Alzheimer’s disease (AD)

The challenge: a radical improvement in the early diagnosis of Alzheimer’s and Parkinson’s diseases (AD and PD)


  • Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic and progressive neurodegenerative disease characterised by a decline in memory, language and other thinking skills, as well as changes in mood and behaviour. Biological changes in the brain can occur even decades before the first symptoms appear. By the late stages of the disease, people are often unable to communicate and become completely reliant on others for even simple day-to-day tasks. AD and related disorders affect some 7 million people in Europe alone. This figure is expected to double every 20 years as the population ages. To care for people with dementia AD currently costs of the order of €130 billion per annum across Europe and around US$ 820 billion worldwide.



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  • Doctors use several methods and tools to help determine whether a person who is having memory problems has “possible Alzheimer’s disease” (dementia may be due to another cause), “probable Alzheimer’s disease” (no other cause for dementia be found), or some other problem. To diagnose Alzheimer’s, doctors may:
    1. Ask the person and a family member or friend questions about overall health, past medical problems, ability to carry out daily activities, and changes in behavior and personality.
    2. Conduct tests of memory, problem solving, attention, counting, and language.
    3. Carry out standard medical tests, such as blood and urine tests, to identify other possible causes of the problem.
    4. Perform brain scans, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), to rule out other possible causes for symptoms.
    These tests may be repeated to give doctors information about how the person’s memory and other cognitive functions are changing over time. Tests can also help diagnose other causes of memory problems, such as mild cognitive impairment and vascular dementia. Alzheimer’s disease can be definitely diagnosed only after death, by linking clinical measures with an examination of brain tissue in an autopsy. (Source: https://www.nia.nih.gov/alzheimers/topics/diagnosis).
    The underlying biology of Alzheimer’s disease is based on the build-up of two proteins – beta amyloid and tau – in the brain, usually caused by advanced age or genetic factors. One of the pathological hallmarks of Alzheimer’s disease is the accumulation of beta amyloid (increased production or reduced clearance) in the brain.
    The major neuropathological hallmarks of AD are the presence of extracellular amyloid plaques that are composed of Aβ40 and Aβ42 and intracellular neurofibrillary tangles (NFT), which is composed of hyperphosphorylated protein Tau (Figure 1). While the amyloid plaques and NFT could define the disease progression involving neuronal loss and dysfunction, significant cognitive decline occurs before their appearance. Although significant advances in neuroimaging techniques provide the structure and physiology of brain of AD cases, the biomarker studies (mainly Aβ40 and Aβ42) based on cerebrospinal fluid (CSF) and plasma represent the most direct and convenient means to study the disease progression. Biomarkers are useful in detecting the preclinical as well as symptomatic stages of AD.
    (Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915796/)
    Figure 1: Pathological cascades and potential biomarkers of AD. Proteolytic cleavage of APP first by β-secretase followed by γ-secretase can produce Aβ42 and other shorter Aβ fragments. The subsequent aggregation of Aβ42 results in oligomers and amyloid fibrils. Amyloid fibrils are eventually deposited as senile plaques as shown. The toxicity of oligomers and amyloid fibrils could lead to the cascade of tau-hyperphosphorylation, which is otherwise bound to microtubules, providing microtubule stability. Upon hyperphosphorylation, tau dissociates from microtubules and aggregates into NFT, which could eventually cause increased cytoskeleton flexibility and neuronal death. (Source: Anoop A, Singh PK, Jacob RS, Maji SK. CSF Biomarkers for Alzheimer’s Disease Diagnosis. International Journal of Alzheimer’s Disease. 2010;2010:606802. doi:10.4061/2010/606802).

    Nerve growth factor (NGF) and Alzheimer's disease:

    Understanding sporadic Alzheimer's disease (AD) onset and progression requires an explanation of what triggers the common core of abnormal processing of the amyloid precursor protein and tau processing. In the quest for upstream drivers of sporadic, late-onset AD neurodegeneration, nerve growth factor (NGF), essential for the maintenance and differentiation of basal forebrain cholinergic neurons has a central role. Initially connected to AD on a purely correlative basis, because of its neurotrophic actions on basal forebrain cholinergic neurons, new evidences place alterations of NGF processing and signaling at the center stage of a new mechanism, leading to the activation of amyloidogenesis and tau processing. Thus, experimental studies on NGF deficit induced neurodegeneration in transgenic mice, as well as the mechanistic studies on the anti-amyloidogenic actions of NGF/TrkA signaling in primary neuronal cultures demonstrated a novel causal link between neurotrophic signaling deficits and Alzheimer's neurodegeneration. Around these results, a new NGF hypothesis can be built, with neurotrophic deficits of various types representing an upstream driver of the core AD triad pathology. According to the new NGF hypothesis for AD, therapies aimed at reestablishing a correct homeostatic balance between ligands (and receptors) of the NGF pathway appear to have a clear and strong rationale, not just as long-term cholinergic neuroprotection, but also as a truly disease-modifying approach.

    Studies also showed that neuroinflammatory alterations constitute a significant event very early in the neurodegeneration process in the mouse brain. Recent work by Cattaneo et al, has pointed to the proNGF protein, the processing precursor of mature NGF, as a major player in the neurodegeneration process, whereby an imbalance in the levels of proNGF and NGF in the brain is an upstream driver for neurodegeneration, as part of a circular loop linking proNGF signaling to AD phenotypic endpoints.

    (Source: Cattaneo 6 Calissano, Mol Neurobiol. 2012 Dec;46(3):588-604. doi: 10.1007/s12035-012-8310-9. Epub 2012 Sep 1.)

    The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the "neuroantibodies" phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of "Neurotrophic imbalance" as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD.

    It further considers the potential of the NGF metabolic pathway as a new pharmacological target to slow down the neurodegenerative process in Alzheimer's disease.

    (Source: Capsoni et al, CNS Neurol Disord Drug Targets. 2011 Aug;10(5):635-47.)

    The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the "neuroantibodies" phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of "Neurotrophic imbalance" as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD.

    It further considers the potential of the NGF metabolic pathway as a new pharmacological target to slow down the neurodegenerative process in Alzheimer's disease.

    (Source: Capsoni et al, CNS Neurol Disord Drug Targets. 2011 Aug;10(5):635-47.)
  • Right now, there is no cure for Alzheimer's disease. Once a person starts showing signs – memory loss and problems with learning, judgment, communication, and daily life -- there aren’t any treatments that can stop or reverse them. But there are medicines that can ease some of the symptoms in some people. They can slow down how quickly the disease gets worse, and help the brain work better for longer. That is the reason because an early diagnosis is very important.
    Some drugs curb the breakdown of a chemical in the brain, called acetylcholine, that’s important for memory and learning. They may slow down how fast symptoms get worse for about half of people who take them. The effect lasts for a limited time, on average 6 to 12 months. There are three drugs of this type: donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon).
    1. Aricept is the only treatment approved by the FDA for all stages of Alzheimer’s disease: mild, moderate, and severe. You can take it as a tablet that you swallow or that dissolves in your mouth.
    2. Razadyne (formerly called Reminyl) is also for mild to moderate Alzheimer’s. You can get it as a tablet that works right away, a capsule that gives off the medicine slowly, and in liquid forms.
    3. Exelon is for people who have mild to moderate Alzheimer’s. You can wear a skin patch that has the drug, or take it in capsules and in liquid form.
    4. Memantine (Namenda)treats moderate-to-severe Alzheimer's disease. It works by changing the amount of a brain chemical called glutamate, which plays a role in learning and memory. Brain cells in people with Alzheimer’s disease give off too much glutamate. Namenda keeps the levels of that chemical in check. It may improve how well the brain works and how well some people can do everyday tasks. The drug may work even better when you take it with Aricept, Exelon, or Razadyne. Namenda’s side effects include tiredness, dizziness, confusion, constipation, and headache.
    5. Namzaric. This drug is a mix of Namenda and Aricept. It's best for people with moderate to severe Alzheimer's who already take the two drugs separately.
      (Source: www.webmd.com)

    NGF therapeutic perspectives:

    The rationale for NGF as a potential therapeutic for AD is very strong. The development of a non invasive therapy for AD, based on the intranasal delivery of NGF, was demonstrated by our group to be a non invasive, safe and effective mean to achieve pharmacologically active concentrations of NGF in the brain. One liability of NGF as a therapeutics is, however, its well established physiological, pronociceptive activity. This severely limit the doses that can be safely given, in human clinical trials. To circumvent these difficulties, Cattaneo’s group, PLoS One. 2015; 10(9): e0136425, have engineered painless NGF molecules, inspired by a human genetic mutation found in HSAN V patients, who suffer from a congenital insensitivity to pain and harbor a point mutation in the gene coding for NGF. They characterized the effect of this mutation on NGF receptor interaction and signaling properties and have engineered an optimized painless NGF that we are now expressing as a recombinant protein and developing for clinical testing in human AD patients. Aiming at the therapeutic application of the "painless" hNGF mutants, it has been reported on the comparative functional characterization of the precursor and mature forms of the mutants as therapeutic candidates, also in comparison to the wild type.

    This structure-activity relationship study has led to validate the concept of developing painless NGF as a therapeutic, targeting the NGF receptor system and supporting the choice of hNGF P61S R100E as the best candidate to advance in clinical development. Moreover, this study contributes to the identification of the molecular determinants modulating the properties of the hNGF "painless" mutants.

  • Over the last 30 years, researchers have made remarkable progress in understanding healthy brain function and what goes wrong in Alzheimer's disease. The following are examples of promising targets for next-generation drug therapies under investigation in current research studies:
    1. Beta-amyloid is the chief component of plaques, one hallmark Alzheimer's brain abnormality. Scientists now have a detailed understanding of how this protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase — to form the beta-amyloid protein that is present in abnormally high levels in the brains of people with Alzheimer’s. Researchers are developing medications aimed at almost every point in amyloid processing. This includes blocking activity of beta-secretase enzyme; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain. Solanezumab is a monoclonal antibody designed to lower the level of beta-amyloid in the brain. The antibody binds to beta-amyloid, preventing the formation of plaques; solanezumab may also help carry excess beta-amyloid away from the brain. Several studies of this drug are under way with the goal determining if solanezumab improves participants’ cognition (thinking and memory) and functioning. Some participants will undergo a brain scan called positron emission tomography (PET) to determine levels of beta-amyloid in the brain.
      (Drug is still in research; not available to the public)


    2. Beta-secretase (BACE) is one of the enzymes that clips APP and makes it possible for beta-amyloid to form. Therapies that interrupt this process may reduce the amount of beta-amyloid in the brain and ultimately intervene in the development of Alzheimer’s disease. Verubecestat is a BACE inhibitor — it inhibits the ability of the beta-secretase enzyme to make beta-amyloid. At the Alzheimer’s Association International Conference® (AAIC®), researchers reported that the drug significantly lowered beta-amyloid levels in people with mild-to-moderate Alzheimer’s. Verubecestat is being tested in two phase 3 clinical trials. One is testing it in more than 2,000 people with mild-to-moderate Alzheimer’s, and the other is testing it in 1,500 individuals with prodromal Alzheimer’s and mild cognitive impairment (MCI). These individuals are at high risk of Alzheimer’s, but still able to function normally.
      (Drug is still in research; not available to the public.)
    3. Tau protein is the chief component of tangles, the other hallmark brain abnormality of Alzheimer’s. Tau protein helps maintain the structure of a neuron, including tiny tube-like structures called microtubules that deliver nutrients throughout the neuron. AADvac1 is a vaccine that stimulates the body’s immune system to attack an abnormal form of tau protein that destabilizes the structure of neurons. If successful, it has the potential to help stop the progression of Alzheimer’s disease. A phase 2 clinical trial enrolling 185 volunteers with mild Alzheimer’s disease began in March 2015 and is expected to be completed in February 2019.
      (Drug is still in research; not available to the public.)
    4. Inflammation in the brain has long been known to play a role in the changes that occur in Alzheimer’s disease. Both beta-amyloid plaques and tau tangles cause an immune response in the brain and microglia cells act as the first form of immune defense against them. However, while microglia help clear beta-amyloid in the brain, they can become overactive in the presence of plaques and produce compounds that damage nearby cells. CSP-1103 (also known as CHF 5074) is a microglial modulator that aims to reduce inflammation in the brain. At AAIC, researchers presented the results of a 90-week phase 2 clinical trial in which CSP-1103 was given to people who had MCI. In MCI, people have subtle memory and thinking problems, but these problems don’t interfere with their ability to carry out everyday activities. Many, but not all, people with MCI go on to develop Alzheimer’s. Preliminary results of the phase 2 study showed that CSP-1103 prevented beta-amyloid from being deposited on neurons. It also reduced problems with thinking and memory (cognition). The cognitive tests of people who had participated for at least 64 weeks showed statistically significant improvements in participants’ cognitive abilities. A phase 3 study of CSP-1103 is planned.
      (Drug is still in research; not available to the public.)


    5. The 5HT6 receptor found on some brain cells can lock in chemicals called neurotransmitters. This decreases the amount of neurotransmitters available for the brain to use for communication between nerve cells (neurons). Only through neuron-to-neuron communication can an individual think and function normally. Acetylcholine is one of these neurotransmitters. People with Alzheimer’s disease have low levels of acetylcholine. Blocking the 5HT6 receptor may increase the amount of acetylcholine and help nerve cells to maintain normal communication. Intepirdine is a 5HT6 receptor antagonist that blocks the receptor’s ability to decrease acetylcholine levels. A phase 3 clinical trial of Intepirdine began in October 2015 with a goal of recruiting 1,150 people with mild-to-moderate Alzheimer’s disease. The trial is expected to be completed in October 2017, at which time researchers compare the thinking and functioning abilities of study participants who received Intepirdine with those who received an identical but inactive pill.
      (Drug is still in research; not available to the public.)

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