The gene comes in three varieties, known as the e2, e3 and e4 variants. Since everyone inherits one version of the gene from each parent, there are six possible combinations. People with one — and especially two — e4 variants are significantly more likely to develop Alzheimer's than people without e4. Researchers also have found that adults with e2 variants have more plaques in their brains but are less likely to have symptoms of dementia. ||||| Variants of apolipoprotein E have been studied extensively as risk factors for many different conditions. For example, APOE alleles have been shown to influence the risk of cardiovascular diseases. People who carry at least one copy of the APOE e4 allele have an increased chance of developing atherosclerosis, which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries. This progressive narrowing of the arteries increases the risk of heart attack and stroke. 
 
 The APOE e2 allele has been shown to greatly increase the risk of a rare condition called hyperlipoproteinemia type III. Most people with this disorder have two copies of the APOE e2 allele, leading researchers to conclude that the e2 allele plays a critical role in the development of the condition. Hyperlipoproteinemia type III is characterized by increased blood levels of cholesterol, certain fats called triglycerides, and molecules called beta-very low-density lipoproteins (beta-VLDLs), which carry cholesterol and lipoproteins in the bloodstream. A buildup of cholesterol and other fatty materials can lead to the formation of small, yellow skin growths called xanthomas and the development of atherosclerosis. 
 
 APOE gene variants have also been studied as a potential risk factor for age-related macular degeneration, an eye disease that is a leading cause of vision loss among older people worldwide. Some studies have suggested that having at least one copy of the APOE e4 allele may help protect against this disease or delay the onset of vision loss, while having at least one copy of the APOE e2 allele may increase the risk of this disease or cause symptoms to appear earlier. However, other studies have not found these associations. More research is needed to clarify what role, if any, APOE gene variants play in the development of age-related macular degeneration. ||||| News_release 
 
 An international team of scientists, led by researchers at University of California San Diego School of Medicine and University of California San Francisco, has developed a novel genetic score that allows individuals to calculate their age-specific risk of developing Alzheimer’s disease (AD), based upon genetic information. 
 
 A description of the polygenic hazard scoring (PHS) system and its validation are published in the March 21 online issue of PLOS Medicine. 
 
 “We combined genetic data from large, independent cohorts of patients with AD with epidemiological estimates to create the scoring, then replicated our findings on an independent sample and validated them with known biomarkers of Alzheimer’s pathology,” said co-first author Rahul S. Desikan, MD, PhD, clinical instructor in the UCSF Department of Radiology & Biomedical Imaging. 
 
 Specifically, the researchers combined genotype-derived polygenic information with known AD incidence rates from the U.S. population to derive instantaneous risk estimates for developing AD. 
 
 “For any given individual, for a given age and genetic information, we can calculate your �?personalized’ annualized risk for developing AD,” said Desikan. “That is, if you don’t already have dementia, what is your yearly risk for AD onset, based on your age and genetic information. We think these measures of polygenetic risk, of involving multiple genes, will be very informative for early AD diagnosis, both in determining prognosis and as an enrichment strategy in clinical trials.” 
 
 To conduct the study, the research team analyzed genotype data from more than 70,000 AD patients and normal elderly controls who were participating in several projects, such as the Alzheimer’s Disease Genetics Consortium, the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. The team scrutinized the data for AD-associated single nucleotide polymorphisms (SNPs), which are variations of a single nucleotide or DNA building block that occur at a specific position in the genome. There is some SNP variation in genomic information in all humans, which affects individual susceptibility to disease. In this case, the researchers looked at SNPs linked to AD risk and for APOE status. Persons with the E4 variant in the APOE gene are known to be at greater risk of developing late-onset AD. 
 
 The researchers developed a continuous polygenic hazard score or PHS based upon this data to predict age-specific risk of developing AD, then tested it in two independent cohorts or defined groups of people. They found persons in the top PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Importantly, PHS also identified people who were cognitively normal at baseline but eventually developed AD. Even among people who did not have the APOE E4 allele, the most important genetic risk factor for AD, PHS informed age of onset; individuals with high PHS scores developed AD 10-15 years earlier than individuals with low PHS. 
 
 The authors found that PHS strongly predicted empirical age of AD onset and progression from normal aging to AD, with strongly associated neuropathology and biomarkers of AD neurodegeneration. 
 
 “From a clinical perspective, the polygenic hazard score provides a novel way not just to assess an individual’s lifetime risk of developing AD, but also to predict the age of disease onset,” said senior author Anders Dale, PhD, director of the Center for Translational Imaging and Precision Medicine and professor in neurosciences, radiology, psychiatry and cognitive science at UC San Diego School of Medicine. “Equally important, continuous polygenic testing of AD genetic risk can better inform prevention and therapeutic trials and be useful in determining which individuals are most likely to respond to therapy.” 
 
 The authors note several limitations to their study, beyond the need for broader and deeper validation studies. For example, their databases primarily represented individuals of European descent and thus are not indicative of AD incidence and genetic risk in other ethnicities, such as African-American or Latino. 
 
 “This limitation is an unfortunate product of available genetic studies. To have good predictive performance, the genetic risk score requires a large amount of data to train, but currently only European cohorts have reached this critical mass,” said co-first author Chun Chieh Fan, MD, in the Department of Cognitive Science at UC San Diego. 
 
 But “given the genome-wide association studies across ethnic populations that are emerging, the health disparities in the field of genetic prediction will be removed,” Fan added. 
 
 Co-authors include: Andrew Schork, Dominic Holland, Chi-Hua Chen, James B. Brewer, David S. Karow, Karolina Kauppi and Linda K. McEvoy, UCSD; Yunpeng Wang, UCSD, University of Oslo and Oslo University Hospital; Howard J. Cabral and L. Adrienne Cupples, Boston University School of Public Health; Wesley K. Thompson, Sankt Hans Psychiatric Hospital, Denmark; Lilah Besser and Walter A. Kukull, University of Washington; Aree Witoelar and Ole A. Andreassen, University of Oslo and Oslo University Hospital; Celeste M. Karch, Washington University, St. Louis; Luke W. Bonham, Jennifer S. Yokoyama, Howard J. Rosen, Bruce L. Miller, William P. Dillon, David M. Wilson and Christopher P. Hess, UCSF; Margaret Pericak-Vance, University of Miami; Jonathan L. Haines, Case Western Reserve University; Lindsay A. Farrer, Boston University School of Medicine; Richard Mayeux, Columbia University; John Hardy, University College London; Alison M. Goate, Icahn School of Medicine at Mount Sinai; Bradley T. Hyman, Massachusetts General Hospital; and Gerard D. Schellenberg, University of Pennsylvania Perelman School of Medicine. 
 
 Funding for this research came, in part, from the National Institutes of Health (NIH-AG046374, K01AG049152, R01MH100351), a National Alzheimer’s Coordinating Center Junior Investigator Award, a Radiological Society of North America resident/fellow award, a Foundation of the American Society of Neuroradiology Alzheimer’s imaging grant, the Research Council of Norway, the South East Norway Health Authority, the Norwegian Health Association and the KG Jebsen Foundation.
– You have one of six possible variations of the APOE gene, having inherited one variant—e2, e3, or e4—from each parent. Reporting in the journal Neuron, University of Hawaii researchers found that the brain development of children as young as preschool age with two copies of e4 or one of e4 and one of e2 seem most adversely affected—an intriguing find in light of previous research that has linked the e4 variant to Alzheimer's. Researchers scanned the brains of 1,187 healthy people between the ages of 3 and 20 and found, for instance, that the size of the hippocampus tends to be smaller in those with the e2/e4 combination. They also found some kids with e4 didn't perform as well on tests of memory, though they caught up with their peers by age 10, reports HealthDay News. And while brain researcher Rebecca Knickmeyer, who didn't participate in the study but wrote an accompanying editorial, says the variants aren't necessarily predictive and people shouldn't start testing their kids, the research suggests that Alzheimer's may in fact be a developmental disorder, not strictly an aging one, reports the Los Angeles Times. That raises the possibility that adjustments to "diet or cognitive training" early on could change someone's "trajectory," per Knickmeyer. Three in four people have at least one copy of e3, which seems to offer a protective effect. About 14% of people have an e4 variant, which has been linked with an elevated risk of Alzheimer's, but Knickmeyer points out that there are many Alzheimer's patients without e4, and many with e4 who never develop Alzheimer's. (Some research suggests that memories lost to Alzheimer's are actually retrievable.)