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Identify/understand all Alzheimer's-related genes

by Cure Alzheimer's Fund
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes
Identify/understand all Alzheimer's-related genes
May 4, 2011

Progress Understanding APOE Genotype

Dr. David Holtzman
Dr. David Holtzman

One of the most important, outstanding genetic questions about Alzheimer's disease is the relationship between the APOE genotype and the risk associated with the disease.  Following a CAF-sponsored meeting with members of our Research Consortium and several other noted researchers, CAF awarded a grant to David Holtzman, MD, in his lab at Washington University in St. Louis to further study this question.

Understanding the APOE linkage to AD. Although the genetic link has been known for 18 years, the critical links remain a puzzle. Other than age, the strongest risk factors for Alzheimer’s disease (AD) are genetic. The most common form of AD is late-onset AD, which accounts for more than 95 percent of Alzheimer’s cases and typically is defined by cognitive decline and dementia beginning after age 60. In this form of the disease, by far the strongest genetic risk factor for AD is one’s APOE genotype. The APOE gene has several subtle differences, or “alleles,” numbered APOE2 through APOE4. Although the APOE4 genetic variant is found in about a quarter of the population, not everyone with the variant will develop AD. Inheritance of the APOE4 form of APOE is associated with increased risk (three times the normal risk for those inheriting one copy of the variant; about 12 times the risk for those people inheriting two copies of the gene), and the APOE2 form is associated with decreased risk. How the APOE genotype is linked with altered risk to develop AD is the big question.

There is mounting evidence that one of the major reasons APOE is linked with AD is the ability of the APOE protein to influence when the amyloid-beta peptide (Abeta) begins to accumulate in the brain to instigate damage.  

Understanding the APOE linkage to AD. Although the genetic link has been known for 18 years, the critical links remain a puzzle. Other than age, the strongest risk factors for Alzheimer’s disease (AD) are genetic. The most common form of AD is late-onset AD, which accounts for more than 95 percent of Alzheimer’s cases and typically is defined by cognitive decline and dementia beginning after age 60. In this form of the disease, by far the strongest genetic risk factor for AD is one’s APOE genotype. The APOE gene has several subtle differences, or “alleles,” numbered APOE2 through APOE4. Although the APOE4 genetic variant is found in about a quarter of the population, not everyone with the variant will develop AD. Inheritance of the APOE4 form of APOE is associated with increased risk (three times the normal risk for those inheriting one copy of the variant; about 12 times the risk for those people inheriting two copies of the gene), and the APOE2 form is associated with decreased risk. How the APOE genotype is linked with altered risk to develop AD is the big question.

There is mounting evidence that one of the major reasons APOE is linked with AD is the ability of the APOE protein to influence when the amyloid-beta peptide (Abeta) begins to accumulate in the brain to instigate damage.  The specific hypothesis for Dr. Holtzman’s project, inspired by the APOE meeting, is that anti-APOE antibodies that specifically target APOE in amyloid-beta containing plaques in the brain will result in less Abeta accumulation in the brain and decrease Abeta-related pathology, and that this treatment will have fewer side effects than the use of anti-Abeta antibodies.

Dr. Holtzman writes: APOE is the most important genetic risk factor for Alzheimer’s disease. A major reason it appears to act as an AD risk factor is via its effects on Abeta (Aβ) metabolism. In vivo (cell) and in vitro (animal) data strongly suggest that APOE influences both soluble Abeta clearance as well as the probability of Abeta aggregation into clusters of the protein called “oligomers” and “fibrils,” which have been determined to be toxic to neural synapses. These effects of APOE on Abeta buildup in the brain are APOE isoform-dependent. In addition, in the absence of APOE, Abeta can still aggregate in the brain; however, the conversion of Abeta into fibrils and probably oligomers is markedly inhibited. In the brain of a mouse genetically engineered to demonstrate Alzheimer’s pathology (APP Tg mouse), and in humans, APOE strongly co-localizes with both amyloid plaques and the buildup of Abeta in certain blood vessels in the brain, a condition known as cerebral amyloid angiopathy (CAA). All of these facts argue that a treatment that could modify APOE/Aβ interaction may provide a novel treatment strategy for AD.

One way to modify the APOE/Abeta interaction once Abeta aggregates in the brain, or in CAA, is to use antibodies, which are proteins produced by the immune system to protect the organism. Numerous studies have injected anti-Abeta antibodies either systemically as well as intracerebrally into various types of APP Tg mice that develop Abeta accumulation in the brain. Via a variety of mechanisms, many of these antibodies are able to decrease Abeta accumulation when given in a prevention mode, and some of them are able to reduce existing Abeta oligomers and fibrils when given in a treatment mode (after plaques have begun to form). While this is potentially good news for treatment development, systemic treatment with certain anti-Abeta antibodies can also result in vasogenic edema (brain swelling) as well as cerebral hemorrhages in both animal models and in humans. Recent studies have attempted to utilize antibodies to reduce a minor component of Abeta plaques in the brain, such as pyro-glutamate-Abeta. These studies have shown a robust plaque-clearing effect, suggesting that if antibodies can bind to Abeta deposits, even if the component is only a fraction of the total material deposited, this can have a strong effect. To date, no one has published whether antibodies to other components of Abeta plaques, such as APOE, can have useful effects on the total amount of Abeta-deposited, Abeta-associated neuritic damage and inflammation, behavior or potentially any side effects.

Stay tuned for updates and progress on this critical work.

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Cure Alzheimer's Fund

Location: Wellesley Hills, Ma - USA
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Laurel Lyle
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