Faculty Bibliography

STUDY OBJECTIVES: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. METHODS: Subjects were recruited from multiple community sources for National Institutes of Health supported studies or normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. RESULTS: Levels of orexin-A, amyloid beta 42 (Abeta42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 +/- 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Abeta42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. CONCLUSIONS: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01962779.

Background: The regulation of CSF Abeta42 is poorly understood. Recent studies show Abeta42 levels affected by sleep, stress, diet, depression, ApoE genotype, white matter lesions (WML), and Abeta plaques. The purpose of this study was to examine the heterogeneity of Abeta42 as related to ApoE genotype when interacting with known AD risk factors in healthy, cognitively normal subjects. Methods: In cross-section, we examined the Abeta42, 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 6 11.9). All participants were non-depressed (HAM-D-10), cognitively normal (CDR = 0) and free of MRI brain pathology. Results: ApoE4+ subjects compared to the ApoE4- had lower levels of Abeta42 (442 6 27 vs. 603 6 22 ng/L; P <0.01), higher levels of T-Tau (289617 vs. 229613 ng/L; P <0.01), higher p-Tau (2861.6 vs. 17 6 21.9ng/L; P <0.01) and higher WMHv (3.77 6 0.41 vs. 2.67 6 0.32 cm 3, P<0.05). Predicting CSF Abeta42 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 Abeta42 (r = .-44, n = 71, P <0.01 and r = -.22, n = 71, P = 0.07). Among ApoE4+ there was a negative correlation between Abeta42 and WMH V (r = -0.45, n = 26, P<0.05). Conclusions: This is the first study to report the effect of multiple risk factor interactions on CSFAbeta42 levels in cognitively normal subjects with different ApoE4 alleles. Our results indicate that the relationship between risk factors and CSF Abeta42 is dependent on the presence/absence of ApoE4. E4 carriers show reduced CSF Abeta42, and lower Abeta42 was associated with more MRI-WML whereas a more typical clinical AD-type phenotype (poor memory, minor depressive symptoms), was associated with decreased CSF Abeta42 levels in the ApoE4-non-carriers. These data suggest that Apoe4 carriers and noncarriers 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