What Went Wrong: Three Major Challenges To Alzheimer's Disease Drug Discovery

Edited from an original interview with Dr. Isacson that was published by Vedi Saina and Biorasi for Clinical Leader, published on June 21st 2022 (clinicalleader.com).

Alzheimer’s disease affects millions of individuals worldwide. It is the most common cause of dementia and is increasingly prevalent in older populations. In the United States alone, the number of adults affected with Alzheimer’s disease has been projected to reach 13.8 million by 2050 (1), with the incidence of the disease occurrence doubling every ten years. Alois Alzheimer published the first case study describing distinctive structures, called plaques, in the brain of a patient with memory impairment in 1906 (2). Since then, our understanding of the disease that bears his name has grown rapidly. However, to date, there is no cure for Alzheimer’s disease, and it inevitably progresses in all patients. Why doesn’t a cure exist yet? There is no simple answer to this question. However, a deeper understanding of the disease process and a closer look at clinical trial challenges may help to shed some light.

Alzheimer’s disease is a neurological condition that clinically manifests as dementia or loss of cognitive capacity in affected individuals. The patients present common symptoms, such as memory impairments, loss of decision-making ability, and behavioral alterations like apathy, social disengagement, and irritability. This loss of cognitive capacity is a severe functional disablement for the patients.

Traditionally, the pathological hallmarks of Alzheimer's disease include the presence of aggregates of two misfolded proteins, namely, beta-amyloid and tau in the brain: tau inside the brain cells and amyloid outside. Unfortunately, this elementary description is one reason we don't have a treatment for this disease.

Complex Pathologies in Alzheimer’s Disease

Alzheimer’s disease presents in many forms. There is familial or inherited Alzheimer's disease and dementias that are seen with people who primarily develop aggregates of beta-amyloid and tau proteins. Inherited forms of Alzheimer’s disease typically present before 65 years of age in persons who have mutations in the genes related to beta-amyloid or tau related proteins. However, the most common form of Alzheimer’s disease is late-onset Alzheimer's disease or LOAD. It develops similarly to the familial disease, but the typical onset of the symptoms starts after 65 years of age. Although LOAD does not have a simple familial-genetic basis, it is interesting to note that the most significant risk factor for this disease in addition to aging, is for people carrying different variants in the gene, apolipoprotein E (epsilon).

Apolipoproteins are proteins that carry fat-or lipids around the body and between cells. They exist in three different types and are abundant throughout the brain and the rest of the body. The people who carry the APOE4 type gene variant tend to develop this late-onset Alzheimer’s disease with a much higher risk. This gene is also associated with generating beta-amyloid and tau aggregates, but the later onset and course of disease is different than the patients with familial disease. Therefore, there may be something happening upstream of the end-stage disease pathology, prior to the formation of the protein aggregates, which decides the course of LOAD.

There is yet another version called vascular Alzheimer's disease or vascular dementia that shares most features with the classic pathology that Alois Alzheimer observed. The blood vessel (vascular) contribution to developing dementias, including AD, is believed to be related to changes in blood-flow in the brain, and likely brain micro-bleeds in many cases. Such vascular changes likely trigger tissue damage and inflammation that interfere with cognitive capacity and in addition accelerate the tombstone and protein aggregate pathology with age.

Many of these Alzheimer’s disease pathologies demonstrate a loss of brain cells called neurons and their connections to each other (synapses). The remains of these dead neurons and synapses form “tombstones” or “ghost tangles” that can be seen at pathological brain examination in patients. The word “tombstone” is generally used to denote the debris formed by dead neurons, synapses, and their misfolded proteins as they remain behind after extensive cell death in the brains of Alzheimer’s patients, similar to the tombstones in a graveyard. Further, among the earliest observances in Alzheimer’s pathology are the specific scavenger cells in the brain called microglia that gather near the tombstones. These cells are typically associated with inflammation, and may trigger a severe immune response in the brain. As Alzheimer’s disease intensifies through inflammation of several origins, infections and inflammatory signals reaching the brain can lead to an abrupt increase in these scavenger cells in the brain (3).

Alzheimer’s disease is made up of a host of different forms and causes. “There is undoubtedly more to the disease process than just the late presence of protein aggregates. Hence, a renewed emphasis on finding new potential therapeutic targets for Alzheimer’s disease is urgently required.

Challenges to Drug Discovery

The only known treatments for the symptomatic forms of Alzheimer’s disease engage the neurotransmitter acetylcholine, which is released locally in the synapses by the neurons, to support cognitive function in the brain circuitry. However, these treatments appear secondary as the lack of acetylcholine is not the reason behind the Alzheimer’s disease pathology development. Acetylcholine only helps improve the memory function (to some extent) that has been lost due to Alzheimer’s disease pathology. Several drugs for treating Alzheimer’s disease have been analyzed over the past few decades, reached phases I, II, and III of the clinical trials, and failed. The problem is manyfold:

• Too much focus on plaques and tangles. Drug companies over the years have made it their main focus to find the agents that can reduce or remove the amyloid and tau plaques from the brain. These clinical trials have mostly neglected the processes that take place before the formation of these plaques.

Perhaps the greatest, should we say, ‘almost’ tragedy of Alzheimer’s clinical trials is an oversimplification – that you can simply reduce these late protein pathologies and expect the patient’s capacity to think and memorize to then return. This is most unfortunate but also a learning opportunity for regulatory bodies, including the FDA, in that relying on ‘pathological markers’ (such as beta-amyloid PET imaging) rather than a real understanding of the neurobiology of disease (such as cellular processes, mechanisms and responses to disease drivers) will not lead to clinical success.

In Alzheimer’s disease research, both the academic and industry representatives convinced regulators that removing plaques in the brain would be the same as improving Alzheimer’s. This turned out to be a serious fallacy. Amyloid plaques are not a good surrogate marker for either brain cognitive function or the disease process that occurs upstream of these plaques. Alzheimer’s disease has a complex pathology and has a very slow and prolonged course of development, amyloid plaques being just a tiny part of it. Although it’s exciting for clinicians and a drug company just to show that their drug can help remove these plaques, it is not sufficient to significantly reduce the disease process or cure Alzheimer’s. And while the industry spent over a decade focusing on drugs that chopped or blocked amyloid precursors, each and all of those trials failed.

One thing is essential in researching Alzheimer’s disease: Realizing that disease pathology is not equal to the disease process. The genetic familial forms may even begin the disease process in a different sequence (protein pathology first) than most common forms of AD, including LOAD, where other upstream events probably dominate in the evolution of the cell and tissue problems leading to brain dysfunction, before the late cell death, plaques and tangles that currently define the clinical pathological diagnostic criteria and definitions of AD.

• Learning from failed clinical trials. We should never again trust a single surrogate biomarker for a disease as complex as Alzheimer’s disease. Instead, the industry needs to focus on a complex biomarker index, which could be a combination of the changes that the brain or blood or the cerebrospinal fluid that occur before we see Alzheimer’s pathology or during the course of its development. In addition, independent computer based computational models of biomarkers and their potential causes can be helpful in defining best targets and treatments for individual patients or people at risk for disease.

• Lost cognitive circuits are difficult to re-form. Most of the clinical trials in Alzheimer’s research have focused on only improving the symptoms of dementia, such as memory, decision-making, and execution in the patients. Although evaluating these functions is essential for measuring the progression and analyzing the severity of the disease, the symptoms are challenging to reverse.

The other major problem with clinical trials in this field is that when someone is symptomatic with a disease, they have lost neurons and synapses. It is tough to reengage the cognitive circuitry to get cognitive enhancement back on track. On the other hand, it also difficult to do ‘the prevention of disease’ trials: The cognitive measures we see change very little during the initiation of the disease process.

One of the key elements is that if you don’t manage to prevent the disease, that is, stopping dysfunction of the synapses, there is less chance of actually improving function. However, there are several attempts and efforts that perhaps can sustain synaptic function and reduce neuroinflammation at early stages of the disease process – such trials may actually be able to open up the door for successful clinical treatments, particularly if combined with reducing the upstream drivers of the disease.”

Over the past several years, the government and the private sector have taken on a host of initiatives to develop a deeper understanding of Alzheimer’s disease. In 2004, the Alzheimer's disease neuroimaging initiative (ADNI) was launched to put together the data from neuroimaging, genetics, psychology, neurophysiology, and molecular neurosciences to define the progression of Alzheimer’s disease (4). Similarly, the Accelerating Medicine Partnership (AMP), a noncompetitive government-industry program, has been developed to look at Alzheimer’s disease from different perspectives (5).

The new route that Alzheimer’s research has taken after these initiatives is encouraging. The researchers in the Alzheimer’s field are now focusing on not only plaques but a variable degree of parameters – putting together the patient readings from brain imaging, genetics, cognitive tests, blood, and cerebrospinal fluid. Several of these findings are open access, allowing scientists, academics, and industry stakeholders to work together to define the disease pathology, and in some cases opening up whole new fields by using artificial intelligence and algorithms that seek to understand how all these variables are linked. Working together, I believe we can connect the dots – uncovering the mechanisms that lead to the neuronal damage and loss of synapses and then focus on a treatment that can prevent or reverse that process.

Finally, there is the promise of finding more specifically defined patients or patients at risk, to deal with their specific drivers of disease, rather than one-treatment fits all. Such ‘cohort enrichment’ trials need to be understood not only in genetic terms but also in what the person is showing as their major cell biological disease drivers – then we can truly intervene and be more successful by using treatments that are more suitable, which is the promise of precision medicine.

The U.S. government recently launched the Precision Medicine Initiative in 2015 with the hope of revolutionizing health and disease.

The precision medicine approach, which customizes and tailors the therapeutic strategy according to more specific and less heterogenous groups of patients (maybe still in the millions), may be the path forward with Alzheimer’s disease (6).

References

1.         L. E. Hebert, L. A. Beckett, P. A. Scherr, D. A. Evans, Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 15, 169-173 (2001).

2.         H. J. Moller, M. B. Graeber, The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections. Eur Arch Psychiatry Clin Neurosci 248, 111-122 (1998).

3.         H. Jahn, Memory loss in Alzheimer's disease. Dialogues Clin Neurosci 15, 445-454 (2013).

4.         J. A. Hendrix et al., The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update. Alzheimers Dement 11, 850-859 (2015).

5.         M. Allen et al., Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Sci Data 3, 160089 (2016).

6.         C. Reitz, Toward precision medicine in Alzheimer's disease. Ann Transl Med 4, 107 (2016).