Faculty Bibliography

Background: In hypertension (HTN), cerebral blood flow (CBF) regulation limits are changed and the blood pressure (BP) threshold at which CBF is safely maintained is higher. This shift may increase the brain's vulnerability to hypoperfusion at lower BP. Despite growing recognition of the link between hypoperfusion and neurodegeneration little is known about whether blood pressure reductions can induce deficient perfusion and promote expression of cerebrospinal fluid (CSF) biomarkers of amyloid and neurofibrillary pathology. We investigated the relationship between longitudinal changes in mean arterial pressure (MAP) and CSF biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. Methods: Longitudinal assessments of blood pressure (MAP), CSF ptau181 (phosphorylated tau), total tau, amyloid beta 1-42 (Abeta42), cognition and whole brain volume were conducted on average 2.060.6 years apart in a group of 77 cognitively healthy elderly (age 63.469.4, range 44-86 years; education 16.962.1, range 10-22 years; 60% women). MAP was calculated as: 1/3 systolic blood pressure + 2/3 of diastolic blood pressure. Results: At baseline HTN was found in 23 individuals (30%). When longitudinal change (y) in p-tau181 was predicted with theyMAP, HTN, and the HTNxyMAP interaction, both the total model (F 3,73=3.9, p=.01), and the interaction term (p=.01) were significant. These data indicate that the relationship between yMAP and yp-tau181 was strongly dependent on the presence or absence of HTN. Only in the HTN group was a decrease in MAP from baseline to follow-up related to an increase in p-tau181 (r=-0.5 p=.01). In addition, only among subjects with HTN, was a reduction in MAP related to the worsening of verbal episodic memory (r=0.46 p=.03). Finally in the entire group the increase in p-tau181 was associated with reduction in the verbal episodic memory score (beta=-.223, p=.048). No relationship was observed between changes in MAP and whole brain volume. Conclusions: In subjects with HTN, MAP reduction is associated with increased CSF p-tau181 and deterioration of episodic memory, possibly resulting from suboptimal perfusion and subsequent accumulation of neurofibrillary tangles. Prior experimental work has demonstrated a relationship between perfusion, energetic reductions and tauopathy

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