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Alzheimer’s genes and methylation

11 new genes that affect the risk for Alzheimer’s disease

Researchers identified 11 new genes that affect the risk for Alzheimer’s disease. The findings point to novel targets for preventing or delaying the disease.

Alzheimer’s disease is the most common cause of dementia in older adults. It affects more than 5 million Americans. A hallmark of the disease is the abnormal accumulation of amyloid protein in the brain. Until 2009, variants in only one gene, APOE, had been identified as a risk factor for late-onset Alzheimer’s disease, the most common form of the disorder. The list of known genetic risk factors has since grown to include several others.

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Large-scale analyses are needed to gain the statistical power to identify additional genetic risk factors. Scientists in the International Genomic Alzheimer’s Project (IGAP) have been working together since 2011 on genome-wide association studies (GWAS), which involve thousands of DNA samples and shared datasets. GWAS are aimed at detecting subtle genetic differences that are statistically associated with disease.

IGAP’s latest effort involved scanning the DNA of more than 74,000 older volunteers from 15 countries. Participants included people with late-onset Alzheimer’s disease and those free of the disorder. It’s the largest genetic analysis yet conducted in Alzheimer’s research. The work was supported in part by NIH’s National Institute on Aging (NIA) and other NIH components. The findings were reported online in Nature Genetics on October 27, 2013.

The scientists confirmed many of the previously identified genes associated with the onset and progression of late-onset Alzheimer’s. In addition, they identified 11 new genes associated with the disease: HLA-DRB5/HLA-DRB1, SORL1, PTK2B, SLC24A4/RIN3, ZCWPW1, CELF1, NME8, FERMT2, CASS4, INPP5D, and MEF2C. The study also highlighted another 13 variants that merit further analysis.

The findings strengthen evidence about the involvement of certain pathways in Alzheimer’s disease, including the immune response, inflammation, cellular protein trafficking, and lipid transport. They also add to evidence for other pathways that may influence disease development, including synapse function, cytoskeletal function, and specialized cells in the brain called microglia.

“Interestingly, we found that several of these newly identified genes are implicated in a number of pathways,” says Dr. Gerard Schellenberg of the University of Pennsylvania School of Medicine, who directs one of the major IGAP consortia. “Alzheimer’s is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play.”

Methylation Tied to Alzheimer’s

People with the neurodegenerative disease are more likely to have certain epigenetic patterns than those without.

In searching for epigenomic variations in people with and without Alzheimer’s disease, two groups have zeroed in on several genes at which methylation states correlate with having had the neurodegenerative disease. “The results are compelling and consistent across four cohorts of patients taken across the two studies,” Jonathan Mill of the University of Exeter who participated in both research projects, told New Scientist.

The results were published in two papers in Nature Neuroscience this week (August 17). In one study, the researchers analyzed genomic methylation patterns in the autopsied brains of 708 people; the other study looked at methylation patterns in brain samples from 122 deceased donors. Some of the participants had Alzheimer’s, others did not.

Several genes popped out as having different methylation states among the donors with Alzheimer’s. Among the few that overlapped in both studies was ANK1, a gene involved in the structure of the cell membrane. “This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease,” Simon Ridley, head of research at Alzheimer’s Research UK, which funded the studies in part, told New Scientist.

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https://clubalthea.com/2016/10/14/your-complete-dna-sequence-will-help-shape-the-future-of-medicine/

Epidemiology of Alzheimer’s Disease

Here are some sobering facts:

While estimates vary, studies to date find that as many as 5.1 million Americans age 65 and older have Alzheimer’s disease.
The greatest risk factor for Alzheimer’s is age. The number of people with the disease doubles for every 5-year interval beyond age 65.
The Bureau of the Census estimates that the number of people age 65 and older in the United States will almost double to 74.1 million by 2030.
Further, the number of Americans over age 85—those at highest risk—is expected to increase from 5.5 million in 2010 to 9.1 million in 2030.

The implication is clear: Unless we find effective interventions to prevent or treat Alzheimer’s disease, the number of affected Americans will soar in the coming decades.

Preparing for the human, financial, and societal challenges of Alzheimer’s disease and related dementias requires an understanding of the disease not just at the level of molecules and cells, but at the level of communities and populations. The National Institutes of Health (NIH) supports a broad range of population studies to address these and related questions.

Studies to date have told us a great deal about who may be at risk for Alzheimer’s, factors that influence the disease, and societal impacts, but it is critical to refine and update this knowledge. Researchers are expanding our understanding of this complex and devastating disease to further the 2025 goal of identifying effective interventions by addressing:

Who develops Alzheimer’s disease, and who seems to be protected?
What other conditions are associated with development of the disease?
What are the financial, economic, social, and policy costs of the disease?

The NIH-led Precision Medicine Initiative^®, which plans to launch a national cohort study of a million or more Americans to propel the understanding of diseases such as Alzheimer’s and related dementias, will take population studies to the next level. The Precision Medicine Initiative’s ultimate goal is to develop therapies that take into account the variability in genes, environment, and lifestyle of each patient.

Progress in Identifying Risk and Protective Factors

Advancing age and genetics are known risk factors for Alzheimer’s disease, but it is becoming evident that a highly complex mix of genetic, environmental, and lifestyle factors may also influence the disease’s onset and progression. Scientists are trying to not only identify risk factors, but tease out how these factors interact with one another, in the search for effective interventions. Recent studies have suggested directions to pursue:

Dementia risk and commonly used drugs

Older adults who take anticholinergic drugs may be at significantly higher risk of developing dementia—and the greater the use of the drugs, the higher the potential risk. Anticholinergics are prescribed for many health conditions, including overactive bladder, seasonal allergies, and depression. Some are available over the counter and are often used as sleep aids. These medications block a neurotransmitter, acetylcholine, in the brain and body and may cause side effects such as impaired cognition, especially in older people.

This side effect was thought to be reversible once the person stopped taking the medication. However, researchers showed that these medications may have a lasting impact (Gray et al., 2015). By analyzing records and data on drugs prescribed over 10 years to 3,434 adults age 65 and older, they calculated cumulative exposure to drugs with strong anticholinergic effects. They found that 78 percent of the study participants used anticholinergics at least once in 10 years and that nearly 800 participants (23 percent) developed dementia, usually Alzheimer’s. They noted that the higher the use of anticholinergics, the higher the risk of dementia, regardless of whether the drugs had been taken recently or years ago.

The findings suggest that physicians treating older people should prescribe alternatives to anticholinergics when possible or lower doses of the drugs. More studies are needed to determine to what extent stopping anticholinergics can reduce the risk of developing permanent dementia.

Is reduced brain blood flow a risk factor?

Having a maternal history of Alzheimer’s disease may put one at greater risk for developing Alzheimer’s-associated reduced blood flow in the brain by midlife. Scientists studied cerebral blood flow using a technique called arterial spin labeling magnetic resonance imaging in middle-aged and older volunteers. The study involved 252 cognitively normal people with an average age of 59 and 75 volunteers with an average age of 75. People in the older group were either cognitively normal, had mild cognitive impairment (MCI) or had Alzheimer’s disease (Okonkwo et al., 2014).

The researchers found that the older participants with MCI or Alzheimer’s disease showed reduced blood flow to the frontoparietal cortex and hippocampus. Reductions in blood flow to these brain regions were also seen in the middle-aged volunteers with normal cognition but who had a maternal history of Alzheimer’s disease. This finding suggests reduced cerebral blood flow in midlife might be a marker for Alzheimer’s risk.

Brain amyloid, sleep-disordered breathing, and mild cognitive impairment

Sleep disturbances, including sleep apnea and other abnormal breathing patterns, are common in people with MCI and Alzheimer’s disease. Researchers studied the possible link between sleep disturbances and levels of brain beta-amyloid in eight cognitively normal volunteers (average age, 69) and five with MCI (average age, 75) (Spira et al., 2014).

For two consecutive nights, the participants’ sleep and breathing patterns were followed by tests that monitor body functions such as eye movements, muscle activity, and heart rhythm during sleep. Their blood oxygen levels and brain beta-amyloid burden were measured as well.

Among participants with MCI, greater severity of sleep disturbance and lower blood oxygen levels were strongly associated with higher levels of brain beta-amyloid deposition. This association was not seen in volunteers with normal cognition.

These results suggest that in people with MCI, abnormal breathing during sleep may contribute to beta-amyloid deposition and possibly speed progression to Alzheimer’s disease. In addition, most of the MCI participants in this study were found to have moderate to severe disordered breathing during sleep that had not been previously diagnosed, compared with only one of the eight participants with normal cognition. Increased clinical screening for sleep-disordered breathing could aid the identification of people at risk for developing Alzheimer’s disease.

BDNF proteins may protect against dementia

Brain-derived neurotrophic factor (BDNF) is a protein found in the blood and brain that promotes the survival of neurons and long-term memory in animal models. New research suggests that BDNF also may help maintain cognitive health in some older people (Weinstein et al., 2014).

Researchers measured BDNF levels in serum samples from 2,131 volunteers from the NIH-supported Framingham Heart Study (whose average age at the start of this particular study was 72) and then tracked their cognitive function over 10 years. During the follow-up period, 140 of the participants developed dementia, including 117 with Alzheimer’s disease.

Participants with higher serum BDNF levels at the start of the study were significantly less likely to develop dementia than those with lower BDNF levels. The reduction in dementia risk was 50 percent for those with the highest serum BDNF levels compared to those with the lowest. Of note, the association between higher BDNF and lower dementia risk was seen only in women, people older than 80, and people with college degrees.

This research suggests that further study should explore treatment with BDNF in preventing dementia, especially in women and in older and more highly educated people. Because BDNF levels can be increased by physical activity and reduced caloric intake, the findings also suggest that exercise and a healthy diet may help reduce dementia risk—but more research is needed.

Diabetes may speed age-related cognitive decline

Diabetes is an established risk factor for Alzheimer’s disease. A research team has now found that diabetes may also increase one’s risk of age-related cognitive decline (Rawlings et al., 2014). The team followed 13,351 black and white volunteers, age 48 to 67 years, participating in the NIH-supported Atherosclerosis Risk in Communities (ARIC) Study. Participants received cognitive tests at the start and twice more during the 20-year study that began in 1985.

After two decades, the researchers found, cognitive decline was 19 percent more severe in participants who had diabetes at the start of the study than in those who were diabetes-free. Of the cognitive abilities tested, processing speed and executive function were the most strongly affected; a smaller impact was seen on verbal memory.

The participants’ blood sugar levels, which are elevated in prediabetes and diabetes, were also measured at the start of the study. People with levels indicative of prediabetes at the start of the study showed greater cognitive decline than those with normal levels, as did people whose diabetes was poorly controlled or of longer duration. The association between diabetes and cognitive decline was similar for black people and white people.

This study suggests that having diabetes or prediabetes in middle age significantly increases one’s risk of cognitive decline in later years. As diabetes and prediabetes are usually treatable, screening for these conditions and managing diabetes may influence cognitive decline. Clinical trials have not yet demonstrated specifically that diabetes management will reduce the risk of cognitive decline or Alzheimer’s. As studies pursue this question, there are many reasons for people to manage diabetes and prediabetes.

Retinoic acid can stimulate the innate immune system into eliminating HIV-infected cells

A new study conducted by researchers at the San Francisco VA Medical Center (SFVAMC) observes that pharmacological enhancement of the immune systems of HIV patients could help eliminate infected cells, providing an important step in the ongoing quest to find a lasting HIV cure.

The study, titled “Stimulating the RIG-I Pathway to Kill Cells in the Latent HIV Reservoir Following Viral Reactivation,” addresses the persistence of latent HIV reservoirs in patients who are on antiretroviral therapy. Latent HIV reservoirs are established during the earliest stage of HIV infection, and they are infected with HIV even though they are not actively producing the virus. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive. When a latently infected cell is reactivated, the cell begins to produce HIV again. For this reason, antiretroviral therapy cannot cure HIV infection.

According to the study, HIV latency depends on immune system suppression, including immune system responses that detect viral pathogens and induce the destruction of infected cells.

According to the study, HIV latency depends on immune system suppression, including immune system responses that detect viral pathogens and induce the destruction of infected cells. The study shows that retinoic acid can stimulate the innate immune system into eliminating HIV-infected cells. In particular, acitretin, an FDA-approved retinoic acid derivative, can increase HIV transcription in the latent HIV reservoir and allow the innate immune system to target and destroy HIV infected cells.

“The current model of HIV treatment can help manage symptoms and increase the quality of life for patients, but it is not a cure,” says the study’s lead author Peilin Li, MD, MHS, Research Associate at SFVAMC, and an Assistant Adjunct Professor at the University of California, San Francisco School of Medicine. “HIV patients on antiretroviral medications must take them for the rest of their lives, and they often experience adverse side effects.”

“It is important to strengthen the body’s defense system against the virus. This will help the antiretroviral drugs do their job,” says Dr. Li. “We want the immune system to recognize and kill the virus. By boosting immune response, the body will be able to kill cells in the latent HIV reservoir that are still capable of producing HIV.”

Dr. Li is hopeful that the study’s findings will lead to new ways of thinking about treating HIV. “I think this can open new doors to fighting HIV. With further research, we can create clinical solutions that can boost immune system functioning and find a lasting cure for this disease. This is a patient-centered approach to HIV treatment that moves beyond treating symptoms and toward whole health.”

More information: Peilin Li et al. Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation, Nature Medicine (2016). DOI: 10.1038/nm.4124

. In particular, acitretin, an FDA-approved retinoic acid derivative, can increase HIV transcription in the latent HIV reservoir and allow the innate immune system to target and destroy HIV infected cells.

More information: Peilin Li et al. Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation, Nature Medicine (2016). DOI: 10.1038/nm.4124