ALZHEIMER; THE HOLY GRAIL

Alzheimer, everything you've always wanted to know, but didn′t dare asking.

Before the arrival of Pasteur and Koch, diseases were defined by their symptoms and not by their cause (etiology).

It may seem incredible, but there are still diseases that are defined by their symptoms, because we don't yet know their source. One of these diseases is Alzheimer's...

Unfortunately, there are many things that we don′t know about Alzheimer:

Is Alzheimer a homogeneous pathology? Are early onset (young linked to genetics) and late onset (elderly and sporadic) the same disease?

Can we say for certain that a patient diagnose of dementia suffers Alzheimer?

Will we ever find medicines to cure it?

We will try to answer these and other questions in this article

 When somebody heard the word Alzheimer immediately make the association with dementia. We tend to think that the diagnosis and pathology of this disease is well stablish. However, when we investigate we could have a great surprise…the scientific community really don′t know what Alzheimer is and how to diagnose it.

The Alzheimer disease was first described by two psychiatrists, Emil Kraepelin and Alois Alzheimer. Alois Alzheimer reported the first case in 1901, although Dr Kraepelin was the first who describe the pathology of the disease. In fact, Kraepelin recognized the discovery of the disease by his colleague, calling this pre dementia in young people “Alzheimer disease”.

 For many years (almost XX century) the definition of Alzheimer disease was an early onset dementia, patients between 45 and 65 years old. However, this terminology changed after a conference in 1977. From that moment and so on we consider Alzheimer disease not only the dementia that happens in young patients but also in elderly patients. Therefore, a disease that was first describe in a 51 years old woman (early frontal dementia) nowadays describe almost 50-70% of the dementia diagnosed in the world (young and elderly patients) Here, it comes the first question…are all the dementias called Alzheimer the same disease?

A quick answer to that question would be…yes if we have a standard method to diagnose it. But (second surprise) we really don′t have a 100% chance to know if the diagnose is correct or not. The diagnose of Alzheimer disease is histological, in other words we are not sure until the patient dies and doctors perform a histopathological analysis. So, how can doctors perform the pre morten diagnosis of these patients? Well the easiest way to answer this question is to say that Alzheimer diagnose is an exclusion diagnosis. Exclusion diagnosis what does it mean? Doctors should exclude first other pathologies to diagnose Alzheimer.

Nowadays, the diagnose is based on person′s medical history, assessing memory testing (ADAS COG) and recently imaging techniques (MRI and PET) or CSF analysis. And someone could think…but if we have a clear knowledge about the disease, why we don′t have a specific test? However, we don′t really know the pathophysiology of Alzheimer disease. Indeed, there are several hypotheses about how the disease appears and evolves (cholinergic hypothesis, B amyloid, tau hypothesis, foil exposure or even celiac disease...)

In summary, we have many questions and not many certainties:

Is Alzheimer a homogeneous pathology? Are early onset (young linked to genetics) and late onset (elderly and sporadic) the same disease?

Can we say for certain that a patient diagnose of dementia suffers Alzheimer?

At this point the reader may think, and how do they intend to find drugs for Alzheimer's if they don't even know what it is?

Through this entry and those that will come, we will try to shed some light on this and other fields like immunopathology.

But what occupies our minds today is finding drugs for Alzheimer's. To start with this arrogant and complex endeavor we are going to start by writing about the epidemiology, pathology and current treatments in Alzheimer's disease.

Later we will review the different drugs that are under development and those that have been discarded. We will focus on the latter by looking for guidelines that can help us determine whether those still under development can be successful.

DEFINITION: In three words Alzheimer is a primary cortical dementia. It is neurodegenerative disease characterized by cognitive impairment (immediate loss of memory) and behavioral disorders. The loss of memory and other higher cognitive abilities increase as nerve cells (neurons) die and different areas of the brain atrophy. The disease usually lasts about 10 years on average after diagnosis.

Although there are different hypotheses of the origin of the disease, the most widely accepted is related to the proteins b amyloid and tau (cascade hypothesis). According to this theory accepted in 1991, the extracellular accumulation of Ab peptide and the intraneuronal aggregation of the tau protein are the causes of Alzheimer's disease.

ab is the product of the cleavage of a transmembrane protein precursor called APP, encoded by the APP gene present in chromosome 21. APP is cleaved by the enzyme b secretase (BACE) and the gamma secretase complex, in which presenilin bears the catalytic site.

The tau protein is a protein encoded by the MAPT gene located on chromosome 17. There are several isoforms of the tau protein (3R or 4R), both of which accumulate in Alzheimer's disease

CLASSIFICATION AND GENETICS: There are two main types of Alzheimer disease:

EAOD: Early onset and genetic related- The dominant mutations involve PSEN1 (cromosome14), PSEN2 (chromosome 1) or APP (chromosome 21)

LOAD: Late onset and sporadic-(apoE4 related) This is the most common Alzheimer disease. If the reader is still awake, she will remember that this type of dementia did not fall within the classic definition. However most of the patients included in clinical trials belong to this group as it is the most frequent.

EPIDEMIOLOGY: Alzheimer disease is the leading cause of dementia: 70% of cases.

Several sources estimate that in 2017, there were 10 million total prevalent cases of AD in the US, Japan, and five major EU markets. The number of total prevalent cases of AD in the US, Japan, and five major EU markets will increase to 16 million.

Increasing aging populations, particularly of those aged 65 years and older, in the US, Japan, and five major EU markets will contribute to the increasing prevalence of AD over the next 20 years

PATOPHISIOLOGY:

Macroscopy: In an Alzheimer brain we could see atrophy (in fact there is a strong correlation between atrophy and neuronal loss), thickness (could be evaluated by MRI) and amyloid angiopathy (maybe a consequence of the synergistic effect of ischemia) 

Microscopy: We should differentiate between positive signs (accumulation, increase…) and negative signs (loss, reduction…)

Positive signs: Parenchymal deposits of AB (could be diffuse, focal or stellate). The well-known cotton wool plaques are focal deposits of AB.

Vascular deposits: AB accumulates in the walls of arteries, capillaries and veins.

Although AB deposits are extracellular, we can see some deposits intracellularly.

TAU aggregates: The protein Tau belongs to a microtubule protein family. Tau is mainly located in the axon but can be found also in the synapses. The accumulation of phosphorylated tau has detrimental implications on synaptic plasticity. We see these aggregates in the cell body of neurons, dendrites and axons. Braak noticed that these lesions were distributed in a chronological order (40 years separate the stages I-II from the stages III-IV)

Negative signs: These lesions are not always easy to determine. There are synaptic and neuronal loss.

The assessment of the level of Alzheimer (low, intermediate or high) is based on three scales that combine the evaluation of different lesions: Thal phases for amyloid deposition, Braak for neurofibrillary stages and CERAD for the plaque score.

Most of the mutations associated with AC are located on APP gen or on genes involved in its metabolism. That idea has brought the conclusion that the accumulation of Ab amyloid is the main cause of AD (accumulation due to hyperproduction in genetic cases, and lack of clearance in sporadic cases) However, scientists know that there are other processes involved, inflammation (monocytes and astrocytes upregulated) and oxidative stress for instance. Furthermore, there are some voices that identified Tau accumulation as the main cause of AD.

Anybody still reading?? Complicating the issue further, there are no differences between neuritic plaques and other lesions as observed in AD patients vs. intact elderly. In other words, the lesions can be observed in cognitive intact elderly, therefore these alterations could be normal with advanced age.

TREATMENTS: Everybody knows that there is an urgent need for treatments in Alzheimer, however the last drug launched was memantine in 2002. Alzheimer has the dubious honor of the highest failure rate in development of treatments. According to the literature there were 105 agents in development for AD in 2017. Twenty-five of them in phase I, 52 agents in phase II, and 28 agents in phase III. As you see there are more treatments in phase II than in phase I, how can be possible? Well in many cases some compounds used for other diseases (apparently safe) try to reach phase III earlier to reduce deadlines. This fact may be behind the loss of many Phase III compounds due to the lack of an adequate safety profile.

Going back to the development pipeline 70 % of the drugs are DMTs or disease modifying therapies, 14% symptomatic cognitive enhancers and 13% are symptomatic behavioral changers. One of the biggest differences between these trials and others form several years ago are the EARLY trials, trials that include patients with preclinical AD (normal patients with high risk) These patients have biomarker evidence of AD. Biomarkers are one of the greatest achievements in the better understanding of AD, because we can have a better idea of the diagnosis and prognosis of the disease. However, not only biomarkers are important but also amyloid imaging (ARIA amyloid-related imaging abnormalities can increase the trial success rate.

One of the main challenges in drug development for AD is recruiting. There is a large number of participants require to conduct the trials and that will represent a substantial challenge to the system. However, the idea of accelerating clinical trials and enhancing the recruitment could be detrimental to the drug discovery because reducing times don′t mean increasing the success rate.

But, do we have any examples of these failures? Can we determine why they fall?

We can look to monoclonal antibodies (disease modifying treatment) for instance to see some examples and possible reasons for its failure.

The first thing that we must consider is the mechanism of action. Monoclonal antibodies one of the most promising treatments for AD target amyloid. These drugs try to clear amyloid; however, amyloid does not correlate with cognitive decline in the symptomatic phase of dementia (reason why they failed?) Furthermore, they target AB amyloid, but which part of it? N terminus, C terminus…and which isoform?

Some examples of mAbs:

Solanezumab: This monoclonal antibody reached phase III, but did not meet the primary or secondary endpoints. There were no changes in PET SCAN (amyloid) or in CSF (levels of tau). However, in a post hoc analysis in the mild Ad group show differences vs placebo.

Bapineuzumb: In this case the problem was safety. Bapineuzumab produced vasogenic edema, therefore the ratio risk-benefit was unfavorable. Some experts believe that the main problem was the low dose. Could be that the dose too low to demonstrate benefit?

Crenezumab: This one is interesting, not because of the drug but because of the trial design. This m Ab was selected for the prevention initiative. The trial selected families who are asymptomatic that have a genetic alteration (presenelin1 E280A mutation) that predisposes to early onset. They are targeting a homogeneous group of patients and not a mix of different Alzheimer′s diseases. Nevertheless, the treatment didn′t show clinical benefit in phase II (a post hoc analysis show benefit in mild patients) but the main objective of a phase II is safety and not efficacy.

Why are drugs failing?

There are several hypotheses:

-         Wrong pathological targets: Are we sure that the amyloid cascade is the main cause?

-         Are treatments too late? Perhaps the problem is not the pathogenesis, or the target the problem is the timelines. We are treating correctly AD patients but maybe is too late.

-         Different diseases: In 1977 several experts decide that early onset and sporadic Alzheimer are the same disease. Since that time, we didn′t talk about Alzheimer diseases to talk about Alzheimer disease, although the authors added that this consolidation did not at all rule out completely different etiologies.

-         Diagnose: As you already know the only way to know 100% that a patient suffer AD is to do a biopsy after death. ADAS-Cog (Alzheimer ′s disease assessment scale in the most common way of diagnosing AD in clinical trial. ADAS-Cog is a test that relies too much in the own investigator judgments (subjective?). Imaging trying to prove that a drug is effective in the treatment of AD when 30% of your patients suffer from another type of dementia Hopefully, today we are seeing the appearance of biomarkers (image and CSF) that can reduce the subjectivity of diagnosis and increase inter-rater reliability.

-         Clinical trial methodologies: There is too much pressure to find treatments and we need a great number of patients to do so. Making the inclusion exclusion criteria more flexible, or skipping developmental stages (dose escalation or safety) will not get drugs to patients earlier but rather the other way around stopping their development earlier.

Lastly, if you've been brave enough to get this far, you may be wondering will we ever find drugs to cure it?

We would like to tell our readers (with all the limitations that this implies) what drugs might eventually work in Alzheimer's disease.

To do this in the age of artificial intelligence, we will follow a homemade algorithm that could give us a hint of what the winners and losers may be:

1.-CT methodology: We will look at clinical trials that, although it seems incredible, do not skip any phase of development and do not go from a phase I to a phase III for example.

2.- Diagnosis: If you do not know the pathology in depth, use all available means at your disposal and not just one for diagnosis (biomarkers + test).

3.- Population: We have so many uncertainties we prefer trials with homogeneous patient populations (e.g. E280A mutation) to reduce some uncertainties.

4.- Combination: It seems that the pathogenesis of Alzheimer's does not involve a single cause. If we could find clinical trials that combine different drugs or mechanisms of action, it would be a good start.

5.- Time: Could be too late? we will focus on trials involving asymptomatic or very early-stage patients.

Maybe a clinical trial with all these characteristics will succeed in the future, or not…