Herpes Virus Infection May Contribute to Alzheimer’s Disease

A virus with a nearly 100% infection rate could increase the risk of developing Alzheimer’s disease.

The idea that Alzheimer’s disease may be caused in part by microbial infections has been around for decades and recently started to gain increased support with the scientific community. Hundreds of studies have observed an increased incidence of many types of infections in Alzheimer’s disease patients. However, most of these studies could not establish a direct causative link, and they provided little insight into the mechanisms of this interaction.

Recently, a study published in the journal Neuron provided some of the strongest evidence yet for the infectious theory of Alzheimer’s. Researches from the Icahn School of Medicine at Mount Sinai collected portmortem brain samples from people with preclinical Alzheimer’s disease, as well as healthy controls, and used an advanced laser-capture technology to analyze the gene expression in their neurons. They then constructed computational models to predict which patterns of gene expression were associated with Alzheimer’s disease. They noticed that many of these genes that had different expression in the Alzheimer’s brains played a role in immune system’s response to viral infection.

This figure from the paper illustrates how researchers employed computational models to connect viral infection rates with the signatures of Alzheimer’s disease.

To further investigate this viral connection, the researchers analyzed the levels of viral RNA in each of the brain samples. They found that the Alzheimer’s brains had significantly more RNA from two types of human herpes viruses (HHV): type 6A and type 7. (Note that HHV is not to be confused with human simplex virus [HSV], which is a sexually transmitted infection.) This suggests that people with Alzheimer’s disease have higher rates of HHV infection in their brains.

Furthermore, they found that the viral infections could perturb many genes that are linked to the development of Alzheimer’s disease, including BACE1, which helps create the sticky plaques that are characteristic of the Alzheimer’s brain. HHV-6A also decreases expression of a microRNA gene called miR-155. When they created mice that lacked expression of miR-155, these mice developed Alzheimer’s plaques in their brains, suggesting that this gene could be an important link between herpes infection and Alzheimer’s.

This figure from the paper shows the complex network of genes that may link herpes virus infection with the development of Alzheimer’s disease.

This study is different from previous ones in several ways. It includes a large sample size from throughout the United States, which provides higher statistical rigor to the conclusions. It also suggests a possible mechanisms by which viral infections could contribute to the development of Alzheimer’s disease via disruption of neuronal gene expression. The results support the intriguing possibility that the toxic amyloid-beta protein, which has long been thought to be the primary cause of Alzheimer’s disease, could actually be a beneficial response to viral infection, a theory that I described in a previous article. While this study is not yet conclusive proof that herpes infection can directly lead to Alzheimer’s disease, it opens that door for many interesting new avenues for research that should be investigated further.

A connection between herpes and Alzheimer’s disease is both troubling and encouraging. HHV types 6 and 7 are extremely common, with nearly 100% of individuals infected by age 3. Most of us are likely infected as infants through the saliva of our parents or other relatives. After the initial infection, the virus becomes latent and remains circulating in the bloodstream for life. For most of us, HHV-6 and HHV-7 infections are completely asymptomatic. However, as we grow older, our immune systems weaken, allowing these viruses to travel from the bloodstream to the brain. Some reports suggest that the resulting neuroinflammation could contribute to common age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

Yet these results also offer hope. If microbial infections such as HHV are the initial cause of Alzheimer’s disease, this suggests that we could treat the disease using immunosuppressant or antiviral drugs. Should future studies confirm this to be true, this could be a huge boon for the development of effective Alzheimer’s therapies.

 

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Sniffing Out Dementia: What Your Nose Can Tell You About Your Brain

Detecting Alzheimer’s disease can be tricky, especially in its earliest stages.  Alzheimer’s is frequently misdiagnosed, due in part to the expensiveness and complexity of the current diagnostic tools. According to a 2012 examination of the National Institute on Aging’s Alzheimer’s Disease Centers, physicians may fail to detect more than 1 in 10 Alzheimer’s cases.

Alarmingly, some centers also had a false positive rate of more than 50%, meaning that half of the patients who were diagnosed with Alzheimer’s actually did not have the disease. The symptoms of these individuals may have been due to other conditions such as vascular dementia or thyroid dysfunction. An incorrect diagnosis could have resulted in the true cause of these patients’ memory loss going untreated (see Is It Really Alzheimer’s? 10 common misdiagnoses you should know about).

However, there might be a simpler and more cost-effective way to help diagnose Alzheimer’s disease: your sense of smell. As strange as it sounds, your nose can provide some key insight into the health of your brain.

Sniffing Out Dementia

Just like vision and hearing, our sense of smell tends to gradually deteriorate as we get older. Anosmia, the complete inability to smell, affects more than 50% of people over the age of 65 and 75% of people over 80. This likely contributes to the loss of appetite that many elderly people experience, as our sense of smell is closely tied to our ability to taste and enjoy food. Changes in the nose’s smell receptors and in the parts of the brain responsible for olfactory processing are likely to blame for age-related anosmia.

While anosmia is common among all elderly individuals, it seems to be especially prevalent in certain neurological conditions, including dementia. The frequency of anosmia among dementia patients has been known since the 1970s, but only recently has this observation begun to attract the attention of researchers.

The ability to identify different odors is frequently impaired in early-stage Alzheimer’s patients, with complete anosmia appearing in the later stages of the disease. A small study involving 90 patients with mild cognitive impairment found that individuals with greater olfactory impairment were more likely to progress to Alzheimer’s disease during the two-year study period. Many of these patients were unaware of their own inability to smell.

#AlzFact: Peanut butter might help identify early-stage Alzheimer’s. A small study from the University of Floria found that Alzheimer’s patients have difficulty smelling peanut butter, especially with the left nostril.

An olfactory assessment called the Pocket Smell Test has shown promise as a diagnostic tool for Alzheimer’s disease. In a small 60-patient study, this simple three-item test was able to distinguish Alzheimer’s from vascular dementia and major depressive disorder with 95% accuracy, a dramatic improvement from the 50% false-positive rate by NIA physicians that I described earlier. All of the Alzheimer’s patients in the study had two or three incorrect responses to the smell test, while nearly all of the vascular dementia and depression patients had zero or one incorrect response.

Another small study suggested that smell tests could also be used to distinguish Alzheimer’s from semantic dementia, frontotemporal dementia, and corticobasal dementia. Notably, smell tests would probably be less useful for distinguishing Alzheimer’s from Parkinson’s disease, since anosmia seems to be equally common in these two conditions. However, simple smell-detection tests could serve as an inexpensive method to improve the accuracy of Alzheimer’s diagnoses when combined with more traditional diagnostic tools.

Could Infections Be To Blame?

The reasons for the prevalence of anosmia in patients with Alzheimer’s or other dementias remain poorly understood. One interesting hypothesis, first proposed back in 1986, posits that the olfactory nerve (which transmits smell information from the nose to the brain) could serve as a potential entry point for environmental toxins or microbial agents to reach the brain. This has since been dubbed the olfactory vector hypothesis.

The brain is protected from external agents by the blood-brain barrier, which prevents most microbes and chemical substances from crossing between the nervous system and the blood. Olfactory neurons are unusual in that they are directly exposed to the external environment, making them vulnerable to infiltration. Unlike any other sensory cells, olfactory neurons connect directly to the brain without any intermediate synapses. Microbes can taken advantage of this direct connection as an ideal route to bypass the blood-brain barrier.

Olfactory neurons (shown in yellow) serve as a direct connection between the nasal cavity and the brain. Image source

Animal studies show that the viruses that cause polio, influenza, rabies, hepatitis, and herpes are all capable of infecting the brain via the olfactory nerve. In addition, many environmental toxins including metals, chemicals, and nanoparticles can be taken up by olfactory neurons and transported to the brain. This may help explain why prolonged exposure to air pollution or certain industrial chemicals can greatly increase the risk of Alzheimer’s (see Air Pollution, Aluminum, and Vitamin D Deficiency Linked to Dementia Risk).

The olfactory vector hypothesis remains a speculative model, and more evidence is needed to prove whether infiltration of the brain by external agents via the olfactory nerve can lead to Alzheimer’s. It is an intriguing idea that certainly warrants further study.

 

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