CSF beta-amyloid, cognition, and APOE genotype in Alzheimer's disease

Objectives: We examined the relationship between CSF amyloid beta peptide (A beta) concentration and AD severity in 31 probable AD patients and explored whether APOE genotype modifies this relationship. Background: A beta deposition in AD brains has been correlated with disease severity and with APOE-epsilon 4 allele frequency. Few studies have examined the effects of APOE genotype on the relationship between CSF AP and disease severity in an antemortem sample. Methods: Patients carried the clinical diagnosis of probable AD and did not have serious medical illness, current or past diagnosis of mood disorder, schizophrenia or alcoholism, or current psychotic features. The Mini-Mental State Examination (MMSE) was administered to the patient within 3 months of CSF collection. CSF was analyzed for A beta 1-40 and A beta 1-42 by sandwich ELISAs, and APOE genotype was determined by PCR run from blood. Correlations were performed between MMSE score and A beta 1-40 and A beta 1-42 concentrations while controlling for potential confounding variables. Results: CSF measures of A beta 1-40 and A beta 1-42 concentrations were correlated with each other (r = 0.56, df = 28, p < 0.01). CSF A beta 1-40 and A beta 1-42 concentrations were positively correlated with MMSE score. The negative association between CSF A beta measures and disease severity remained significant after controlling for age (A beta 1-40 and MMSE score: r = 0.46, df = 28, p = 0.01; A beta 1-42 and MMSE score: r = 0.35, df = 28, p = 0.05). Among the APOE-epsilon 3/3 homozygotes there was a significant positive correlation only between A beta 1-42 and MMSE score (A beta 1-42, r = 0.94, p = 0.02; A beta 1-40, r = 0.79, p = 0.11). Conclusions: We hypothesize that an increased deposition of Ap in plaques results in decreased CSF A beta concentration. The stronger relationship between MMSE score and CSF A beta, specifically in APOE-epsilon 3/3 homozygotes, suggests that patients with APOE-epsilon 3/3 genotype may have different pathogenic mechanisms than the other genotypes for A beta deposition or clearance.