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In the brains of patients with AD, BIN1 protein expression levels increase in several regions, especially the hippocampus, and are correlated with tau pathology ( Holler et al, 2014). The SNP rs744373 is in almost complete linkage disequilibrium (LD) ( D’=0.98, r 2=0.94) with functional rs59335482, which is associated with an increase in BIN1 transcriptional activity ( Chapuis et al, 2013). Recently, the results of pooled analysis and meta-analysis indicated that the rs744373 polymorphism contributed to AD with similar genetic risk in East Asian and Caucasian populations ( Liu et al, 2013). AlzGene meta-analysis revealed that the G allele confers a 1.17 greater odds of developing LOAD than does the A allele ( ). BIN1 rs744373 is one of the most significant and best replicated single-nucleotide polymorphisms (SNPs) associated with AD in Caucasian populations, and it is located >25 kB upstream from the BIN1 coding region ( Lambert et al, 2013 Seshadri et al, 2010). Moreover, our previous studies also found that genetic variants in BIN1 were significantly associated with LOAD in the Han Chinese population ( Tan et al, 2013a, 2014). Among them is the bridging integrator 1 ( BIN1) gene, located on chromosome 2q14.3, which has been identified as the most significant risk locus for LOAD after APOE ( Bertram et al, 2007). In recent years, large genome-wide association studies (GWAS) have identified several other genes/loci that, along with APOE ɛ4, contribute to a high proportion of genetic risk for LOAD. Apolipoprotein E ( APOE) has been clearly demonstrated to be the major genetic risk factor for LOAD, exhibiting semidominant inheritance.
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The majority of AD is LOAD, which is genetically complex with heritability estimates as high as 80% ( Gatz et al, 2006). A combination of genetic, neuropsychological, and neuroimaging strategies may prove useful in this regard ( Wishart et al, 2006).
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Unfortunately, there is currently no valid method to identify asymptomatic adults at risk for developing late-onset AD (LOAD). Given that the disease process begins years before the onset of observable cognitive problems, there is an increasing push to identify the earliest disease stages and the at-risk individuals who will benefit most from disease-modifying interventions and prevention ( Jiang et al, 2012). To date, no effective treatment is available to delay the onset or slow the progression of AD. Our findings demonstrate that rs744373 itself or a variation in linkage disequilibrium may provide a neurogenetic mechanism for BIN1 while further validating the possibility of combining genetic and neuroimaging strategies to monitor individuals at risk for AD.Īlzheimer’s disease (AD) is the leading cause of dementia and is characterized by a slowly progressive decline in cognitive functions that typically begins with a deterioration in memory ( Holtzman et al, 2011). Here using an imaging genetic strategy in large-sample Chinese subjects, we show that healthy homozygous carriers of the rs744373 risk allele exhibit worse high-load working memory (WM) performance, larger hippocampal volume and lower functional connectivity between the bilateral hippocampus and the right dorsolateral prefrontal cortex (DLPFC), mirroring clinical evidence of disturbed memory and connectivity in patients. However, how and when the established genetic risk locus BIN1 rs744373 confers risk to late-onset AD has yet to be determined. The bridging integrator 1 ( BIN1) gene has recently been identified in several large genome-wide association studies (GWAS) as the second most important risk locus for AD following apolipoprotein E (APOE). Alzheimer’s disease (AD) is the most common form of dementia and exhibits a considerable level of heritability.