A pharmacogenomic approach to Alzheimer's disease

Single nucleotide polymorphisms (susceptibility genetics) and genomic point mutations (mendelian genetics) can be used in Alzheimer's disease (AD) for diagnostic, predictive and therapeutic purposes. Using a matrix genetic mo del, including APOE, PSI and PS2 allelic variants, we have studied the dist ribution of 36 different genotypes in the AD population (N = 479) and the g enotype-related cognitive response to a multifactorial therapy in AD patien ts with mild-to-moderate dementia. The 10 most frequent AD genotypes are th e following: 1) E33P112P2 + (17.75%), 2) E33P112P2 - (15.55%;,). 3) E33P111 P2 + (10.85%), 4) E34P112P2 + (9.60%), 5) E34P112P2 - (7.56%,), 6) E33P111P 2 - (7.10%), 7) E34P111P2 + (4.80%), 8) E33P122P2 + (4.38%), 9) E34P111P2 ( 4.18%), and 10) E34P122P2 + (3.55%). APOE-4/4-related genotypes represent l ess than 3%;, in the following order: E44P112P2 + > E44P111P2 + = E44P111P2 - > E44P112P2 + > E44P122P2 + = E44P122P2 -. Multifactorial therapy with C DP-choline (1000 mg/day) + piracetam (2400 mg/day) + anapsos (360 mg/day) d id improve mental performance during the first 6 - 15 months in a genotype- specific fashion. The best responders in the APOE series were patients with APOE-3/4 genotype(r = +0.013), while the worst responders were APOE-4/4 pa tients (r = - 0.93). PS1-related genotypes responded in a similar manner; a nd patients with a defective PS2 gene exon 5 (PS2 +) always showed a poorer therapeutic response than PS2 patients. All these data suggest that the th erapeutic outcome in AD exhibits a genotype specific pattern, and that a ph armacogenomic approach to AD might be a valuable strategy for drug developm ent and monitoring.