Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

BACKGROUND: Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. METHODS: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aß positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. RESULTS: OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aß positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aß pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. DISCUSSION: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aß.

Alzheimer's disease prevention: Apolipoprotein e4 moderates the effect of physical activity on brain beta-amyloid deposition in healthy older adults.

OBJECTIVES: To investigate if higher baseline physical activity levels are associated with less ß-amyloid burden and whether the ApoE4 genotype moderates this association cross-sectionally and longitudinally. DESIGN: Prospective cohort study. METHODS: 204 cognitively normal older adults (74.5 ±â€¯6.6 years; 26 % ApoE4-carrier) were analyzed. Baseline physical activity was measured using the Minnesota Physical Activity Questionnaire. Brain ß-amyloid burden was measured with positron emission tomography using 11C-labeled Pittsburgh compound. A subsample of 128 participants underwent longitudinal positron emission tomography (2.0 ±â€¯0.9 scans over 5 ±â€¯3 years). Statistical analysis was run according to physical activity (high/low group) and the ApoE4 genotype (carrier/noncarrier). RESULTS: The ApoE4 genotype moderated the relationship between physical activity and ß-amyloid, such that low physical activity had a greater impact on ß-amyloid deposition in ApoE4-carriers than noncarriers. This ApoE4 × physical activity effect on brain ß-amyloid deposition was also observed when all available ß-amyloid scan timepoints were included in the model. ß-amyloid deposition increased over time (p < 0.001), and ApoE4-carriers had disproportionately greater ß-amyloid accumulation than ApoE4-noncarriers. The lower physical activity group had marginally greater ß-amyloid accumulation than the higher physical activity group (p = 0.099), but there was no significant ApoE4 effect on ß-amyloid accumulation. CONCLUSIONS: Low physical activity in combination with the ApoE4-carrier genotype is associated with increased ß-amyloid burden, suggesting that ApoE4 moderates the effect of physical activity on ß-amyloid load. However, this effect was insufficient for baseline physical activity to modulate the change in ß-amyloid accumulation over time.