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 model, including APOE, PS1 and PS2 allelic variants, we have studied the distribution of 36 different genotypes in the AD population (N= 479) and the genotype-related cognitive response to a multifactorial therapy in AD patients with mild-to-moderate dementia. The 10 most frequent AD genotypes are the following: 1) E33P112P2 + (17.75%), 2) E33P112P2- (15.55%), 3) E33P111P2+ (10.85%), 4) E34P112P2+ (9.60%), 5) E34P112P2- (7.56%), 6) E33P111P2- (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 less than 3% in the following order: E44P112P2 + > E44P111P2+ = E44P111P2- > E44P112P2+ > E44P122P2+ = E44P122P2. Multifactorial therapy with CDP-choline (1,000 mg/day) + piracetam (2,400 mg/day) + anapsos (360 mg/day) did 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 patients (r= -0.93). PS1-related genotypes responded in a similar manner; and patients with a defective PS2 gene exon 5 (PS2+) always showed a poorer therapeutic response than PS2- patients. All these data suggest that the therapeutic outcome in AD exhibits a genotype-specific pattern, and that a pharmacogenomic approach to AD might be a valuable strategy for drug development and monitoring.
EuroEspes Biomedical Research Center, Institute for CNS Disorders, La Coruña, Spain. cacabelos@euroespes.com
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Cacabelos
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Alvarez
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Fenández-Novoa
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Lombardi
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005091:Exons; D005260:Female; D005838:Genotype; D006027:Glycosides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010889:Piracetam / Q000494:pharmacology* / Q000627:therapeutic use; D053764:Presenilin-1; D053766:Presenilin-2; D011379:Prognosis; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D001057:Apolipoproteins E; D006027:Glycosides; D008565:Membrane Proteins; D018697:Nootropic Agents; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D003566:Cytidine Diphosphate Choline; C006870:anapsos; D010889:Piracetam