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
Source: PubMed


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.
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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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