O2-03-04

Individuals carrying the ApoE4 genotype are at high risk for developing late-onset Alzheimer's disease (AD). As compared to non-carriers (E4-), asymptomatic E4 carriers (E4+) show reduced cerebral metabolic rates for glucose (CMRglc), as measured in vivo with Positron Emission Tomography (PET) imaging with 2-[18F]fluoro-2-Deoxy-D-glucose (FDG). To examine whether CMRglc abnormalities in E4+ subjects were associated with known CSF measures of AD pathology, and whether such association was altered in the presence of subjective memory complaints (SMC) in cognitively normal individuals. Twenty-eight normal subjects (NL, age 45–70 yrs, 60% female, education>12 yrs, MMSE 28–30) were examined, including 13 E4+ [6 with SMC (SMC+) and 7 without SMC (SMC-)], and 15 E4- [7 SMC+ and 8 SMC-];. Subjects received a dynamic FDG-PET scan with arterial blood sampling to measure CMRglc (mmol/g/min), and a lumbar puncture to measure CSF total and hyperphosphorylated tau (T-tau and P-tau), amyloid beta (Aβ40 and Aβ42), and isoprostane (IP). Correlations between CMRglc and CSF measures were examined, and when significant, a CMRglc-CSF association index was created. After partial volume correction and adjusting for global CMRglc, as compared to E4-, E4+ subjects showed decreased CMRglc in AD-related cortical regions, and associated higher CSF levels of IP, P-tau, and T-tau (P'sheterozygous>homozygous E4+). There was a significant ApoE by SMC interaction, with the E4+/SMC+ showing the most severe PHG CMRglc reductions and IP increases (P<0.001). The CMRglc-CSF association between IP and PHG CMRglc discriminated E4+/SMC+ from all other subgroups with 79% accuracy (odds ratio, OR=3.1, 95% C.I.=1.4–9.1, P=0.001), which increased to 86% in combination with temporal cortex CMRglc (OR=2.3, 95% C.I.=1.1–6.3, P<0.001). These results suggest that the combination of FDG-PET and CSF measures may be sensitive for detection of a preclinical AD state in individuals at risk for future cognitive impairment.