Foundational Genetics

Find all genes that contribute to risk for or protection against Alzheimer’s disease; prioritize those with the greatest impact.

Whole Genome Sequencing

Researchers: 
Funding year(s): 
2012 to 2014
Funding to date: 
$3,000,000

We will carry out Whole Genome Sequencing (WGS) of all subjects in the National Institute of Mental Health (NIMH) Alzheimer’s disease family sample (1,510 subjects; 437 AD families). We will identify functional DNA variants throughout the human genome that are inherited as risk factors for Alzheimer’s disease. We also will analyze DNA from brain samples of subjects who exhibited significant Alzheimer’s pathology at autopsy, but never suffered from dementia; this will allow us to identify protective gene variants as well.

This study constitutes Phase III of the Alzheimer’s Genome Project™. While Phase I and II informed regarding which genes are implicated in risk for Alzheimer’s disease, this study will allow us to assess the entire human genome, including the 96 percent that is not made up of “genes,” per se, but instead includes the DNA that regulates the activity of the genes. While the goal of Phases I and II was to identify all of the genes involved in Alzheimer’s disease susceptibility, in Phase III, we will (1) determine all of the DNA variants in the Alzheimer’s genes that directly influence risk for the disease; and (2) determine all of the DNA variants in the rest—the (intergenic) portions of the genome that regulate the activities of the Alzheimer’s genes.

As in the past, we will use this information to determine exactly how each Alzheimer’s gene (emerging from Phase I and II), functionally affects risk for the disease at the biological level. These findings then will be used not only to better understand the causes of Alzheimer’s disease, but also to guide drug discovery efforts to slow down, stop or, perhaps, even reverse the disease process.

 

Upkeep and Maintenance of the AlzGene Database

Researchers: 
Funding year(s): 
2006 to 2013
Funding to date: 
$389,172

Cure Alzheimer’s Fund is funding the upkeep and continued development of a revolutionary Web-based database. AlzGene is a fantastic resource for Alzheimer’s researchers, providing data and meta-analyses from hundreds of genetic association studies in an easy-to-use, searchable database. Scientists interested in a particular gene can search for it in AlzGene to see what previous studies have reported, receiving a wealth of information in a very short amount of time. Family history is the second-greatest risk factor for Alzheimer’s disease after age, and the growing understanding of AD genetics is a critical part of the science behind the disease. In previous decades, hundreds of reports have been published claiming or refuting genetic association between AD genes and disease risk. Presently, nearly a dozen AD association studies are being published monthly from research groups worldwide.
The pace of genetics research was substantially stepped up by the advent of genomewide association studies (GWAS), of which more than a dozen already have been published on AD. An even steeper increase can be expected to result from a widespread application of so-called “next-generation sequencing” technologies. For the AD genetics research community, this wealth of information is becoming increasingly difficult to follow, evaluate and interpret. The AlzGene database has been developed to manage this huge amount of information and to allow it to be used productively. AlzGene is undergoing a major software upgrade in order to efficiently handle data emerging from large-scale genetics studies.

To access the database, visit www.alzgene.org. (AlzGene is embedded into the Alzheimer Research Forum [www.alzforum.org].)

The Amylin Protein of Diabetes Mellitus is an Antimicrobial Peptide

Funding year(s): 
2010 to 2013
Funding to date: 
$900,000

The goal of this project is to determine whether the amylin (IAPP) protein has a role in innate immunity (similar to Abeta) in order to significantly advance our understanding of the origins of diabetes pathology and its possible linkage to Alzheimer’s disease.

The underlying cause of Type 2 diabetes mellitus remains unclear. In 1987, researchers found an important clue to the pathological mechanisms underpinning the disease—insoluble deposits of a small protein called amylin (IAPP) that form in pancreatic islets of those with diabetes. Proteinaceous deposits of this kind are known as amyloid and are a pathological hallmark of a number of common diseases, including Alzheimer’s disease (AD). Different amyloid-forming proteins are associated with different diseases. However, amyloid-forming proteins often share physiochemical properties and their associated diseases overlapping pathologies. The similarities between IAPP and Abeta are particularly striking. Abeta is present in the brains and pancreatic islets of patients with diabetes. Both IAPP and Abeta are small, amphipathic molecules generated by cleavage of larger membrane-associated precursor proteins and bind the molecular chaperone apolipoprotein E. Abeta and IAPP also share another important similarity—despite two decades of intensive study, the normal non-pathogenic functions of these proteins are poorly understood. Our laboratory recently advanced the novel idea that Abeta is part of the innate immune system and belongs to a family of proteins called antimicrobial peptides (AMPs). AMPs function as natural antibiotics to protect against invading pathogens. In vitro Abeta can inhibit the growth of at least eight clinically important pathogens. In addition, homogenates prepared from the brains of AD patients have specific Abeta- mediated antimicrobial activity. Preliminary data from our latest experiments show IAPP also has antimicrobial activity and inhibits the growth of the important human pathogens Candida albicans and Listeria monocytogenes. In initial tests, IAPP antimicrobial activity was equivalent to Abeta, although the peptide may target a narrower microbial spectrum.

Our discovery of Abeta’s role in immunity identifies pharmacological manipulation of the innate immune system as a new and promising therapeutic strategy for treating AD. Strong epidemiologic evidence suggests an association between AD and Type 2 diabetes, but the critical pathological mechanism common to both diseases has yet to be identified. Our preliminary findings link, for the first time, the amyloid-forming proteins of these two disorders with a common non-pathological function as innate immune effector molecules. We propose a project to investigate IAPP for a role in innate immunity using an experimental paradigm similar to that used in the study of Abeta. We think findings from this new line of inquiry may significantly advance our understanding of the origins of diabetes pathology and is potentially the basis for a new therapeutic strategy for curbing the rising diabetes epidemic.

Alzheimer’s Genome Project™

Researchers: 
Funding year(s): 
2005 to 2014
Funding to date: 
$9,841,400

The goal of this project is to evaluate our new Alzheimer’s disease gene candidates for effects on Alzheimer’s pathology and related biological pathways, including APP processing, amyloid beta protein generation, tangle formation and cell death. These studies are being carried out as part of Phase II of the Alzheimer’s Genome Project (AGP) and entail functional analyses of the Alzheimer’s gene candidates identified in Phase I of the AGP. We have focused the Phase II studies on the novel Alzheimer’s genes known as ADAM10, ATXN1 and CD33, all identified in 2008 as part of Phase I
of the AGP.

The functional studies, aimed at how these genes influence risk for Alzheimer’s, are carried out in both cell-based and animal models. We also have performed genetic follow-up and functional studies for AD-associated aberrations in the human genome, known as copy number variants (CNV). This has led to the identification of several CNVs in novel Alzheimer’s genes underlying the inheritance of cases of familial early-onset Alzheimer’s that were not explained by the known early-onset Alzheimer’s genes co-discovered by our lab in the 1980s and ’90s (amyloid precursor protein, presenilin 1 and presenilin 2).

The knowledge gained from how the newly identified Alzheimer’s genes (from Phase I) biologically increase or decrease risk for Alzheimer’s disease is being implemented to design new drug discovery efforts, also as part of Phase II of the AGP. Phase III of the AGP is being carried out parallel to Phase II and includes Whole Genome Sequencing of the human genomes of subjects from both early-onset and late-onset Alzheimer’s families. The goal of Phase III of the AGP is to identify all of the biologically relevant functional gene variants that influence risk for Alzheimer’s disease. Once identified, these gene variants will be analyzed using similar methods to those described here in Phase II of the AGP. A detailed description of Phase III of the AGP can be found in the section under “Whole Genome Sequencing of Alzheimer’s Disease Families.”

Longitudinal Study of AD Genotypes

Funding year(s): 
2006
Funding to date: 
$100,000

This study draws on a unique community-based longitudinal cohort of 378 subjects who span the range of impairment between normal aging and mild Alzheimer's disease (AD). This research focuses on two key steps to find AD genes and to understand their impact.

  1. Investigate the relationship of amyloid deposition to memory impairment using Pittsburgh Compound B (PIB), a new imaging technique.
  2. Collect DNA samples for a complete a genome screen of the full cohort, and analyze using a set of optimal quantitative phenotypes. The hypothesis is that longitudinal quantitative phenotypes will provide greater power to detect AD genes than conventional affection status (AD vs. no AD) approaches.
     

Relating AD Brain Morphology to AD Genotype

Funding year(s): 
2006
Funding to date: 
$100,000

The Massachusetts Alzheimer’s Disease Center has collected approximately 800 brain samples, providing an extraordinary resource for clinical-pathological correlations for Alzheimer’s disease and other dementias.
This research project involves comparing quantitative phenotypes to genetic markers. In earlier studies, these brain samples were used to study the consequences of inheritance of apolipoprotein E-ε4, and of the ubiquilin 1 risk alleles (described by Dr. Rudolph Tanzi). This research will use 500K chips to do a total genome scan, and also utilize the quantitative phenotypes noted above. Such an analysis will give us a window on discovering new genes that impact the rates of progression of patients, the amount of amyloid buildup and deposition, the formation of neurofibrillary tangles, and the amount of neuronal loss.
The research will give us an outstanding pilot data set to test the hypothesis that genetic variations can impact the amount of “reserve” that individuals have against the disease process, and also evaluate genetic influences on rate of progression, amyloid generation, and amyloid deposition.

Identification of Agents that Inhibit the Generation and Neurotoxicity of Cross-linked B-amyloid Protein Species

Funding year(s): 
2006 to 2007
Funding to date: 
$200,000

We have coined the term CAPS to describe cross-linked-Beta-amyloid protein species. CAPS, particularly dimeric forms, are highly neurotoxic. CAPS are also abundant in vivo, with dimeric species alone comprising as much as 40 percent of the total Abeta pool in late state AD brain. In this study we plan to screen compound libraries for potential therapeutic agents that attenuate the levels and/or cytotoxic activity of CAPS.

Fine Mapping of Prioritized GWAS Results

Researchers: 
Funding year(s): 
2008
Funding to date: 
$127,880

In this application we propose to utilize next-generation sequencing combined with high-efficiency genomic sequence capture to systematically fine-map the 14q31 region which, based on the currently available data, very likely contains an important AD susceptibility locus(i). Newly identified variants will be followed up in more than 5,500 DNAs from both family-based and case-control backgrounds.

Modulation of Abeta Assembly and Cytotoxicity by a Fragment of Myelin Basic Protein

Funding year(s): 
2008
Funding to date: 
$100,000

We have identified myelin basic protein (MBP) as a novel factor in brain that can bind Abeta and potently inhibit its assembly into fibrils. In light of this novel finding the overall hypothesis of this proposal is that defined fragments of MBP can regulate Abeta assembly and modulate its cytotoxic properties. This will provide the basis for developing novel and potent Abeta assembly inhibitors.

Molecular Mechanism Underlying Hippocampal Neurogenisis by Familial AD-linked Presenilin-1 Variants

Funding year(s): 
2008
Funding to date: 
$100,000

The specific hypothesis behind the proposed research is that presenilin 1 regulates cell fate determination of adult neural progenitor cells by interfering with instructive intercellular signals prevailing within the neural progenitor cell niche, and that expression of the familial AD-linked presenilin 1adversely affects this process.