Alzheimer’s disease (AD) is strongly influenced by inheritance and genetic susceptibility as evidenced by numerous family and twin studies. Over the past two and a half decades, our laboratory has co-discovered the three early-onset familial AD genes, APP, PSEN1, and PSEN2, which can carry any of >200 fully penetrant mutations characterized by mendelian inheritance. For late-onset AD, the only well-established risk factor is the epsilon 4 variant of APOE, which increases risk by 3.7-fold in the heterozygous state and >10-fold when two copies are inherited. It has been estimated that 50-70% of the genetic variance of AD remains unexplained by the four established AD genes. We are engaged in two major efforts to identify the additional AD genes as part of our Alzheimer’s Genome Project funded by the Cure Alzheimer’s Fund. First, for published AD candidate genes, we have developed the AlzGene.org website, a comprehensive, online encyclopedia and database, which includes data on >650 AD candidate genes and >~3000 DNA variants that have been tested for association with AD. For all DNA variants tested in at least four independent samples (~300), AlzGene.org provides meta-analyses to determine the most promising AD candidate genes. These studies have led to over 40 candidate AD genes, including APOE, that yield significant results. However, the effects of these variants on risk are tiny compared to APOE (.75≤O.R.≤1.25).

We are currently exploring whether these associations are being driven by rare late-onset AD mutations in linkage disequilibrium with the disease-associated common variants. We found this to be the case for the APP alpha-secretase gene, ADAM10,in which we discovered two rare mutations that severely impair ADAM10 cleavage of APP both in vitro and in transgenic mice. Second, in a parallel effort, we have carried out several genome-wide association studies on >800 well-characterized late-onset AD families (NIMH and NCRAD samples) using Affymetrix genotyping arrays containing either one million (6.0) or 500,000 (5.0) genomic single nucleotide polymorphisms (SNPs) as well as arrays containing 20,000 coding SNPs. We have previously reported four novel loci that achieved genome-wide significance (besides APOE) including a novel gene on chromosome 14q, GWA-14q, the ataxin 1 gene, the innate immune system lectin gene, CD33, and the synaptic gene, DLGAP1.

Functional studies of the ATXN1 gene carried out both in vitro and in vivo in ATXN1 knockout mice show that ATXN1 can regulate Ab levels via modulation of beta-secretase. We will also present new data implicating Ab as an anti-microbial peptide in the innate immune system. These latter data in combination with several novel candidate genes emanating from the Alzheimer’s Genome Project suggest that innate immune system in the brain may play a central role in the etiology and pathogenesis of AD, raising new possibilities for novel drug discovery. Along these lines, I will present data on several promising therapeutics aimed at preventing and treating AD based on knowledge gained from AD genes.

The NIH Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.

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