Accelerating the Search for Genetic Causes and Risk Factors

Until recently, only four of the approximately 30,000 genes in the human genome were conclusively shown to affect the development of AD. Mutations in three genes—the APP gene found on chromosome 21, the presenilin 1 gene on chromosome 14, and the presenilin 2 gene on chromosome 1—are linked to the rare early-onset form of familial AD. The APP gene is responsible for making APP, the precursor to beta-amyloid. The presenilin genes contain the information necessary to make the proteins that are part of one of the enzymes that help to cleave APP to form beta-amyloid. Mutations in each of these genes promote the breakdown of APP in a way that leads to increased production of harmful beta-amyloid.

The fourth gene, APOE, found on chromosome 19, contains the information necessary to make a protein called apolipoprotein E (ApoE). ApoE carries lipids in the bloodstream and is important in clearing lipids from the blood. APOE has three common forms, or alleles—ε2, ε3, and ε4. The ε2 form may provide some protection against AD, and ε3 is thought to play a neutral role. The ε4 form is a known risk-factor gene for the common late-onset form of AD, and many studies are underway to clarify its impact.

• Boston University School of Medicine scientists supported by the National Heart, Lung, and Blood Institute (NHLBI) and NIA examined whether APOE ε4 affects the relationship between brain volume and cognitive performance in 1,477 participants in the Framingham Study population (Palumbo et al., 2007). Those with an APOE ε4 allele and smaller brain volume did less well on tests of visual memory, new learning, and executive function than those without APOE ε4, who also had smaller brain volumes. It may be that having APOE ε4 not only increases the risk of AD, but also leads to poorer outcomes in those who do not yet have symptoms of the disease.
  
  
• People who have two copies of the APOE ε4 allele may be at high risk of developing AD at an earlier age of onset and for experiencing far more rapid declines in memory performance, compared with people without this allele and people with only one copy. Such memory declines, even within a normal range of performance, could be early markers of disease, detectable before the individual experiences clear symptoms of the disorder. Investigators supported by NIMH and NIA examined how performance on neuropsychological tests by a sample of healthy adults in their 50s and 60s related to their APOE ε4 status (Caselli et al., 2007). The investigators, with the Mayo Clinic in Scottsdale, Arizona, and the University of Arizona, found that even before a diagnosis of aMCI, individuals with two copies of APOE ε4 showed higher rates of cognitive decline than those at lower genetic risk for AD.
  
  These findings support the notion of a presymptomatic state of disease, the identification of which might aid in early detection and diagnosis of AD among people at increased genetic risk. Further prospective studies are needed to examine how rates of cognitive decline relate to rates of AD disease progression and conversion to a final diagnosis of AD. Results from these studies may suggest new targets for possible interventions to delay onset or progression of AD.
  
  
• Though scientists know that APOE ε4 is a risk factor for cognitive decline that eventually leads to AD, they have yet to understand the steps in that process. Many think that it involves an interaction between genetic and environmental factors. One study, supported by NIMH and conducted by a research team at the University of California San Diego examined the role of one such environmental factor, prolonged psychological stress (Peavy et al., 2007). Stress generally involves elevations in the hormone cortisol, which have been linked to hippocampal atrophy and to memory and learning impairments. This study assessed APOE status, stress levels, salivary cortisol, and memory performance of 91 older adults without dementia.
  
  The researchers found that having either one or two APOE ε4 alleles and high stress were associated with reduced memory performance. In addition, the investigators found significant interactions between stress and APOE ε4; participants with high levels of stress and the APOE ε4 allele consistently manifested worse memory and higher cortisol concentrations than other participants. These findings point the way to future studies that could follow individuals over time to determine whether stress levels and APOE status in combination could be used to predict future development of cognitive decline leading to clinically diagnosable dementia.

Most experts believe that in addition to APOE ε4, at least half a dozen more genes may influence the development of late-onset AD in some way. Geneticists around the world are searching for these genes.

• In 2007, a worldwide collaboration of scientists supported by NIA, the National Human Genome Research Institute, NCRR, the Canadian Institutes of Health Research, and private foundations in the United States, Canada, and Japan unveiled their discovery of a new AD risk-factor gene called SORL1 (Rogaeva et al., 2007). This gene is involved in recycling APP from the surface of cells, and its association with AD was identified and confirmed in three separate studies (Lee JH et al., 2008; Lee JH et al., 2007; Meng et al., 2007). The researchers found that when SORL1 is expressed at low levels or in a variant form, harmful beta-amyloid levels increase, perhaps by moving APP away from its normal pathways and toward cellular compartments that generate beta-amyloid.
  
  Studies are ongoing to clarify SORL1’s role in the AD process. For example, NHLBI-supported scientists at Boston University School of Medicine conducted a genome-wide association study on Framingham Study participants using cognitive data collected in an NIA-funded add-on study (Seshadri et al., 2007). A genome-wide association study tests for linkage between genes and a particular disease across all the genes in a specific population of individuals. The researchers found that the SORL1 gene was associated with measures of abstract reasoning and that another gene, CDH4, was related to total cerebral brain volume. This association of an AD risk-factor gene with cognitive function suggests there may be a common pathway in the brain aging process and in AD.
  
  NIA’s Alzheimer’s Disease Genetics Initiative (ADGI) provides critical support to all of this work. Launched in 2003, this study aims to identify at least 1,000 families with members who have late-onset AD and members who do not have the disease. Investigators are collecting blood samples and other clinical data from participating volunteers. These biological specimens allow investigators to create and maintain “immortalized” cell lines—cells that are continuously regenerated in the laboratory. The cell lines will be used in DNA analyses to further understand SORL1 and to identify additional AD risk-factor genes, a critical task even if individual risk-factor genes may have relatively small effects on AD development. More than 4,000 new cell lines are now available for researchers to study risk-factor genes for late-onset AD.
  
  A second investigator-led initiative, the Alzheimer’s Disease Genetics Consortium, was launched in 2007 to accelerate the application of genetics technologies to late-onset AD through collaborations among leading researchers in AD genetics. The ultimate goal of this effort is to obtain genetic material from 10,000 people with AD and 10,000 cognitively healthy people and then to scan the entire genome for the remaining AD risk-factor genes, as well as genes for age-related cognitive decline. Some of the genetic material will be drawn from existing samples of blood and tissue that are mostly held at Alzheimer’s Disease Centers. Other genetic material will be collected from new participants.
  
  With such efforts, the search for the genetic underpinnings of late-onset AD is intensifying, allowing investigators to identify who is at high risk of developing AD, understand the mechanisms at work, and focus on new pathways amenable to prevention or treatment.

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