Aducanumab: Third Time’s the Charm?

        This week we review the current status of a previously tested investigational treatment for Alzheimer’s disease (AD) reflecting the clinical trial approval process. In March of 2019 two phase III clinical trials of Biogen’s Aducanumab, a monoclonal amyloid-clearing antibody, terminated due to lack of efficacy after an interim futility analysis. As disappointing as these initial results were, the Aducanumab story most likely won’t stop here.  

       Biogen, has appealed the FDA to receive approval for the drug after sub-group analyses showed possible efficacy. These analyses were required because, of two parallel phase III trials (301 and 302), only one showed efficacy while the other failed to meet its endpoints. The FDA review board, and the academic community at large, are divided as to whether approving this drug would be a progression in AD treatment or a roadblock to future progression. Approving an ineffective drug “will slow down finding something that does work” says Michael Greicius, a professor of Neurology at Stanford. Let’s look at both sides of the issue.

       Biogen, having had one phase III trial that showed efficacy and one that did not, explained that these differential results may be due to variance in the study sample as the 301 trial had changed dosing directions mid-study and also had a large sample of “rapid progressors”. This left the review board to ponder whether the single successful 301 trial, if viewed on its own, provided sufficient evidence that the drug worked as intended. Only one member voted that the 302 trial supported approval of the therapy. Five members agreed that the treatment reduced amyloid-beta plaques in the brain, however, they were not convinced that the reduction of amyloid correlated to clinical improvements in cognition.

       One review board member, Joel Perlmutter, stated he “recognized the urgent, unmet need for treatment […] However, approving a treatment that ultimately does not work can be harmful” due to the fact that approval of this drug would “substantially slow recruitment into ongoing and future studies” and could reduce “enthusiasm and support for testing other potentially more effective treatments”. With this in mind, it seems reasonable to maintain skepticism when it comes to inconsistent results like those in the Aducanumab trials.

       Furthermore, Perlmutter explains an even larger concern, being that if it were approved “we may be required to test any new treatment not against placebo but against this drug”. In other words, if this drug is not effective in treating AD but is approved, all future treatments simply have to show more improvement than Aducanumab, meaning that other less effective drugs could continue to be approved and administered to patients simply because they are less ineffective. However, if Aducanumab really does work, we could be setting ourselves back years while we wait for another effective treatment to successfully complete phase III in the clinical trial process. As you can see, the research and clinical review processes are quite complicated and must proceed with caution. Making an incorrect decision at one stage has the potential to fully derail a field of study such as AD treatment.  We hope the FDA requires a new Phase III trial for Biogen’s Aducanumab to prospectively test its effectiveness.

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Source:
Talan, J. FDA Panel Votes ‘No’ to Approving Aducanumab for Alzheimer’s, Citing Inconsistent Data [Internet]. NeurologyToday. 2020. Available from: https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_Votes__No__to_Approving_Aducanumab_for.1.aspx#:~:text=An%20advisory%20panel %20of%20the,and%20more%20research%20is%20needed.

Iron and Amyloid: Correlations to Entorhinal Cortex Degeneration

3D illustration brain nervous system active, medical concept.

       Research into the prevention and treatment of Alzheimer’s disease (AD) frequently starts small, with the discovery of risk factors that correlate with elevated deposition of AD biomarkers: amyloid (Aꞵ) plaques and neurofibrillary tangles (NFTs). Recently, researchers observed one such phenomenon involving the build-up of iron in the brain and the localization of Aꞵ.

       Firstly, it has been known that iron, a vital mineral in the body, has the capability to build up in the brain as we age. Normally, iron is bound in heme, a component of red blood cells, in order to aid in the binding of oxygen for distribution throughout the body. When there is too much iron in the body it forms iron deposits that can induce oxidative stress and cell damage. Furthermore, iron is also found within the molecules of Aꞵ and NFTs, and previous studies suggest iron deposits may encourage AD pathology.

       In the current study, researchers used Amyloid-PET and T2-weighted MRI imaging of 70 cognitively normal participants to measure cortical amyloid burden and non-heme iron deposited in the striatum of the brain. They did not find a direct correlation between amyloid burden and striatal iron concentration, and hypothesized this may be due to striatal iron deposition being limited until the later stages of AD. They did, however, notice that in cases of high amyloid and high striatal iron the entorhinal cortex degenerated in relation to age, while those with amyloid but low iron levels in the brain had larger entorhinal cortices suggesting reduced degeneration.

       The researchers hypothesized that reduced degeneration of the entorhinal cortex in the presence of amyloid but low iron might be due to amyloid plaques’ tendency to surround iron deposits, effectively protecting nearby brain regions from the negative impacts of iron deposits. Unfortunately, this protective effect doesn’t last with continued iron deposition having a negative impact on entorhinal cortex size.

       There are current and upcoming trials aimed at reducing/removing iron deposits prior to onset of neurodegeneration that show some promise as a preventative treatment. It is especially promising considering that the correlation between iron levels in the brain and entorhinal cortex degeneration were detectable even amongst non-impaired participants, suggesting that this method of treatment may work even in mildly symptomatic or even presymptomatic individuals, preventing brain volume loss before it has even begun!

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Bilgel, M. & Bischof, G. N. Early role of iron in modulating amyloid’s association with neurodegeneration [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/18/809?sso=1&sso_redirect_count=1&oauth-code=BZ9uF6n9xCjHLHF8kd-f8zPfZ6Vgxd2gqxNz-SF3y2w

Anti-Depressant Drugs and Alzheimer’s: A Surprising Relationship

       Most of our blogs emphasize treatments that directly affect the mechanisms that induce Alzheimer’s disease (AD). However, recent research into the use of anti-depressant drugs and their relationship to AD has provided some interesting results. Namely, administration of escitalopram seems to reduce deposition of amyloid-ꞵ42, which could, in theory, slow the onset or progression of AD.

       Escitalopram belongs to a drug class called Selective Serotonin Reuptake Inhibitors (SSRIs) and is one of many similar molecules that are frequently used to treat depression by up-regulating serotonin signaling. Previous research on SSRIs in animal models found that increased serotonin signaling was associated with reduced amyloid-ꞵ42 levels, leading investigators to study its possible benefits for use in older adults with AD.

       The current study, a clinical trial, administered escitalopram under 4 conditions: 20 mg/day for 2 weeks, 20 mg/day for 8 weeks, 30 mg/day for 8 weeks, and placebo to cognitively normal older adults to see if it affected amyloid-ꞵ42 burden during that time frame. The treatment groups, on average, experienced a 6.0% (± 1.2%) reduction in CSF levels of amyloid-ꞵ42 while the placebo group experienced a 3.5% (± 2.2%) increase in amyloid-ꞵ42 levels in the CSF. These results suggest that increased serotonin signaling decreases amyloid burden by the activation of a signaling pathway that ends in the production of α-secretase, which suppresses Aꞵ42 generation. This is very important because the degree to which Aꞵ42 produces plaques and impairs neuronal function is dependent upon the concentration of Aꞵ42 present. In animal models, reductions of 10-25% in overall interstitial fluid Aꞵ42 concentrations significantly reduced plaque deposition.

       While those in the treatment group of the current study did not see reductions in the 10-25% range, they did see reductions in comparison to the placebo group who actually had an increase in Aꞵ42, meaning that it is possible that SSRI administration may become a preventative strategy to reduce the initiation or progression of AD. However, we first need to determine if reductions in CSF Aꞵ42 correlate to reductions in plaque formation rate in humans, as was shown in rats. On the bright side, many people already use SSRIs regularly so in terms of possible treatment options, this one is very safe and accessible, but only time will tell.

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Sources:
Sheline, Y. I., Snider, B. J., Beer, J. C., et al. Effect of escitalopram dose and treatment duration on CSF Aꞵ levels in healthy older adults [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/19/e2658?sso=1&sso_redirect_count=1&oauth-code=AtOok5tDWVPGT3Tmk7Na0iVfQN-vP7YljIOYAQ7VLe8
Cirrito, J. R., Disabato, B. M., Restivo, J. L., et al. Serotonin signaling is associated with lower amyloid-ꞵ levels and plaques in transgenic mice and humans [Internet]. Proceedings of the National Academy of Science of the United States of America. 2011. Available from: https://www.pnas.org/content/108/36/14968

 

A New Investigational Approach to Clinical AD Treatment: ATH-1017

       Alzheimer’s disease (AD) has long eluded a cure, causing researchers to delve deeper into the biological underpinnings of the disorder for new, inventive, and multi-factorial strategies to reduce neurodegeneration before and after onset. One investigational treatment provided by Athira, called ATH-1017, recently began Phase II clinical trial enrollment with our clinic. If this blog peaks your interest, please feel free to reach out to us and see if you or someone you know might be applicable for involvement in the trial.

       ATH-1017 is a Hepatocyte Growth Factor (HGF) Receptor Agonist, meaning that administration simulates the presence of HGF, activating a kinase receptor-protein called MET. The HGF/MET complex is a neurotrophic factor meaning, when functioning properly, it protects neurons from degeneration and may induce regeneration of lost neuronal connections in dysfunctioning brain regions (such as the hippocampus in AD). Patients with AD have reduced hippocampal MET receptors. ATH-1017 targets the HGF/MET complex in order to enhance the neuroprotective CNS effects.

       In animal studies the investigational drug improved learning and memory in aged rats, prevented motor symptoms and neuronal loss in rat models of Parkinson’s disease (PD), and stimulated dendritic arborization and synaptogenesis. Furthermore, in humans during a Phase I trial it improved brain activity as measured by gamma power and p300 latency in participants with AD (both measures of increased learning, memory, executive functioning, and processing speed). It also produced a dose-related increase in gamma power in healthy controls suggesting that ATH-1017 may have wide therapeutic effects outside of just AD and PD. Furthermore, in all dosage groups of the Phase I trial, no investigational-drug-related adverse events were recorded, meaning the therapeutic dose required is very safe. Cognitive testing is now added to the new trial in order to assess clinical efficacy.

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Sources:
ATH-1017 [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/therapeutics/ath-1017
Zhu, Y., Hilal, S., & Lai, M. Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer’s Dementia [Internet]. Frontiers in Aging Neuroscience. 2018. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787106/
Wright, J. & Harding, J. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer’s Disease [Internet]. 2015. Available from: https://pubmed.ncbi.nlm.nih.gov/25649658/

LATE and AD: Clinical Interactions

       Most neurological disorders are associated with a biomarker, a protein or biological by-product whose concentration correlates to the development of the disorder. AD’s biomarkers, as you may already know, are amyloid-beta (Aꞵ) precipitated as plaques and misfolded tau protein that forms neurofibrillary tangles (NFTs). Another common biomarker of neurological disorders is TAR DNA binding protein 43 (TDP-43, shown above) which presents in cases of Frontotemporal dementia (FTD), Hippocampal Sclerosis (HS), and Limbic-Predominant TDP-43 Encephalopathy (LATE). But neuropathology is rarely cut and dry which raises the question, “What happens when these biomarkers/disorders occur together?”.

       Recently, researchers answered this question using retrospective analyses on 1,356 elderly participants who were diagnosed at autopsy with either AD, LATE, or AD & LATE (along with cognitively normal participants for control). The researchers used results of cognitive testing over their lifetimes to complete between-group comparisons of cognitive trajectories for global cognition and 5 specific domains (episodic, semantic, and working memory, perceptual speed, and visuospatial processing).

       The results suggest that LATE and AD interact to produce a differential cognitive trajectory. Patients with pure-AD and LATE/AD experience increased decline in global cognition and all sub-domains in comparison to healthy controls. Patients with pure-LATE have increased decline in global cognition, but in sub-domains, only had accelerated decline in episodic memory compared to healthy controls. In comparison to those with pure-AD, those with LATE decline slower in global cognition and episodic memory, while those with LATE/AD decline faster in global cognition and all domains.

       The increased rate of cognitive decline in the AD/LATE group suggests these two disorders appear to have additive effects that produce a specific, accelerated cognitive trajectory. While this may not seem significant, it does support the concept that differential progressions of AD (as well as other neurodegenerative disorders) may be due to interactions with comorbid disorders, such as LATE. This allows for better diagnostics and treatments because, without information about additive effects, physicians may see a patient with AD/LATE and determine that it is a more severe case of AD. Using cognitive trajectories for sub-groups such as AD/LATE, however, they could gain a head-start in diagnosing and treating both disorders.

       Unfortunately, a diagnostic method like this will require a significant amount of research to properly establish due to the amount of people required to create a generalizable cognitive trajectory. Using retrospective analyses, like they did here, saves quite a bit of time but is limited by the outcome measures used in the original study. As such, we will have to make a concerted effort to develop these trends for the numerous neuropathological groups that exist.

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Kapasi, A., Yu, L., & Boyle, P. Limbic pre-dominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/14/e1951.long

What Are Coarse-Grained Plaques?

       Alzheimer’s disease (AD) was identified in 1901 by Alois Alzheimer but despite being known for over a century, researchers are discovering new things about the disease today. For example, our regular readers should be familiar with the term “amyloid plaques” which are likely the most well researched biomarkers of AD. There are also sub-types of amyloid plaques and a group of pathologists recently observed what they believe to be a unique sub-type of plaque termed “coarse-grained plaques”. This week we will discuss these new plaques and their significance to AD research.

       Coarse-grained plaques form a core of amyloid-ꞵ with 42 residues (Aꞵ42) surrounded by a shell of Aꞵ40, and are packed with a protein called norrin, a marker of blood-vessel damage. These plaques tend to localize near blood vessels but cannot cross the blood-brain barrier (BBB). 84% of the analyzed coarse-grained plaques had direct contact with vasculature, suggesting that they may induce cerebrovascular dysfunction rather than neurological dysfunction directly.

       They are more common in people with two copies of the ApoE4 allele or those with early onset AD. In this study out of 28 non-ApoE4 carriers, 15 had sparse/frequent coarse-grained plaques, compared to 25 out of 33 for heterozygous ApoE4 carriers. All 11 homozygous carriers had moderate/frequent deposition of the coarse-grained plaques. This suggests interaction between the ApoE gene and coarse-grained plaques. In fact, there may even be a separate ApoE4-induced AD sub-type in homozygous carriers.

       Researchers used laser scanning microscopy to visualize the plaques and saw that out of 74 brains, 38 had early onset AD, 21 had late onset, and 15 were never diagnosed with dementia though amyloid positive. This diverse grouping shows that, while coarse-grained plaques might induce early AD in many cases, it does not guarantee a specific pathological presentation. Staining techniques and complement testing were utilized to discover more about the plaques on a molecular level.

       The stained coarse-grained plaques showed amyloid precursor protein (APP) and prion protein suggesting they may damage nearby neurons. The complement testing also revealed that these plaques have markers for extreme neuroinflammation and presence of astrocytes and microglia. In fact, microglia and astrocytes cover these plaques in a particular pattern which seems to further differentiate this type of plaque from those which were known previously, confirming the unique nature of these new plaques.

       In summary, these specific plaques are only just beginning to be researched but already it seems there is a close relationship between the presence of coarse-grained plaques, the ApoE4 allele, cerebrovasculature, and AD pathology. With more studies and larger sample sizes, research of this topic may lead to innovation in the diagnosis and differing treatment options for subtypes of AD.

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Introducing the Coarse-Grained Plaque – A New Type of Amyloid [Internet].Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/introducing-coarse-grained-plaque-new-type-amyloid

Cognitive Resilience: Developmental Vs. Genetic Factors

       A recent discovery of a genetically unique family has shown that developmental disorders may predispose or change the presentation of Alzheimer’s disease (AD) dementia. The family studied consisted of 10 siblings, 8 of whom presented with developmental language problems and 1 with a sub-syndrome of frontotemporal dementia known as logopenic variant primary progressive aphasia (lvPPA). All members had average total brain volumes but decreased left cortical volume, and reduced functional connectivity between the left superior temporal cortex (responsible for auditory processing) and language areas in both hemispheres resulting in the language dysfunction.

       The researchers hypothesized that developmental delays in language and changes in brain morphology may induce AD symptomology effectively matching that of lvPPA. Due to the pre-existing changes and vulnerability of the language network, these networks are first to dysfunction. In those without developmental language delays, AD selectively affects executive functioning first. This contrasting pathology shows that pre-existing conditions and morphological changes in the brain might interact to change or accelerate the development of other disorders.

       If pre-existing dysfunctional networks contribute to the development of AD, it’s possible hyper-functional networks may be neuroprotective. To assess this theory elderly participants received biennial amyloid PET scans and underwent yearly cognitive testing for 14 years. The presence of the APOE-2 gene, lower pulse pressure, and higher baseline scores on cognitive tests appeared to be neuroprotective. Engagement in paid work and increased life satisfaction also predicted resilience to cognitive decline, but to a lesser degree. Furthermore, in amyloid-positive participants, never having smoked also predicted cognitive resilience.

       While the APOE-2 genotype is neuroprotective via reduced likelihood of amyloid build-up, the relationship between pulse pressure, cognitive testing scores, and AD are in need of further study. In those who are amyloid positive, higher baseline cognitive scores and never having smoked predicted increased cognitive resilience. This suggests that networks with greater functional connectivity (in comparison to the family with language deficits who had decreased connectivity) are indeed able to remain cognitively normal for longer. Additionally, cerebral vasculature appears to play an important role in cognitive resilience, with those with lower pulse pressure remaining cognitively normal for longer. On top of this, smoking increases blood pressure further supporting the concept that those who never smoked were also more cognitively resilient.

       Genetics are only one factor in the multifaceted disorder that is AD. Presence of amyloid does not guarantee AD pathology, AD pathology may present differently in a brain with morphological and functional changes induced by other genes, and non-genetic factors such as smoking and lifestyle also play a role. Researchers are now tasked with finding the intersection of genetics, lifestyle, and comorbid disorders to determine how these things influence AD and from there, how to counteract cognitive decline or even prevent it in the first place!

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Sources:
Hillis, A. E. & Kolundžić, Z. Developmental and degenerative deficiencies in the language network [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/7/281
Snitz, B. E. et al. Predicting resistance to amyloid-beta deposition and cognitive resilience in the oldest-old [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/8/e984

Insulin and Alzheimer’s Disease

Insulin

        Insulin is typically associated with regulating blood glucose levels and diabetes, but it also serves as a crucial signaling molecule throughout the body, including the central nervous system (CNS). In fact, there is evidence that insulin may play a role in the development of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Dysregulation of insulin signaling negatively impacts cognition and increases deposition of amyloid plaques and tau tangles. Luckily, there are also mechanisms that can upregulate insulin sensitivity and these treatments have potential to reduce or alleviate AD symptoms.

       Insulin is a hormone released primarily by the pancreas. It can cross the blood-brain barrier (BBB) to have CNS effects. However, if one develops insulin resistance, which is correlated with AD, normal tissues fail to sufficiently respond to the presence of insulin. In these cases, insulin dysregulation induces hyperglycemia, too much sugar in the blood, which leads to glucose neurotoxicity, reduced cerebral blood flow, and accumulation of toxic byproducts in the brain, all of which can lead to cognitive impairment.

       There are several ways to test insulin resistance but they all follow a basic method of administering insulin and monitoring the response of the target tissue, whether peripheral or in the CNS. There is a close bi-directional relationship between insulin functioning in the body and the brain. For patients with AD there is a trend towards insulin insensitivity and hyperinsulinemia (too much insulin in the blood). Excess insulin downregulates the receptors that move insulin through the BBB into the CNS, meaning less insulin in the brain.

       A reduction in CNS insulin is significant because insulin in the brain protects against amyloid-beta synaptotoxicity and promotes clearance of plaques. AD patients with peripheral insulin resistance have increased amyloid deposition compared to healthy controls. Tests of peripheral insulin resistance successfully predict amyloid deposition in the brain 15 years later, as confirmed by an amyloid PET scan. Furthermore, patients with altered insulin signaling from diabetes have increased tau levels in cerebrospinal fluid. A final additive risk factor is that excess insulin acts as a vasoconstrictor limiting blood flow to the brain and decreasing amyloid and tau clearance. Dysfunctional insulin signaling may be a risk factor for AD.

       Understanding how insulin resistance impacts AD risk has improved our range of potential treatments. Intranasal insulin administration allows it to bypass the BBB and enter the CNS, reducing AD pathology and improving memory in rats after long-term administration. In humans, twenty-one days of treatment enhanced episodic memory. However, clinical trials testing intranasal insulin show mixed results indicating the need for further research. One can also increase insulin sensitivity with “insulin sensitizers”, such as Metformin, but evidence for these treatments in AD is limited. In mice and primates a GLP-1 agonist, which stimulates insulin production and regulates glucostasis, called liraglutide preserved memory and increased hippocampal neuronal density. Liraglutide is currently in a Phase II clinical trial for use in humans with AD.

       Although these potential treatments are promising there are proven ways to enhance insulin sensitivity and reduce AD risk right now and without a prescription. Consuming a diet of primarily polyunsaturated fatty acids, nuts, and plant-based foods correlates with increased insulin sensitivity and decreased risk of AD-related cognitive decline compared to diets containing higher saturated fats, animal proteins, and refined sugars. Additionally, regular exercise is a powerful modulator of insulin sensitivity and has also been shown to reduce risk of AD. In the meantime, while we wait for the aforementioned therapies to be approved, a lifestyle and diet change is not only protective against AD, but can also improve your overall general health.

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Sources:
Kellar, D. & Craft, S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches [Internet]. The Lancet Neurology. 2020. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1474442220302313

Learning Impairment in Preclinical AD

Diagram

       Memory impairment is often the hallmark symptom of Alzheimer’s disease (AD). However, research recently discovered a trend suggesting that decreased learning may preface memory loss in the preclinical phase of AD. Amyloid-positive patients in the preclinical stage of AD first experience a decline in learning ability while their memory is still comparable to amyloid-negative healthy controls. This discovery, much like the blood test we discussed a few blogs ago, may become a means of determining whether someone is going to develop AD well before memory impairment ensues.

       During the preclinical stage of AD both amyloid-positive and amyloid-negative participants score equivalently on episodic memory tests. Over several years of repeat testing the amyloid-negative group improved their scores as a product of practice while amyloid-positive participants stagnated. This suggests that an impairment of learning precedes an impairment of episodic memory in the preclinical stage of AD.

       Investigating further, scientists developed a test called the Online Repeated Cognitive Assessment (ORCA) where participants spend 30 minutes a day viewing Chinese characters paired with a correct or incorrect English word. After each session, patients reviewed their scores to see what pairings correctly matched, allowing them to learn from their previous mistakes. After several days participants began learning which Chinese characters represented the correct English words and which were incorrect. A previous study using this same paradigm found that amyloid-positive participants made more mistakes than the amyloid-negative group by the second session, and the gap continued to widen over the following days.

       A more recent study tested 80 cognitively normal participants, 38 of whom were amyloid positive, on the ORCA along with other cognitive tests and neuroimaging. The amyloid-positive group showed learning deficits in the first session and the reduced learning compared to amyloid-negative individuals continued to grow over 6 days. After 6 days, the average ORCA scores of the two groups differed significantly, with amyloid-positive individuals showing reduced learning abilities compared to amyloid-negative patients. However, on episodic memory tests, both groups scored similarly, supporting the hypothesis that learning deficits may establish before memory impairment begins in amyloid-positive patients.

       A well-designed learning test may be more useful for testing in the early stages of AD than the current standard measures of delayed recall. Generally, this type of “practice effect” learning, is avoided in clinical trials as it can confound memory test scores. Although, some experts who promote practice effect testing feel that decreased learning of new information echoes patient complaints of those that notice dysfunction but score normally on memory tests. This provides a means of testing the longitudinal progression of AD prior to the onset of memory impairment. Unfortunately, the test is not yet ready for use in clinical trials. Hopefully in the future this improved testing will translate to improved therapies for AD but only time will tell.

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In Preclinical Alzheimer’s, Learning Falters Before Memory [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/preclinical-alzheimers-learning-falters-memory

New Discovery in Tau Pathology

TauTangle

      We frequently discuss what factors increase or reduce risk for Alzheimer’s disease (AD) and other memory-impairing disorders. However, with research constantly ongoing there is always more to learn. Recently, researchers discovered an important impact of misfolded tau protein in rat brains with AD that sheds some light on how tau increases risk, providing an important window into the mechanism of AD progression. Once researchers understand how tau impacts the brain, it will be much easier to discover ways to combat the process.

       Many theories exist as to how misfolded tau protein impacts neuronal communication and promotes degeneration, but few have been empirically proven or replicated. Without this key factor, researchers only know what biomarker causes the degeneration (tau) and what impairment it causes, but not how. Unfortunately, without understanding how misfolded tau leads to impairment, it’s difficult to counteract the mechanism causing the impairment. Luckily, a recent study discovered a unique relationship between tau, nitric oxide (NO), and cerebral vasculature that occurs even before tau forms neurofibrillary tangles (NFTs).

       Specifically, in rats with overexpression of mutant tau proteins, the tau can be translocated to the dendrite where it displaces an important protein called neuronal nitric oxide synthase (nNOS) involved in the production of NO in the brain. Under normal circumstances NO is a product of neural activity, signaling blood vessels in the area to expand increasing oxygen to support the increase in activity. This process is called neurovascular coupling. Neurovascular uncoupling occurs in disease models when tau proteins bind to the receptor on neurons that nNOS would normally bind to, thereby preventing NO production and transmission of the signal to expand blood vessels. Reduced blood flow to areas of high activity in the brain prevents many cellular processes that allow for optimal cognition. This is why vascular complications can induce cognitive impairment even without AD.

       Increased blood flow not only provides oxygen and nutrients to neurons, but also serves as a garbageman, taking away unnecessary or toxic proteins. Without clearance of these waste products, they build up much more quickly and induce dysfunction. Mutant tau proteins are one of these toxic molecules that would normally be cleared from the brain by the blood. When not cleared, the tau proteins can aggregate into NFTs inducing further dysfunction and even cell death.

       These findings indicate that tauopathy development supports the progression of its own NFT buildup, through reduction of vascular waste clearance, creating a cycle of impairment and degeneration. If we can find a way to override nNOS silencing by tau, we would expect cognition to improve with further clearance of tau tangles and Aꞵ due to increased blood flow, in turn slowing or halting disease progression.

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With Tau in Synapses, NO Neurovascular Coupling [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/tau-synapses-no-neurovascular-coupling.
Park, L., et al. Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration [Internet]. Nature Neuroscience. 2020. Available from: https://www.nature.com/articles/s41593-020-0686-7.