Searching for New Alzheimer’s Genes

(NIH) Age is the best known risk factor for Alzheimer’s disease. Most people with Alzheimer’s do not start showing symptoms until age 65 or older. However, in rare cases, people develop Alzheimer’s disease much earlier, between the ages of 30 and 60. This “early-onset” form of Alzheimer’s always runs in families. It is caused by a mutation in one of three genes inherited from a parent that cause abnormal proteins to be formed.

alzheimer's genesJ Neural Transm 2000;59(Suppl.):155–161. Alzheimer’s disease. Online Mendelian Inheritance in ManTM, National Library of Medicine, National Institutes of Health. Accessed on 21 January 2003.

Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP); a mutation on chromosome 14 causes abnormal presenilin 1 to be made; and a mutation on chromosome 1 leads to abnormal presenilin 2. Scientists know that each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet known. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease.

The more common “late-onset” form of the disease typically occurs after age 65. While no single gene mutation is known to cause this form of Alzheimer’s, evidence of a hereditary component is mounting. Environmental and lifestyle factors may also contribute to the risk of developing late-onset Alzheimer’s.

The apolipoprotein E (APOE) gene is the strongest genetic risk factor identified to date for late-onset Alzheimer’s. This gene, found on chromosome 19, comes in three different forms, or alleles: ε2, ε3, and ε4. The APOE ε2 allele is the least common form, found in 5 percent to 10 percent of people, and appears to reduce risk. The APOE ε3 allele, the most common form, is found in 70 percent to 80 percent of the population and appears to play a neutral role in the disease. The APOE ε4 allele, found in 10 percent to 15 percent of the population, increases risk for Alzheimer’s disease by three- to eight-fold, depending on whether a person has one or two copies of the allele. The APOE ε4 allele is also associated with an earlier age of disease onset.

APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with one or two APOE ε4 alleles never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles.

Researchers are working hard to identify many other genes that may influence risk for late-onset Alzheimer’s. Those doing genome-wide association studies (GWAS) have identified a number of genes in addition to APOE ε4 that may increase a person’s risk for late-onset Alzheimer’s. Using high-throughput analytical approaches and a large number of DNA samples, researchers have now confirmed six new risk-factor genes: PICALM, CLU, CR1, BIN1, MS4A4, and CD2AP.

Scientists will continue to identify and study other risk-factor genes, including known candidates SORL1, CD33, EPHA1, ABCA7, and TREM2. In addition, scientists are looking for genes that protect against the disorder. These discoveries help to uncover the cellular pathways involved in the disorder and lead to new avenues for therapeutic approaches.

These images show increasing levels of amyloid plaque deposition in cognitively normal adult groups (average age, 63) at three levels of genetic risk for Alzheimer’s disease, as well as in a group of people diagnosed with Alzheimer’s dementia. Courtesy of Banner Alzheimer’s Institute.

New Functions for Alzheimer’s Genes: Synaptic Plasticity

While we know that the APP, presenilin, and APOE genes are involved in regulating brain beta-amyloid levels, researchers are investigating other roles they may play in Alzheimer’s disease. For example, these genes may influence synaptic plasticity, the ability of synapses to weaken or strengthen connections to other synapses—a function critical to learning and memory.

For example, researchers at the University of Washington, Seattle, found that the presenilin 1 (PS-1) gene regulates a form of synaptic plasticity known as “homeostatic scaling” (Pratt et al., 2011). Homeostatic scaling is a mechanism that protects brain cells by preventing groups of neurons from altering their firing patterns too drastically in response to changes in the environment. Neurons from Alzheimer’s model mice with a PS-1 mutation failed to show homeostatic scaling when tested in tissue culture, and this abnormality appeared unrelated to defects in beta-amyloid processing. This suggests that deficits in homeostatic scaling could contribute to the development of Alzheimer’s disease in people with PS-1 mutations.

The ApoE protein binds to several different receptors in the brain, including ApoE receptor 2 (ApoEr2). ApoEr2 is known to promote synaptic plasticity and memory formation in mice, but how it does so is unknown. Georgetown University, Washington, DC, researchers showed that in rodent brain tissue, ApoEr2 increases the number and promotes the stability of dendritic spines and synapses, structures that are important to learning and memory (Dumanis et al., 2011). It does this in part by regulating the assembly of a complex of proteins involved in constructing dendritic spines, dynamic structures that appear and disappear depending on how much synapses are stimulated.

Understanding the mechanisms by which ApoEr2 promotes synapse formation may provide insights into how the APOE ε4 allele increases risk of Alzheimer’s and age-related cognitive decline.

Searching for New Alzheimer’s Genes

During the past 3 years, scientists have identified a number of new candidate risk genes for Alzheimer’s by comparing the genomes of people with the disease to those without it. A method for identifying genes and relating them to cell function and cellular pathways is to search for genes that show different expression patterns (i.e., genes that are activated to a greater or lesser extent) in the brains of people at high risk versus low risk of Alzheimer’s. Such genes may or may not directly influence the risk of Alzheimer’s, but their expression levels may serve as markers of the disease process and provide insight into disease mechanisms.

Researchers at Albert Einstein College of Medicine, New York City, identified early gene expression “signatures” in the brains of young individuals at high risk for Alzheimer’s (Conejero-Goldberg et al., 2011). The researchers compared gene expression patterns in brain tissue donated for autopsy by volunteers who had died relatively young (average age, 42) from causes other than Alzheimer’s. Volunteers were identified as being at either high risk or low risk of developing Alzheimer’s based on whether or not they carried copies of the APOE ε4 allele.

The researchers identified 70 genes that were expressed at significantly higher or lower levels in the brains of the participants at high risk for Alzheimer’s compared with those at low risk. Many of those genes are involved in biological pathways previously shown to play a role in the disease, such as mitochondrial function and regulation of calcium levels in the cell. Interestingly, however, none of the genes identified is known to be involved in beta-amyloid processing.

This study identifies new sets of genes that may be involved in the Alzheimer’s process. In addition, because the gene expression differences were evident long before beta-amyloid accumulation typically begins in Alzheimer’s, it raises the possibility that beta-amyloid accumulation results from other cellular changes that begin earlier in the disease process.

Down Syndrome and Alzheimer’s Disease

Down syndrome is a set of mental and physical symptoms that result from having an extra copy of chromosome 21. While symptoms of Down syndrome can range from mild to severe, typically they include slower-than-usual mental and physical development, including impaired language skills and problems with learning and memory.

A striking feature of Down syndrome is that almost all people with the disorder eventually develop Alzheimer’s disease. Moreover, they develop it much earlier than is typical for the general population, with Alzheimer’s-like pathology (plaques and tangles) appearing by age 40 and clinical symptoms apparent by age 50.

This fact suggested to scientists that the biology of Down syndrome and Alzheimer’s disease might be linked in some way. The key link turned out to be the APP gene. The APP gene encodes the precursor to beta-amyloid protein, which is the main component of amyloid plaque. The APP gene lies on chromosome 21, and people with Down syndrome carry an extra copy the gene. The APP gene is also mutated in certain forms of early-onset Alzheimer’s disease that can occur at people in their 30s, 40s and 50s. In both Down syndrome and early-onset Alzheimer’s disease, abnormalities of the APP gene lead to accumulation of beta-amyloid.

The life expectancy of individuals with Down syndrome is increasing in developed countries. With that comes increased risk for Alzheimer’s and unique challenges in treatment and diagnosis in this population. For example, Alzheimer’s disease drugs used in the general population, such as memantine and donepezil, are not effective in people with Down syndrome, so alternative therapies are needed. Additionally, diagnosing mild cognitive impairment (MCI) and Alzheimer’s disease in people with Down syndrome is challenging as other, ongoing cognitive limitations may mask symptoms.

Now, a research team led by investigators at New York State Institute for Basic Research in Developmental Disabilities, New York City, may have identified a new, genetics-based test for diagnosing MCI and Alzheimer’s in people with Down syndrome (Jenkins et al., 2010). They used blood samples to measure the length of telomeres, the regions found at the ends of chromosomes that act to prevent chromosome ends from fraying and sticking to one another. The scientists discovered that people with both Down syndrome and MCI or Alzheimer’s had shorter telomeres than did people with only Down syndrome.

Because measuring telomere lengths proved highly sensitive and specific, doing so could prove to be a useful biomarker for early stages of dementia in people with Down syndrome, and inform treatment decisions early in the course of disease for these individuals.


Source:  2011-2012 Alzheimer’s Disease Progress Report

National Institute on Aging