P2-016: Metabolism of CSF beta-amyloid 42 is affected by vascular risk factors, memory and depressive symptoms differently in cognitively normal APOE-ε4 carriers

The regulation of CSF Aß42 is poorly understood. Recent studies show Aß42 levels affected by sleep, stress, diet, depression, ApoE genotype, white matter lesions (WML), and Aß plaques. The purpose of this study was to examine the heterogeneity of Aß42 as related to ApoE genotype when interacting with known AD risk factors in healthy, cognitively normal subjects. In cross-section, we examined the Aß42, T-Tau and P-tau levels as predicted by ApoE4 status in its interaction with depressive symptoms (HAM-D), MRI white-matter hyperintensity volume (WMH V), and memory (Wechsler Logical-Memory). We studied 41 ApoE4+ and 71 ApoE4- subjects (mean age 62.0 ± 11.9). All participants were non-depressed (HAM-D≤10), cognitively normal (CDR = 0) and free of MRI brain pathology. ApoE4+ subjects compared to the ApoE4- had lower levels of Aß42 (442 ± 27 vs. 603 ± 22 ng/L; P <0.01), higher levels of T-Tau (289 ± 17 vs. 229 ± 13 ng/L; P <0.01), higher p-Tau (28 ± 1.6 vs. 17 ± 21.9ng/L; P <0.01) and higher WMHv (3.77 ± 0.41 vs. 2.67 ± 0.32 cm 3, P<0.05). Predicting CSF Aß42 levels, controlling for age, we observed three significant 2-way interactions: ApoE genotype X mood, ApoE genotype X memory, ApoE genotype X WMH V (F-values range = 4.03-12.35, P<0.05). No interactions were seen for T-tau or P-Tau. Among ApoE4-, mood symptoms, and to a lesser extent worse memory, had a negative correlation with Aß42 (r = .-44, n = 71, P <0.01 and r = -.22, n = 71, P = 0.07). Among ApoE4+ there was a negative correlation between Aß42 and WMH V (r = -0.45, n = 26, P<0.05). This is the first study to report the effect of multiple risk factor interactions on CSF Aß42 levels in cognitively normal subjects with different ApoE4 alleles. Our results indicate that the relationship between risk factors and CSF Aß42 is dependent on the presence/absence of ApoE4. E4 carriers show reduced CSF Aß42, and lower Aß42 was associated with more MRI-WML; whereas a more typical clinical AD-type phenotype (poor memory, minor depressive symptoms), was associated with decreased CSF Aß42 levels in the ApoE4-non-carriers. These data suggest that Apoe4 carriers and non-carriers may offer divergent trajectories of brain and symptom changes. A better knowledge of the presymptomatic early stages of AD and the interactions with the ApoE4 allele may help us understand the variability of our CSF biomarker measures.