Monthly Archives: September 2017

New Alzheimer’s Study Sheds Light on the Mysterious Tau Protein

If you’re a regular reader of AlzScience, you know that Alzheimer’s disease is believe to be caused by two toxic proteins that accumulate in the brain: amyloid-beta and tau. (For more background, see Alzheimer’s Disease: A General Overview.) Recently, it’s been shown that tau is actually a better predictor of Alzheimer’s disease progression than amyloid-beta, suggesting that this mysterious protein might have a larger role in the disease than we once thought.

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Amyloid-beta plaques and tau tangles form toxic clumps in the brains of Alzheimer’s patients. Source

A study published last week in Nature provided deeper insight into tau. The scientists were interested in studying the ApoE gene, which is considered the strongest genetic risk factor for Alzheimer’s (see The Genetics of Alzheimer’s Disease.) Specifically, having two copies of the ApoE4 allele increases your risk of Alzheimer’s by nearly 15 times, and it’s been shown that people with this allele have greater buildup of amyloid-beta in their brains. However, the researchers in this study wanted to see whether ApoE could also affect tau accumulation.

To test this, they used genetically engineered mice that overexpress the tau gene, causing them to develop many of the symptoms of Alzheimer’s. They then tampered with these mice’s genes so that they would also overexpress ApoE4. (Note: Overexpressing the tau and ApoE4 genes means those genes were more active than they normally would be in the mice. Think of it like a light switch stuck in the “on” position.) They found that these mice had more tau in their brains, and also more severe brain shrinkage due to neuronal death.

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This figure from the paper shows brain slices from different mice. The far left panel shows a healthy mouse brain. The next two (representing the ApoE2 and ApoE3 alleles) have slightly more brain atrophy, while the harmful ApoE4 allele causes very severe atrophy. In contrast, the far right brain, which does not express ApoE at all, has relatively little atrophy.

To figure out how ApoE4 might be causing more tau accumulation, the researchers looked at the mice’s microglia, the immune cells of the brain. The microglia overexpressing ApoE4 tended to overreact to infections, releasing high amounts of pro-inflammatory molecules called cytokines. Neurons and other brains cells are very sensitive to cytokines, and high levels might cause them to produce more tau.

Finally, the researchers turned to human research. They used postmortem brain tissues taken from people who had tauopathies, which are diseases caused by accumulation of tau (but not amyloid-beta) in the brain.  The people possessing the ApoE4 allele had more severe neurodegeneration and greater tau buildup in certain areas of the brain.

Overall, this study demonstrates that ApoE4 does not only act on amyloid-beta, but tau as well. It gives strong support to the notion that tau may be as important as amyloid-beta in understanding the pathology of Alzheimer’s disease. In an interview with Science News, Harvard neurologist Dennis Selkoe described this deadly combination of amyloid-beta and tau as a “double whammy.” Yet this study provides hope that future therapies against ApoE4 could be capable of halting both of these toxic proteins at once.

 

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Artificial Intelligence Could Help Us Predict Alzheimer’s Disease

Many experts agree that preventing the progression of Alzheimer’s disease is much more effective than trying to reverse it once the damage is done. This makes early diagnosis critical. Unfortunately, most Alzheimer’s patients are not diagnosed until relatively late in disease progression, when toxic amyloid plaques have already accumulated in their brains to potentially irreversable levels. However, this might soon be changing with the recent surge in artificial intelligence technology.

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This diagram shows the stages of Alzheimer’s disease, which can begin up to 20 years before diagnosis. Most patients are not diagnosed until the mild or moderate stage, since this is when cognitive impairments become more noticeable. Image Source

This research was described in a paper published in Neurobiology of Aging by scientists from McGill University in Canada. Their goal was to create an algorithm to predict whether people with mild cognitive impairment would progress to dementia. They utilized a noninvasive technology called positron emission tomography (PET). PET involves the patient lying inside a donut-shaped machine, similar to a CAT scanner. The machine can measure which areas of the brain have higher or lower activity levels based on how much glucose each brain region is consuming.

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A patient lying inside of a PET machine. Image Source

The researchers used PET scans from 273 patients with mild cognitive impairment. 43 of these patients were diagnosed with probable Alzheimer’s disease at a follow-up appointment two years later. Then the scientists trained an artificial intelligence algorithm to predict which patients would develop Alzheimer’s based on their PET scans.

They used the data to generate the map of the brain that’s shown below. The red-colored areas indicate a higher odds ratio (OR). This means that unusual activity levels in those brain areas are associated with an increased risk of Alzheimer’s disease. For example, an odds ratio of 3 means that a person with unusual activity levels in that brain area is 3 times as likely to develop Alzheimer’s compared to someone with normal activity levels.

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Figure 2 of the paper shows which brain regions are the most important for predicting the risk of Alzheimer’s disease.

The algorithm was able to predict which patients would progress to Alzheimer’s disease with an accuracy of 84%. This is better than any previously-developed PET algorithms, and comparable to more invasive diagnostic techniques such as spinal taps. This is exciting news because it suggests that a painless, noninvasive technology can be used to predict Alzheimer’s disease with a fairly high degree of accuracy.

As always, we have to point out a few problems with this study. For one thing, it’s impossible to know for sure whether the patients’ Alzheimer’s disease diagnoses performed by doctors at the follow-up appointment were actually correct. This is because many forms of dementia have similar cognitive symptoms, and can be easily confused during diagnosis. Parkinson’s disease, vascular dementia, or even a urinary tract infection can be misdiagnosed as Alzheimer’s disease. (For more info see Is it really Alzheimer’s? 10 common misdiagnoses you should know about). Only a postmortem brain analysis can reveal for sure whether the patients truly had Alzheimer’s. This muddles our ability to judge how accurate the algorithm really was.

Another problem is that PET scans can be quite expensive, costing upwards of $7,000. If a patient is incorrectly diagnosed with Alzheimer’s, this could lead to futher costs for medication to treat a disease they don’t actually have. Finally, while the mild cognitive impairment stage is earlier than most Alzheimer’s patients are diagnosed, it can still be up to ten years after the true beginning of the disease. We still have no reliable way to make diagnoses that early. Nonetheless, this study is at least a step in the right direction. With future advances in artificial intelligence, we might be able to improve our diagnostic accuracy at earlier stages of the disease.

 

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