Genetic variation in APOE cluster region and Alzheimer's disease risk

Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Neurobiology of aging (Impact Factor: 5.01). 07/2011; 32(11):2107.e7-17. DOI: 10.1016/j.neurobiolaging.2011.05.023
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We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3' to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.

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Available from: Sebastián Cervantes, Jun 02, 2014
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    • "In our series, APOE e4 allele was significantly associated with both an increased conversion rate from MCI to AD and a shortened time-to-progression; consistent with these results, we recently also observed that APOE e4 allele reduced time-to-progression in MCI-converters (Samaranch et al. 2010). The extent to which genetic variability other than APOE influences the conversion from MCI to AD is unknown (Cervantes et al. 2011). Microtubule-associated protein tau (MAPT H1/H2) H1/H1 haplotype (Samaranch et al. 2010), vascular endothelial growth factor (VEGF rs699947) AA genotype (Chiappelli et al. 2006), brainderived neurotrophic factor (BDNF rs6265) Met allele (Forlenza et al. 2010), and butyrylcholinesterase (BuChE rs1803274) Wt allele (Ferris et al. 2009) were associated with a higher risk of AD-conversion in MCI patients. "
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    ABSTRACT: Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.
    Journal of Neural Transmission 11/2012; 120(5). DOI:10.1007/s00702-012-0920-x · 2.40 Impact Factor
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    • "In this study, we hypothesized that APOE ␧4 and MAPT H1/H1 genetic variants could be associated with differential brain atrophy, given the recent evidence suggesting that both APOE ␧4 and MAPT H1/H1 accelerate progression from MCI to dementia [26]. We found specific atrophic brain regions associated with APOE ␧4 and MAPT H1/H1 in amnestic MCI subjects at the time of diagnosis. "
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    ABSTRACT: The aim of our study was to elucidate whether specific patterns of gray matter loss were associated with apolipoprotein E ε4 (APOE ε4) and microtubule-associated protein tau (MAPT)-H1 genetic variants in subjects with mild cognitive impairment (MCI) at a baseline visit. Gray matter voxel-based morphometry analysis of T1 magnetic resonance imaging scans was performed in 65 amnestic-MCI subjects. MCI APOE ε4 carriers compared with non-carriers showed increased brain atrophy in right hippocampus and rostral amygdala, superior and middle temporal gyrus, and right parietal operculum, including inferior frontal gyrus, inferior parietal, and supramarginal gyrus. MAPT-H1/H1 MCI carriers showed an increased bilateral atrophy in superior frontal gyri (including frontal eye fields and left prefrontal cortex) and precentral gyrus but also unilateral left atrophy in the inferior temporal gyrus and calcarine gyrus. In addition, MCI subjects carrying both APOE ε4 and MAPT-H1/H1 variants showed gray matter loss in the supplementary motor area and right pre- and postcentral gyri. The effect of APOE ε4 on gray matter loss in right hippocampus suggests that, at least in some AD sub-types, the neuronal vulnerability could be increased in the right hemisphere. The pattern of frontal gray matter loss observed among MCI MAPT H1/H1 carriers has also been found in other tauopathies, suggesting that MCI may share etiological factors with other tauopathies. Frontal and parietal cortex vulnerability was found when adding MAPT H1/H1 and APOE ε4 effects, suggesting a synergistic effect of these variants. These results could be due to changes in APOE ε4 and MAPT expression.
    Journal of Alzheimer's disease: JAD 10/2012; 33(4). DOI:10.3233/JAD-2012-121174 · 4.15 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: β-amyloid [Aβ]) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. Abnormalities in Aβ and tau can be measured upon neuropathological examination, in cerebrospinal fluid or by PET. Etiologically, a growing body of evidence suggests that susceptibility to AD is genetically controlled. However, the precise nature of the underlying risk genes and their relation to AD biomarkers remains largely elusive. To this end, we performed a qualitative review of 17 studies (covering 47 polymorphisms in 26 genes) and investigated the potential relation between the most compelling AD risk genes and markers for Aβ and tau in cerebrospinal fluid, PET imaging and neuropathological examination. Of all covered genes, only APOE and PICALM showed consistent effects on Aβ but not on tau, while no obvious effects were observed for CLU, CR1, ACE, SORL and MAPT.
    Biomarkers in Medicine 08/2012; 6(4):477-95. DOI:10.2217/bmm.12.56 · 2.65 Impact Factor
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