- or placebo-based treatment. Studies were identified via the Cochrane Collaboration and MEDLINE databases. Trial-selection and data-extraction were carried out separately by two reviewers working independently. Any differences of opinion that arose were resolved by discussion. RESULTS: We identified 49 trials published in the period 1 January 1981 - 1 May 1997. Of these, 21 were randomized controlled trials, eight parallel-group and 13 cross-over type. In the random trials, tacrine dosage ranged from 25 to 200 mg/day, with a duration of 3-36 weeks. In all, 3555 patients with mild to moderate AD started treatment and 1149 failed to complete the course (mean 33.4% patients per trial). Over 80% of patient withdrawals were tacrine-related. Adverse events affected a mean of 59% patients per trial (range 34-90%), mainly in the form of cholinergic manifestations (mean 30.2%, range 5-62%) and transaminase elevations (mean 28.6%, range 0-53%). Adverse events were more frequent at doses of > or = 100 mg/day and disappeared on discontinuation of tacrine treatment. Just over 20% of patients given tacrine experienced improvements in cognitive function (3-4 points in Alzheimer's Disease Assessment Scale cognitive subscale and 2-3 points in Mini-Mental State Examination) and in functional ability at 3-6 months of treatment. No study gave a description of concealment of the randomization sequence or the success of the double-blind procedure. CONCLUSIONS: Tacrine shows a modest degree of efficacy among a small proportion of patients with mild to moderate AD, yet has important adverse effects which limit its clinical usefulness. It is not known which AD patient subgroup could benefit from the treatment. Information on the long-term effects of tacrine (over periods exceeding 7 months) and its effects on quality of life, patient institutionalization and mortality and patient burden on caregivers is inadequate.
