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Default mode network (DMN) is vulnerable to the effects of APOE genotype. Given the reduced brain volumes and APOE ε 4-related brain changes in elderly carriers, it is less known that whether these changes would influence the functional connectivity and to what extent. This study aimed to examine the functional connectivity within DMN, and its diagnostic value with age-related morphometric alterations considered.
Whole brain and seed-based resting-state functional connectivity (RSFC) analysis were conducted in cognitively normal APOE ε 4 carriers and matched non-carriers (N=38). The absolute values of mean correlation coefficients (z-values) were used as a measure of functional connectivity strength (FCS) between DMN subregions, which were also used to estimate their diagnostic value by receiver-operating characteristic (ROC) curves.
APOE ε 4 carriers demonstrated decreased interhemispheric FCS, particularly between right hippocampal formation (R.HF) and left inferior parietal lobular (L.IPL) (t=3.487, p<0.001). ROC analysis showed that the FCS of R.HF and L.IPL could differentiate APOE ε 4 carriers from healthy counterparts (AUC value=0.734, p=0.025). Moreover, after adjusting the impact of morphometry, the differentiated value of FCS of R.HF and L.IPL was markedly improved (AUC value=0.828, p=0.002).
Our findings suggest that APOE ε 4 allele affects the functional connectivity within posterior DMN, particularly the atrophy-corrected interhemispheric FCS before the clinical expression of neurodegenerative disease.
Default mode network (DMN) has been reported to be susceptible to APOE ε 4 genotype. However, the APOE ε 4-related brain changes in young carriers are different from the ones in elderly carriers. The current study aimed to evaluate the cortical morphometry of DMN subregions in cognitively normal elderly with APOE ε 4.
11 cognitively normal senior APOE ε 4 carriers and 27 matched healthy controls (HC) participated the neuropsychological tests, genotyping, and magnetic resonance imaging (MRI) scanning. Voxel-based morphometry (VBM) analysis was used to assess the global volumetric changes. Surface-based morphometry (SBM) analysis was performed to measure regional gray matter volume (GMV) and gray matter thickness (GMT).
Advancing age was associated with decreased GMV of DMN subregions. Compared to HC, APOE ε 4 carriers presented cortical atrophy in right cingulate gyrus (R_CG) (GMV: APOE carriers: 8475.23 ± 1940.73 mm3, HC: 9727.34 ± 1311.57 mm3, t = 2.314, p = 0.026, corrected) and left insular (GMT: APOE ε 4 carriers: 3.83 ± 0.37 mm, HC: 4.05 ± 0.25 mm, t = 2.197, p = 0.033, corrected).
Our results highlight the difference between different cortical measures and suggest that the cortical reduction of CG and insular maybe a potential neuroimaging marker for APOE 4 ε senior carriers, even in the context of relatively intact cognition.
Background: An increasing number of studies have suggested a link between cholesterol metabolism and Alzheimer's disease (AD), which may be mediated by its effect on amyloid processing. Intracranial cholesterol is primarily eliminated into the bloodstream through conversion into 24-hydroxycholesterol by the enzyme cholesterol 24-hydroxylase (encoded by the CYP46A1 gene). CYP46A1 is an essential gene modulating cholesterol metabolism in the brain.
Method: To investigate whether polymorphisms in the CYP46A1 gene modulate the risk of AD, we studied four common polymorphisms (IVS1-192, IVS2-150, IVS3-128 and IVS4-122) in 182 Chinese AD patients and 179 age-matched healthy Chinese subjects.
Results and conclusion: We found that the IVS3-128 polymorphism was associated with the risk of AD (p < 0.05). Subjects homozygous for the C alleles were protected from AD with an adjusted odds ratio (OR) of 1.53 [95% confidence interval (95% CI) 0.98–2.37, p = 0.047]. However, another minor allele, IVS1-192 C, was more prevalent in the AD group and was associated with an increased risk. Haplotype analysis revealed that two of the eight common haplotypes formed by the four polymorphisms were rarely found in the AD group, suggesting a protective effect of these two haplotypes (GTCA and CCTA). The results supported the involvement of the CYP46A1 gene and cholesterol metabolism in the pathogenesis of AD.
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