Tag Archives: tau

Amyloid-Beta: Villain or Hero in Alzheimer’s Disease? (Podcast)

Last week I was interviewed on Straight from a Scientist, a podcast series where scientists talk about their research for a general audience. In Part 1, which you can listen to here, we had an informal conversation about my research and background. You can now listen to Part 2, a roundtable segment where the host, Connor Wander, and I discuss current topics in Alzheimer’s disease research, including a new look at the physiological roles of amyloid-beta. Enjoy!


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Vascular Damage May Affect Progression to Alzheimer’s Dementia


Guest author: Rachana Tank has a master’s degree in Neuropsychology from Maastricht University in the Netherlands. Her goal is to pursue a PhD in psychology exploring cognitive ageing, where her research interests lie.

As we grow older, we tend to become a little forgetful which is thought to be a normal part of ageing, but when does forgetfulness turn into abnormal ageing? Sometimes even slight but noticeable changes in thinking skills can be symptoms of an underlying issue. Alzheimer’s dementia is a continuous process, a progression taking place over many years, during which individuals experience considerable deficits before reaching clinical dementia. Stages leading up to Alzheimer’s dementia are referred to as predementia stages and are considered to be on the spectrum of Alzheimer’s dementia. In such stages, cognitive deficits are typically experienced as deterioration of memory, attention, and language skills.

Predementia stages can include individuals who self-report a decline in cognitive abilities (subjective cognitive impairments), or experience cognitive impairments that can be diagnosed by standardised testing (mild cognitive impairments). Both of these can, but not always, indicate an initial phase of neurodegeneration that may suggest they are in an early stage of Alzheimer’s dementia.


The difference between normal brain ageing (purple line) and stages of cognitive decline experienced as part of abnormal brain ageing in dementia. Image source

Individuals with subjective or mild cognitive impairments tend to have a higher incidence of future cognitive decline than the general population and more often show Alzheimer related pathology. However, it is still difficult to predict which individuals in these stages will progress to Alzheimer’s dementia.

Differentiating between those who will progress and who will not is a difficult task. However, biomarkers can be utilised to indicate the presence of Alzheimer’s pathology to detect and diagnose predementia stages. Namely, amyloid protein plaques and neurofibrillary tau tangles are the hallmarks of Alzheimer’s disease, with amyloid pathology being the earliest identifiable change in the brain. Although amyloid and tau have both been fundamental to understanding and estimating the pathological cascade, there is a lot of emerging evidence to suggest that it is not just tau and amyloid in isolation that contribute to progression of Alzheimer’s pathology and subsequent cognitive symptoms.

As evidence indicates there is more to consider than amyloid and tau, recent research, including my master’s research, investigates mixed Alzheimer’s pathology in early stages. Mixed pathology refers to hallmark Alzheimer pathology, such as amyloid and tau, that coexist with additional abnormalities such as vascular disease. Vascular disease is of particular interest in predementia stages as it is the most common disease to coexist with typical Alzheimer pathology early in the disease process.

Vascular disease can be defined as any condition that affects the arteries, veins, and capillaries responsible for carrying blood to and from the heart. Vascular damage can compromise brain health by reducing blood flow to vital areas, leading to loss of neurons. Such damage to the brain affects how well certain areas function, sometimes leading to decreased cognitive abilities such as language difficulties, attention problems or memory issues. There is evidence that vascular disease shortens time to progression when coexisting with traditional Alzheimer pathology. However, the mechanisms by which they may interact is not known.


Arterial plaques are one example of vascular disease. Image source

My research investigated mixed pathology in 269 memory clinic patients aged 39 or older with subjective or objective cognitive impairments. Levels of amyloid burden and vascular damage were recorded at baseline and at follow-up between 1 and 5 years later. Those who progressed to Alzheimer’s dementia were then compared to those who did not. Vascular damage was assessed using MRI scans, and level of amyloid pathology was determined via cerebrospinal fluid samples.

The results of my research found that Alzheimer’s disease patients with vascular damage had less amyloid in their brains than Alzheimer’s patients who did not have vascular damage. This suggests that vascular damage may worsen the effects of amyloid plaques on cognitive decline and Alzheimer’s. These findings are compatible with other studies that investigated vascular damage in relation to amyloid burden.

Different amounts of amyloid in patients did not show any direct relationship with vascular damage, suggesting that the presence or absence of vascular disease does not influence the presence of Abeta. However, both vascular damage and amyloid pathology increased the risk of progressing to Alzheimer’s dementia significantly, and 93% of individuals who progressed to Alzheimer’s dementia showed abnormal levels of both amyloid and vascular pathology, indicating that both contribute to the development of Alzheimer’s dementia. These research insights help us to better understand early stages and the influencing factors involved. This allows us to develop interventions, for example, promoting cardiovascular health in those at risk by encouraging memory clinic patients to participate in exercise programs.

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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.


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.

Screenshot 2017-09-29 17.29.13

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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Breakthrough in Alzheimer’s Research: What We Thought About Tau Tangles May Be All Wrong

The main hallmark of Alzheimer’s disease is the accumulation of toxic protein species in the brain. These toxic deposits include senile plaques (made of the amyloid-beta protein) and neurofibrillary tangles (made of the tau protein). In general, recent drug development research for Alzheimer’s has focused on targeting amyloid-beta. This is because previous research suggested that amyloid-beta is responsible for initiating a set of chemical reactions that lead to the phosphorylation of tau. This p-tau (phosphorylated tau) is then more prone to sticking to itself and forming tangles. Thus, the thinking was that if we could get rid of amyloid-beta, tau would no longer form tangles, allowing us to eliminate both toxic proteins at once.


Plaques and tangles in a normal and Alzheimer’s disease brain.

However, a study published this week in the journal Science may completely change how we think about amyloid-beta and tau. Researchers from Australia looked at enzymes of the p35 family, which are believed to mediate amyloid-beta’s ability to initiate p-tau formation. They focused on a member of this protein family called p35-delta (p35D), after determining that it was the only p35 protein that localized to synapses (the communication junctions between neurons.)

The exciting part of this study came when the researchers generated Alzheimer’s mice that lacked the gene for p35D. These mice experienced exacerbated symptoms of Alzheimer’s disease, including worsened excitotoxicity, memory loss, and premature death. The researchers determined experimentally that these worsened symptoms were dependent on p35D’s ability to create p-tau. In other words, it seems that the presence of p35D (and in turn, the presence of p-tau) was actually protecting the mice from more severe symptoms of Alzheimer’s disease.

This study is big news in the field of neuroscience because it suggests that the formation of tangles by the p-tau protein may be helpful rather than harmful. Whereas in the past scientists have viewed tangles as a harmful side effect of amyloid-beta plaques, these new results indicate that p-tau may actually be a beneficial reaction to the plaques which keeps their toxicity in check. This is consistent with additional data from the study showing that humans with Alzheimer’s disease have reduced expression of p35D. The authors of the paper suggested that a decline in p35D expression, and in turn a decline in p-tau levels, may be a major contributor to the development of Alzheimer’s disease.

Alzheimer’s researchers around the world are very excited about this paper and the ramifications it could have for future studies. Where previously we had been trying to deplete toxic p-tau, this strategy may actually worsen the disease. Rather, perhaps we should be trying to increase levels of p35D and/or p-tau in early Alzheimer’s patients in order to prevent disease progression. It’s possible that this study may also help explain why approximately 1 in 5 elderly adults contain the signature pathology of Alzheimer’s in their brains and yet do not experience any cognitive deficits. Perhaps these individuals benefit from higher expression of p35D which helps fight of the toxicity of amyloid-beta. Future studies will investigate whether this is indeed the case.

As always, we must interpret these results with caution. Since this study was based in mice, a lot of additional research will be needed to determine whether similar neurochemical pathways occur in humans and, if so, whether these can be utilized to design a preventative treatment for Alzheimer’s. Only time can tell how far-reaching the impacts of this study will be.


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A New Possible Mechanism for the Development of Alzheimer’s Disease


Alzheimer’s disease is characterized by the buildup of toxic protein species in the brain. One of these proteins is tau. Tau normally is involved with stabilizing the cytoskeleton that gives neurons their structure. However, in people with Alzheimer’s disease, certain enzymes attach too many phosphate groups to tau. Molecules of this hyperphosphorylated tau can stick to each other to form tangles of fibers that accumulate inside of neurons.

It was originally assumed that these tau tangles contributed to neuronal death in Alzheimer’s disease. However, it has since been discovered that less than 17% of neurons in an Alzheimer’s brain contain tangles, even in the most advanced disease stages. Additionally, it was recently shown that the tangles are not associated with memory deficits or neuronal death in a mouse model. This has led some researchers to speculate that the soluble form of tau, which does not accumulate into tangles, might actually be the toxic species.

New Results

In a study published last week in Nature Medicine, researchers uncovered a possible mechanism for the toxicity of soluble tau. At the time, they were studying mice with a mutation that causes them to express high levels of tau. The researchers noticed that a particular fragment of tau called ∆tau314 (named so because it had been cleaved after the 314th amino acid) was more abundant in the mice that had greater memory impairment. They then looked at human brain tissue from 85 elderly subjects and found that tau fragments similar to ∆tau314 were present at significantly higher levels in cognitively impaired subjects compared to non-impaired controls. They demonstrated experimentally that this fragment was soluble and did not form the large tau tangles.

Subsequent experiments determined that an enzyme called caspase-2 was capable of cutting the ∆tau314 fragment from full-length tau. When they reduced the levels of caspase-2 in the brains of their Alzheimer’s mice, the levels of ∆tau314 decreased and the mice showed complete reversal of cognitive impairment.

The researchers were also able to determine the mechanism by which ∆tau314 leads to cognitive impairment. Previous studies had shown that in Alzheimer’s disease, tau improperly localizes to dendritic spines, the part of the neuron where it receives communicative inputs from other neurons. These communication sites can malfunction when too much tau is present. The researchers created mice expressing a form of tau that was resistant to cleavage at the 314th amino acid. They found that this form of tau did not localize to dendritic spines. Additionally, the mice did not experience any cognitive impairment or neurodegeneration, despite expressing high levels of this modified tau.

The main conclusion of this study was that in order for tau to induce the pathology of Alzheimer’s disease, it must first be cut at the 314th amino acid by caspase-2. This is an intriguing result, as it suggests that caspase-2 might be a useful therapeutic target for future drug research. In theory, if we can prevent caspase-2 from cutting tau, this could in turn prevent tau from causing malfunctions in dendritic spines. In addition, this study provides further support for the hypothesis that soluble tau, rather than insoluble tau tangles, is the more harmful species in Alzheimer’s disease.

An important caveat of this study is that it was performed almost exclusively on mice. These mice are only a simulation of human Alzheimer’s disease, and thus the same mechanisms may not translate to humans. Though significantly higher levels of ∆tau314 were found in cognitively impaired human brains, further research is needed to determine whether blocking caspase-2 cleavage of tau offers the same benefits in humans as it does in mice.

Additionally, the mice in question only simulated the tau pathology of Alzheimer’s. Tau is only one aspect of human Alzheimer’s disease. Other relevant pathologies include beta-amyloid plaques, neuropil threads, and neuroinflammation. Thus, it seems unlikely that eliminating the toxicity of tau could entirely reverse the disease in humans. A more likely scenario is that a caspase-2 drug therapy might be combined with other drugs that target the other pathological agents.

Despite these caveats, this paper represents an exciting development in Alzheimer’s disease research. Only time can tell whether it will translate to human drug candidates down the road.


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Research Highlights from the Alzheimer’s Association International Conference

This year’s Alzheimer’s Association International Conference took place July 22-28 in Toronto. The meeting brings some of the world’s leading Alzheimer’s researchers together to discuss their latest findings. I’ve compiled brief descriptions for some of the most exciting research presented at the meeting.

Mental Stimulation Greatly Influences Risk of Dementia

An unhealthy “Western” diet is associated with an increased risk of many health problems, including dementia. However, results presented at AAIC suggest mental stimulation in the form of higher education, a cognitively complex job, and/or social engagement can reduce the risk of cognitive decline in elderly adults, even those with a poor diet. Additionally, the highly-publicized ACTIVE study found that elderly subjects who participated in 10 years of regular cognitive training (similar to brain-training games like Luminosity) had a 48% reduced risk of dementia during the course of the study. Read more

Symptoms Checklist May Aid in Earlier Diagnosis of Alzheimer’s

Researchers have defined a new later-life neuropsychiatric condition called Mild Behavioral Impairment (MBI), which may be a precursor for Mild Cognitive Impairment and/or dementia later in life. The symptoms associated with MBI are grouped into five broad categories: mood, impulse control, apathy, social appropriateness, and psychosis. A recent study found that more than 80% of elderly adults at a memory clinic displayed at least one symptom of MBI, and that the symptoms were associated with increased caregiver burden. The researchers plan to refine the MBI checklist to be applicable to younger, non-demented subjects. Read more

Alzheimer’s Patients Receiving Treatment Have Reduced Mortality and Financial Burden

The medications for Alzheimer’s disease currently on the market can decrease the rate of cognitive decline but do not slow the overall progression of the disease. However, new results suggest that receiving treatment can reduce both mortality rates and medical costs for Alzheimer’s patients post-diagnosis. Patients who took dementia medications had a 28% reduced risk of dying during the approximately 2-year course of the study, and also paid more than $1,000 less each month in healthcare costs. Read more

High Cost of Preventable Hospitalizations Among Alzheimer’s Patients

A recent study shows that 1 in 7 hospitalizations among individuals with Alzheimer’s and related dementias is potentially preventable. These include hospital visits as a result of acute conditions like infection or dehydration, as well as chronic diseases including diabetes, cardiovascular disease, or respiratory illness. In total, preventable hospitalizations of dementia patients cost Medicare $2.58 billion dollars during 2013. Read more

Smell and Eye Tests May Predict Cognitive Decline

Two of the first brain regions affected by Alzheimer’s disease are the olfactory (smell) and visual systems. Studies presented at AAIC showed that neurodegeneration of the optic nerve or retina could be an effective predictor for the development of Alzheimer’s. Two other labs found that low scores on the University of Pennsylvania Smell Identification Test were associated with cognitive decline and dementia. Read more

Promising Anti-Tau Drug Fails in Clinical Trials

Alzheimer’s is characterized by the buildup of two toxic proteins in the brain: beta-amyloid and tau. After hundreds of drugs targeting beta-amyloid failed in clinical trials, researchers have recently begun to look into anti-tau drugs instead. Unfortunately, a promising anti-tau drug called LMTM failed in phase 3 of clinical trials. Apart from in a small subgroup of participants, the drug did not improve cognitive or neurological symptoms better than a placebo. Additionally, 80% of subjects experienced at least one adverse side effect. Read more

Men with Dementia are More Likely to Be Misdiagnosed than Women

It’s a commonly-held belief that women are at a greater risk of Alzheimer’s than men. However, it’s possible that innacurate diagnoses may contribute to this discrepancy (see Is It Really Alzheimer’s? 10 common misdiagnoses you should know about). A study of more than 1600 postmorten brains found equal rates of Alzheimer’s among men and women. Men typically have a younger age of onset and are more likely to exhibit atypical symptoms, increasing the risk of misdiagnosis. Another postmortem brain study found that across genders, approximately 10% of Alzheimer’s diagnoses were incorrect, with the true cause of memory loss usually being vascular dementia. Read more

Reducing Dependence on Antipsychotics in Dementia Care

Multiple studies have demonstrated that prescribing antipsychotics to dementia patients can accelerate the rate of cognitive decline and death. Nonetheless, this remains a common practice for treating the symptoms of dementia. In a recent study, nurses in 60 long-term care facilities were trained to manage patients’ dementia symptoms without the need for drugs. The patients’ doses of antipsychotics were incrementally reduced until they were eliminated. Most of the subjects were able to successfully cease antipsychotic use after a one-year follow-up. Read more


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