The Genetics of Alzheimer Disease: Back to the Future

Abstract

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…TGF-b1 contributes to Ab precursor expression and Ab deposition (van der Wal et al 1993;Wyss-Coray et al 1997;Burton et al 2002); however, TGF-b1 attenuates microglia clustering to Ab aggregates, and TGF-b1 expression in astrocytes causes a reduction in overall plaque burden (Wyss-Coray et al 2001;Huang et al 2010). Interestingly, TGF-b1 is enriched in plasma lipoprotein samples of apoliprotein E3 (apoE3), but occurs at a lower concentration in lipoproteins containing apoE4, a genetic risk factor for late-onset Alzheimer's disease (Tesseur et al 2009;Bertram et al 2010). Impairment in TGF-b/Smad signaling and decreased neuronal expression of TbRII are both characteristics of disease pathology, providing further evidence for a role for TGF-b in Alzheimer's disease (Tesseur et al 2006;Ueberham et al 2006;Wang et al 2010).…”

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…Further analyses of SNPs and copy number variations (CNVs) have revealed the existence of more than 200 distinct disease-causing mutations. 19,20 More recently, GWAS have revealed the association of many common polymorphisms to ND sporadic cases, providing in about 3 years more reproducible and consistent findings than 2 decades of candidate-gene-driven research. 21 However, despite the step forward, the identification of potential causative loci associated to ND by GWAS explained only a little percentage of the cases, and the 'missing heritability' issue (ie, the contribution of epigenetic modifications on gene expression) 22 is still a limitation.…”

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…2 Attempts to identify additional AD genes have been largely limited to the search for simple DNA sequence variants (mutations and singlenucleotide polymorphisms) that influence AD susceptibility or time-to-onset. 3,4 Genome-wide association studies have identified several common AD-associated polymorphisms with very small effect sizes. 5 Recent studies estimate that structural variations in the genome, including copy number variations (CNVs) 6 make a significant contribution to genetic and phenotypic variation.…”