CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner
Department of Neurosciences, University of California, San Diego, CA, USA.Brain Imaging and Behavior (Impact Factor: 4.6). 09/2011; 6(1):16-26. DOI: 10.1007/s11682-011-9137-0
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer's disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
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ABSTRACT: The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P<0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.
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ABSTRACT: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. Published by Elsevier Inc.
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ABSTRACT: Common polymorphisms of the Cholestryl Ester Transfer Protein (CETP) gene may predict lower risk of cognitive decline. We investigated the association of cognitive function with CETP genotype in a population-based cohort of 4135 persons aged 35-82 years. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points) and CETP I405V and Taq1B genotypes were determined by polymerase chain reaction. RFFT score was not associated with I405V genotype in persons aged 35-64 years. Remarkably, beyond age 65, homozygous valine carriers had higher RFFT scores than heterozygous carriers and noncarriers: RFFT (SD), 52 (21), 49 (18), and 47 (17) points, respectively (p = 0.005). There also was a statistically significant interaction between I405V genotype and age. Beyond age 65, the difference between homozygous valine carriers and noncarriers increased by 0.11 point per year (p = 0.005). RFFT score was not associated with Taq1B genotype. In conclusion, CETP I405V valine homozygosity was associated with better cognitive function in persons aged 65 years or older.
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