- Technology, Collaboration Key to Genetic Advances
- New Gene Variants Associated with Risk of Alzheimer’s Disease
- Disrupted Microglial Gene Function
- Microglial Gene Triples Alzheimer’s Risk
- Finding Genes Involved in Tau Pathology
- Microglial Function and the CD33 Gene
- Alzheimer’s Risk Gene and the Oldest-Old
Age and genetics are the best-known risk factors for Alzheimer’s disease.
Age and genetics are the best-known risk factors for Alzheimer’s disease. Most people with Alzheimer’s do not start showing symptoms until age 60 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 causes abnormal proteins to be formed.
In early-onset Alzheimer’s disease, 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 cleavage of APP, a protein whose precise function is not yet known. This breakdown is part of a process that generates harmful forms of beta-amyloid, which lead to 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 common genetic risk factor identified to date for late-onset Alzheimer’s. The APOE 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 but is not the direct cause. Inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and many who develop Alzheimer’s do not have any APOE ε4 alleles.
NIA researchers screen thousands of DNA samples to identify the gene variants that influence Alzheimer’s and other neurodegenerative diseases.
Researchers are working collaboratively on genome-wide association studies (GWAS) to identify other genes that may influence Alzheimer’s disease. Technological advances have enabled them to detect subtle gene variants involved in this complex disorder by scanning thousands of DNA samples from people with Alzheimer’s disease and from unaffected individuals. By identifying genetic factors that may confer risk or protection, we gain insights into the molecular mechanisms and disease pathways that influence disease onset and progression.
Until 2009, APOE ɛ4 was the only known genetic risk factor for Alzheimer’s, but now GWAS researchers have detected and confirmed a growing list of others: PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1, and TREM2. In 2013, this list expanded to include another 11 genes, described below.
Scientists are using other techniques as well. Whole genome sequencing, which identified the TREM2 gene, captures genetic variations in an entire complement of a person’s DNA. Researchers are also looking for genes that protect against the disease. In 2013, they identified one such protective gene, a variant of the APP gene, described below. These discoveries are helping to uncover the cellular pathways involved in Alzheimer’s and could lead to new avenues for therapeutic approaches.
In the largest GWAS of Alzheimer’s disease to date, the International Genomic Alzheimer’s Project (IGAP) identified 11 new genes that contribute to risk of late-onset Alzheimer’s disease (Lambert et al., 2013). The IGAP, a collaboration among four consortia in the United States and Europe, found the new genes by analyzing DNA sequence data from more than 74,000 older volunteers with and without Alzheimer’s disease from 15 countries.
The newly discovered genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4) strengthened evidence about the involvement in Alzheimer’s disease of certain biological pathways, including amyloid metabolism and immune responses. The results also pointed to new candidate pathways, including pathways involved in microglial function and cellular protein degradation.
This GWAS study brought to light not only 11 new Alzheimer’s disease risk genes, but also another 13 DNA sequence variants that merited further analysis. Researchers at Washington University School of Medicine in St. Louis, the Alzheimer’s Disease Genetics Consortium, the European Alzheimer’s Disease Initiative, and others followed up on one of these, a sequence variation lying near the triggering receptor expressed on myeloid cells 2 (TREM2) gene that appears to protect against Alzheimer’s disease (Benitez et al., 2013). This sequence variant turned out to lie not in the gene for TREM2, but in a nearby gene, the TREM-like 2 (TREML2) gene. As with TREM2, TREML2 is expressed by microglia but seems to have effects opposing those of TREM2—it reduces inflammation rather than promoting it. This study emphasizes the importance of deeper analysis of GWAS “hits” associated with Alzheimer’s disease and supports the idea that changes in microglial gene function can impact disease risk.
To better understand which biological processes go awry in Alzheimer’s disease, researchers at the Icahn School of Medicine at Mount Sinai, New York City, looked for networks of genes whose normal pattern of activation is disrupted in the brains of people with the disease (Zhang et al., 2013). (Activated genes are those from which protein is actively being made; different sets of genes are activated in different tissues.) The researchers compared the activation patterns of almost 40,000 different genes in brain tissue samples at autopsy from 376 participants with late-onset Alzheimer’s disease and 173 with normal cognition.
They identified gene networks that are disturbed in the brain regions most damaged by Alzheimer’s disease. The most strongly affected network contained genes responsible for controlling the brain’s immune system, in particular the function of microglia—cells that help maintain brain health by removing cellular debris and infectious agents. Activation of many of these genes is controlled by a master regulatory gene called TRYOBP. Because TRYOBP is also involved in the clearing of beta-amyloid by microglia, it may be a promising therapeutic target.
Alzheimer’s geneticists discovered rare mutations in the TREM2 gene that appear to increase Alzheimer’s disease risk as much as three-fold (Guerreiro et al., 2013). Scientists had previously found that both copies of the TREM2 gene are mutated in some cases of frontotemporal dementia. To learn if mutations in just one copy of the gene might be associated with Alzheimer’s disease, the scientists, from a number of academic institutions and NIA, analyzed thousands of DNA sequences from people with and without Alzheimer’s.
They identified a set of TREM2 mutations that occurred at much higher frequencies in people with Alzheimer’s disease than in controls. Unlike APOE ε4, the TREM2 mutations are very rare in the general population. Nonetheless, the discovery of these mutations sheds new light on the biology of Alzheimer’s.
Alzheimer’s disease GWAS studies typically look for DNA sequence variations that occur more frequently in people with cognitive symptoms of the disease and then compare them with the DNA of cognitively normal volunteers. A research team from the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), led by scientists at the Washington University School of Medicine, St. Louis, took a different approach. They looked for sequence variations associated with two protein biomarkers of the disease: elevated levels of tau and phosphorylated tau (ptau) in the cerebrospinal fluid (CSF) (Cruchaga et al., 2013).
The researchers studied DNA samples from almost 1,300 participants, about half of whom had Alzheimer’s disease and the rest of whom were cognitively healthy. Four sets of DNA sequence variations were associated with increased CSF tau and ptau levels. Two of these variations lay within genes already associated with Alzheimer’s disease, APOE and TREM. The third variant lay in a region of chromosome 3 that contains several genes involved in development of synapses. The fourth lay in a gene called GLIS3 that has been implicated in diabetes. These new genetic discoveries could improve our understanding of how abnormal tau contributes to Alzheimer’s disease and point to possible new drugs that might target tau pathology.
Microglia help maintain brain health by scavenging and digesting cellular debris, including beta-amyloid plaque. Previous GWAS have indicated a link between Alzheimer’s disease and variations in the DNA sequences of certain microglial genes, but it has been unclear how those microglial genes might influence pathology. Studies from researchers at Massachusetts General Hospital, Boston (Griciuc et al., 2013), and a group from ADNI, Brigham and Women’s Hospital, Boston, and Rush University, Chicago (Bradshaw et al., 2013), now suggest that one of these genes, CD33, regulates the ability of microglia to clear beta-amyloid from the brain.
The Massachusetts General researchers found that microglia in the brains of Alzheimer’s disease patients produce higher levels of CD33 protein than do microglia in the brains of people with normal cognition and that microglia in mouse models of Alzheimer’s lacking the CD33 gene proved better at engulfing and digesting beta-amyloid. They also found that in human brains, a CD33 gene variant that protects against Alzheimer’s disease reduced both CD33 production and beta-amyloid levels in human brains.
The other group of researchers found, conversely, that a variant of the CD33 gene that increases Alzheimer’s disease risk was associated with increased levels of both CD33 protein and brain beta-amyloid. These studies show that CD33 gene variants can either increase or decrease levels of CD33 protein in the brain, and that CD33 protein inhibits the ability of microglia to clear beta-amyloid. Therefore, the CD33 gene may prove a viable therapeutic target.
Τhe ε4 allele of the APOE gene, the most established genetic risk factor for late-onset Alzheimer’s disease, appears to have less impact on risk of cognitive decline in people over age 90 than in younger people. University of California, Irvine, researchers evaluated cognition every 6 months for an average of 2.3 years in 904 volunteers age 90 years and older in The 90+ Study (Corrada et al., 2013). In this group of the “oldest-old,” carriers of the APOE ε4 allele did not develop dementia or die at higher rates than did noncarriers. This finding suggests that the known risk associated with this gene may be age dependent and that the gene may not play a role in dementia and mortality at very old ages.