Alzheimer’s – There’s still light at the end of the tunnel

by • December 28, 2018 • FeatureComments Off on Alzheimer’s – There’s still light at the end of the tunnel431

D Weaver
Research Director, Krembil Brain Institute 
University Health Network 
University of Toronto 
Toronto, Canada 

The Problem 

The spectrum and spectre of Alzheimer’s disease and related dementias are affecting every nation in the world and it’s only going to get worse.  At present, more than 45 million people worldwide have Alzheimer’s, a mind-robbing condition that impairs memory, thinking and behaviour, often leading to death within 3 to 9 years after diagnosis.  Adding to this problem, there are 7.7 million new cases per year worldwide – that’s another person with Alzheimer’s every four seconds.  The number of people with Alzheimer’s is projected to rise by 55% by 2030, and by 2050 more than 135 million people will be struggling with (and – unless we can find a cure – ultimately dying from) Alzheimer’s.  In Canada, some 750,000 Canadians suffer from this, and one new person joins them every five minutes.  It is estimated that by 2030, this number will have nearly doubled to 1.4 million.  Considering that Alzheimer’s is already the 7th leading cause of death worldwide, the impending toll, as the Alzheimer’s pandemic fully manifests, may become catastrophic.    

Alzheimer’s is not only a profound human tragedy, it also imposes an overwhelming socioeconomic cost in terms of direct medical, social and informal care costs. Due to the length of time people live with the illness and need care, it’s among the most expensive medical conditions in the world and may soon become the costliest disease in human history.  Dealing with dementia already costs Canadians $15 billion a year, a figure that by some estimates will rise to over $150 billion annually by 2040.  In 2015, the total global cost of dementia was estimated to be $818 billion, equivalent to 1.1% of global gross domestic product.  It is estimated that if the number of patients increases as projected in the years ahead, the costs to care for them will exceed $1.2 trillion annually in North America alone. Thus, future costs for Alzheimer’s threaten to bankrupt not only individual families but even national healthcare systems. Alzheimer’s and related dementias are a truly immense problem – a problem that is currently posing potentially insurmountable healthcare and fiscal challenge, and a problem that we cannot afford to ignore any further.   

The Disease 

All Alzheimer’s is dementia, but not all dementia is Alzheimer’s.  Dementia is the loss of cognitive functioning – memory, language skills, visual perception, problem solving, self-management, and the ability to focus and pay attention – to such an extent that it interferes with a person’s ability to carry out the day to day activities of their normal life.  Dementia is an overall term for a set of symptoms; dementia is not a specific disease.  Alzheimer’s, on the other hand, is a specific disease and is a specific type of dementia.  Alzheimer’s is an chronic, irreversible, progressive type of dementia that is associated with brain atrophy and with the deposition of abnormal protein clumps, called plaques and tangles, in the brain of the afflicted individual (Figures 1-3).  Alzheimer’s is by far the most common type of dementia accounting for approximately 75% of all dementia cases.  Other types of dementia include vascular dementia, frontotemporal dementia, progressive supranuclear palsy, Lewy Body dementia, and chronic traumatic encephalopathy.  Neither Alzheimer’s nor dementia are a normal part of aging.  Alzheimer’s is one of those diseases that is affecting us from “cell to society”, having the ability to harm or even destroy individual lives, families, or possibly even the healthcare system of a country.      

The world’s first G8 Dementia Summit was held in London on 11 December 2013, bringing together government ministers, researchers, pharmaceutical companies and charities to discuss what can be done. Delegates agreed that Alzheimer’s is a huge health and economic global challenge with the capacity to threaten the socioeconomic well-being of entire countries; they also heard that these challenges must be met through innovation and that the response to dementia must be a concerted worldwide effort.   

At the level of the family, Alzheimer’s can be overwhelming for the families of affected people and for their caregivers.  Parents with dementia are often moved into family homes causing domestic stress; typically, children also give up their jobs to care for their dementing parents – causing additional strains within a family unit.  At the level of the individual, Alzheimer’s is truly devastating. The disease robs people of their recollections, erases personality and makes even routine tasks like dressing and bathing impossible.  The afflicted individual is unable to recognize their spouse of fifty years and is incapable of identifying their own children.  Bigger than cancer, bigger than heart disease or lung disease – for seniors, dementia is the single greatest cause of disability and debilitation.  

At the cellular and tissue level, Alzheimer’s is characterized by the death of brain cells (neurons) and the activation of brain support (glial) cells.  A normal adult human brain weighs 1300-1400 g; a person who has succumbed to Alzheimer’s will have a brain weighing less than 900 g.  The thick grey cortical mantle of cells that envelop and embrace the brain (as the cortex) will be especially devastated.  Ultimately, plaques (aggregates of beta-amyloid protein) and tangles (aggregates of tau protein) will become the tombstones of dead neurons, as the brain irreversibly degenerates.   

At the molecular level, the two protein pathologies characteristic of Alzheimer’s are amyloid plaques composed of Aβ and neurofibrillary tangles of tau. Aβ is composed of 39 to 43 amino acids and is generated by proteolytic cleavage of amyloid precursor protein (APP), a transmembrane protein of unknown physiological function. Cleavage of APP occurs by two competing enzymes: α-secretase and β-secretase. In Alzheimer’s, cleavage by β-secretase at the N-terminus and intramembranous cleavage by γ-secretase at the C-terminus liberates Aβ from neuronal cells. Above a certain critical concentration, Aβ monomers undergo a shape change from a random or α-helical state to β-pleated sheets. This conformational change, known as nucleation, prompts self-assembly into Aβ dimers, trimers and oligomers. Oligomers can further polymerize to form soluble protofibrils, followed by insoluble and highly ordered fibrils that deposit to form amyloid plaques. Small oligomeric clumps of Aβ are toxic to brain and contribute to the cause of Alzheimer’s; the plaques on non-toxic.  The other proteopathic hallmark of Alzheimer’s is the presence of neurofibrillary tangles composed of microtubule-associated tau protein. Normally, tau stabilizes neuronal microtubules in axons, but in Alzheimer’s, abnormal phosphorylation facilitates disassociation from the microtubule and loss of function. Similar to Aβ, the change prompts self-assembly into highly toxic soluble oligomers, which eventually form larger fibrils and tangles that deposit within neurons.    

However, (and thankfully) our molecular level understanding of Alzheimer’s is still evolving.  In 2018, there are two dominant hypotheses concerning the cause of AD: (1) the proteopathy hypothesis; (2) the immunopathy hypothesis.  As discussed above, the proteopathy hypothesis proposes that proteins such as β-amyloid and/or tau misfold and become oligomerized or clumped. These species become toxic to the brain, destroying neurons and eventually causing Alzheimer’s to progress.  The immunopathy hypothesis proposes that immune cells in the brain, called microglia, become “overactive” in Alzheimer’s; these activated microglia elicit the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue, damaging neurons and thus causing Alzheimer’s to progress.   

The Pessimism 

In 2018, there are no “disease modifying” or “curative” agents for AD.  The only agents on the market for Alzheimer’s are “symptomatic” agents that temporarily help with the symptoms, but do not affect the relentless progression of the disease.   Over the past two decades, of the more than 200 compounds assessed as disease modifying agents for Alzheimer’s assessed in more than 400 clinical trials, all have failed – it hasn’t even been close.  And these failures have cost the pharmaceutical industry billions of dollars, while understandably diminishing their enthusiasm for continuing in this area.  Indeed, a number of large pharmaceutical companies have withdrawn from active research in the dementia field.  The amyloid hypothesis based on blocking the neurotoxic effects of amyloid protein misfolding seemed like such a logical target, yet all drugs exploiting this approach have failed.  This has led to the oft-quoted but probably premature declaration that “the amyloid hypothesis is dead!”  Where do we go from here, and do we even have a direction to pursue?  Is this a problem that we cannot cure?  

The Optimism 

There is room for optimism – lots of optimism.  An antibody called BAN2401 (a humanized IgG1 version of the mouse monoclonal antibody mAb158, which selectively binds to large, soluble Aβ protofibrils) when used at its highest dose reduced decline in two measures of cognitive function in Alzheimer’s after 18 months, while reducing amyloid burden, according to data presented by the drug’s manufacture at a conference in July 2018.  While questions persist concerning the study methodology, this is the first large clinical trial to support the proteopathic hypothesis of Alzheimer’s.  This is a step in the right direction.      

Thus, the design and optimization of a pioneering disease modifying drug must remain as a neuropharmacological priority.  The disappointing results of the past 20 years have revealed the pressing need for novel targets in disease-modifying drug design. Currently, four leading hypotheses attempt to explain the etiology of AD: (i) abnormal folding of both Aβ and tau (not just Aβ alone) and their subsequent assembly into oligomers, (ii) neurotoxic activation of the innate immune system, (iii) mitochondrial dysfunction, and (iv) oxidative stress.  All of these hypotheses offer a wealth of druggable targets, offering new avenues of hope.  And these are not the only interesting hypotheses.   

My own laboratory is contributing to these new avenues of hope (Figure 4).  Over the past ten years, we have devised an innovative computer-based (in silico) model of protein misfolding.  We identified a common binding site based on epitope commonality between multiple misfolded amyloid proteins. This information was used to create CCM (Common Conformational Morphology), a proprietary methodology for constructing models of the earliest stages of protein misfolding during the initial oligomerization stages – not during the late pre-plaque fibrillization stage.  CCM represents a protein shape – not an amino acid sequence – that predisposes proteins to toxic misfolding.  Using CCM we performed an in silico screen of 11.8 million compounds, allowing for the identification and optimization of numerous classes of potent, drug-like compounds –making structure-based design a reality for anti-amyloid drug discovery.  This has enabled us to pioneer the design of molecular classes capable of preventing the misfolding of Aβ, tau, either individually or together.  To develop these agents further, we have founded a biotech company, Treventis Corp.  Earlier this year, Treventis announced a strategic research partnership with Servier, an international pharmaceutical company governed by a non-profit foundation, with its headquarters in France.  The collaboration covers a large drug discovery program targeting both tau and Aβ and their earliest phases of oligomerization. 

As 2018 draws to a close there are many changes giving optimism and hope.  The amyloid hypothesis isn’t dead, it has been reshaped and is still a source of druggable targets.  New agents will be targeting amyloid misfolding at its earliest stages and will also be tackling the equally important misfolding of tau.  Multiple other areas of investigation are still in their infancy but will offer exciting opportunities for drug design.  In particular, the role of neuroinflammation and neuroimmunology in the pathogenesis of Alzheimer’s is presenting a bright future for therapeutic opportunities.  Everything doesn’t have to be about the neurons; drugs that target the microglial support cells may have the ability to slow disease progression down.  There is also a growing realization that there may not be a single magic bullet that takes out Alzheimer’s.  As with high blood pressure, it may take a cocktail of different agents targeting different receptors.  All of these realizations are conceptual advances paving the way for the discovery of potentially useful drugs.       

Arguably, halting the full impact of the impending Alzheimer’s pandemic may take more than a drug.  Alzheimer’s is a disease that devastates not only individuals, but a disorder that afflicts families, societies and nations.  And a lot of people already have it and will require care.  Addressing this epidemic requires a multi-prong attack, targeting all aspects of this disease, from molecules to cells, from individual lives to their families and societies. To achieve this goal, we need to better understand all these diverse and varied aspects of Alzheimer’s.       

Four Figures for this piece: 

Figure 1: Atrophic Brain with Alzheimer’s Pathology 

Figure 2: Normal Adult Human Brain 

Figure 3: Plaques and Tangles in a Brain with Alzheimer’s Pathology 

Figure 4: In Silico Representation of Model Drug Docking to Beta-amyloid Peptide 

(Figures 1-3, courtesy of Dr. S. Darvesh, Halifax; Figure 4 courtesy of Dr. A Meek) 

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