- Technology, Collaboration Key to Genetic Advances
- International GWAS Identifies 11 New Gene Risk Factors
- Microglial Gene Triples Alzheimer’s Risk
- Protective Gene Mutation and Beta-Amyloid in Alzheimer’s
- Natural Selection and Alzheimer’s Risk Genes
- Brain Imaging and New Insights Into Alzheimer’s Genetics
- Gene Variants Influence Hippocampal Volume
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 that 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 as well as 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 developing the disease. This year, 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 October 2013, the International Genomic Alzheimer’s Project (IGAP) announced the results of a GWAS that offer important new insights into the disease pathways involved in late-onset Alzheimer’s disease. IGAP, comprised of four research consortia in the United States and Europe and supported in part by the National Institutes of Health (NIH), scanned the DNA of more than 74,000 volunteers—the largest genetic GWAS yet conducted in Alzheimer’s research. The researchers shared DNA samples and data sets in a collaborative effort that resulted in the identification of 11 new genes. The study also brought to light another 13 variants that merit further analysis.
The IGAP findings strengthened evidence about the involvement of certain pathways in the disease, such as the role of SORL1 in amyloid deposition, a hallmark of the disease. The results also shed light on new gene risk factors that may influence several cell functions, such as the ability of microglial cells to respond to inflammation (Lambert et al., 2013).
The researchers identified the new genes by analyzing previously studied and newly collected DNA data from 74,076 older volunteers from 15 countries. The newly discovered risk genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4) and previously identified variants are now being examined for the roles they play in Alzheimer’s disease. For example, investigators are exploring how SORL1 and CASS4 influence amyloid, how CASS4 and FERMT2 affect tau, and how some of these genes impact lipid transport, synaptic function, and other cell functions.
The National Institute on Aging (NIA)-funded Alzheimer’s Disease Genetics Consortium (ADGC), at the University of Pennsylvania School of Medicine, Philadelphia, is one of the four IGAP founding partners. Its goal is to identify genetic variants associated with risk for Alzheimer’s. Other NIA research infrastructure resources have supported the ADGC by making available DNA samples, data sets containing biomedical and demographic information about participants, and genetic analysis data.
The other three founding partners of IGAP are the Cohorts for Heart and Aging Research in Genomic Epidemiology, supported in part by several NIH institutes and NIH-supported databases from the AGES-Reykjavik Study and the Atherosclerosis Risk in Communities Study; the European Alzheimer’s Disease Initiative in France; and Genetic and Environmental Research in Alzheimer’s Disease in Wales.
Alzheimer’s geneticists discovered rare mutations in a gene called TREM2 (triggering receptor expressed on myeloid cells) that 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 University College London and NIA, analyzed thousands of DNA sequences from people with and without Alzheimer’s; the data came from the investigators’ own collections and several other large collections from around the world.
The analysis identified a set of TREM2 mutations that occurred at much higher frequencies in people with Alzheimer’s 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.
The protein encoded by the TREM2 gene is found on the cell membranes of microglia, the major class of immune cells in the brain. Microglia help maintain brain health by attacking and removing infectious agents. They also digest cellular debris, including beta-amyloid, and participate in the ongoing remodeling of communication between cells that is vital for learning and memory. This finding points to microglial cell dysfunction as a major route by which the disease can develop and will no doubt prompt researchers to probe further the biology of microglia.
The discovery of a rare gene mutation that protects people against Alzheimer’s provides some of the strongest evidence yet that overproduction of beta-amyloid plays a role in the disease (Jonsson et al., 2012). The A673T mutation, which lies in the gene for APP, was discovered when researchers at deCode Genetics in Iceland scanned the DNA sequence of the APP gene in 1,795 Icelanders. The mutation, which is extremely uncommon, slows the rate at which the APP protein is processed to generate the more toxic forms of beta-amyloid.
To look at how the gene mutation affects cognition, the researchers studied 3,700 nondemented nursing home residents between 80 and 100 years of age. The 41 volunteers in the group who carried the APP gene mutation had better cognitive scores than those of peers of similar age who did not have the protective gene mutation. This discovery lends fresh hope to the idea that beta-amyloid-lowering drugs could prove useful in treating Alzheimer’s.
The apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer’s. Nonetheless, natural selection has favored inheritance of the APOE gene during recent human evolution.
Researchers at Harvard Medical School, Boston, and Rush University, Chicago, analyzed data from two large-scale GWAS and discovered that the inheritance patterns of four Alzheimer’s susceptibility genes (PICALM, BIN1, CD2AP, EPHA1) also show evidence of positive selection during recent evolution (Raj et al., 2012). The researchers suggest that these genes signal the body to produce specific proteins that, interacting with other proteins, serve a common function—perhaps an immune function—that benefits humans during evolution. Since these Alzheimer’s disease susceptibility genes did not affect reproductive status, they were carried through numerous generations to today’s population, which is living longer and thus developing the disease.
Efforts to understand the genetic basis of Alzheimer’s disease are challenging because of the complexity of diagnosing the disorder. No two people with Alzheimer’s show exactly the same cognitive or behavioral symptoms, and symptoms may fluctuate from day to day. However, imaging studies of people with dementia are identifying common patterns of Alzheimer’s-related brain changes. Images of these brain changes, which tend to be more stable and can be measured more accurately than clinical symptoms, are offering new insights into the genetic basis of Alzheimer’s.
The brains of people with Alzheimer’s show a breakdown of functional connections within the default mode network, a group of brain areas used when the mind “wanders,” as in daydreaming. In a functional magnetic resonance imaging (fMRI) study of nearly 350 cognitively normal participants age 45 to 91, researchers at Washington University, St. Louis, found early signs of breakdown in the default mode network in people with a family history of late-onset Alzheimer’s disease (Wang et al., 2012). None of the study participants carried the APOE ε4 allele, the strongest genetic risk factor for Alzheimer’s. This study suggests that other genes, in addition to APOE ε4, contribute to the risk of Alzheimer’s in people with a family history of the disease. Also, testing for declines in the default mode network may help identify those at increased risk.
Alzheimer’s disease is also marked by reduced blood flow to certain brain regions. University of Wisconsin, Madison, researchers used MRI to study blood flow in the brains of more than 250 middle-aged people (Okonkwo et al., 2012). Those with a maternal history of late-onset Alzheimer’s disease showed Alzheimer’s-like changes in brain blood flow patterns, including reduced blood flow to the hippocampus and certain regions of the cortex. Further investigation is needed to examine any possible influence of a maternal history of Alzheimer’s.
Hippocampal atrophy, a recognized biological marker of Alzheimer’s disease, is influenced by various vascular and metabolic factors. Hippocampal volume is a heritable, measurable trait that shows detectable changes throughout life. Researchers at Boston University and other institutions explored genetic influences on hippocampal volume by conducting a GWAS analysis in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium in dementia-free people from community-based studies (Bis et al., 2012).
The investigators detected genetic loci associated with hippocampal volume, implicating genes related to the health and normal functioning of neurons (list genes), cell death (HRK), development (WIF1), oxidative stress (MSR3B), protein clearance (FBXW8), and neurogenesis (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4). This finding suggests genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
Researchers from Boston University and other institutions looked for genes associated with patterns of brain degeneration commonly seen in people with Alzheimer’s disease, including degeneration of the hippocampus, a brain region important for learning and memory (Melville et al., 2012). They analyzed MRI scans from more than 1,600 older individuals with Alzheimer’s, mild cognitive impairment, or normal cognition who are participating in the Alzheimer’s Disease Neuroimaging Initiative.
The research team identified four genes associated with degeneration of the hippocampus, including three new genes not previously suspected to be involved in Alzheimer’s: F5, SELP, and SYNPR. The F5 and SELP genes direct the production of the proteins Factor V and P-selectin, which are involved in blood clotting and blood vessel function, respectively. SYNPR is involved in production of a protein that is vital to normal functioning of synapses.