Has the overreliance on animal models stagnated the development of Alzheimer’s disease therapeutics?

18 January 2023

by Shaarika Sarasija

Alzheimer’s disease is cruel. It steals from people those very things that make them unique: their memories, their cognitive skills, their personalities, and finally their lives. It can also significantly affect their loved ones, who must slowly watch the health of their family member or friend deteriorate. On top of all that, Alzheimer’s has tremendous social costs.

As baby boomers enter retirement age, a rapid rise in cases of Alzheimer’s disease should not come as a surprise. Globally, there are currently over 55 million people living with dementia; these numbers are expected to almost triple by 2050.

Age is the biggest risk factor for developing Alzheimer’s disease. Patients typically experience chronic and progressive loss of cognitive function, and develop characteristic pathologies like neuronal loss, amyloid plaques, and neurofibrillary tangles in the brain. Some 116 years have passed since the discovery of Alzheimer’s as a condition, and yet, we remain largely in the dark regarding its underlying causes.

Current therapeutic intervention is focused on symptom management with drugs, which come with a myriad of side effects and can have diminishing impact as the disease progresses. Over the past 60 years, the amyloid hypothesis has been the focus of drug development. This hypothesis postulates that amyloid-β peptides form clumps, which deposit and accumulate in the brain, triggering the neurodegenerative processes that lead to memory loss and the diminution of cognitive ability that are typically observed in Alzheimer’s disease. However, therapeutic strategies developed to prevent the formation and accumulation of amyloids, or to increase their clearance from the brain, have failed in clinical trials.

Lecanemab, a monoclonal antibody targeting amyloid-beta protofibril (large soluble aggregates), seems to decrease cognitive decline. However, when measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 0·45-point difference on the 18-point CDR-SB Lecanemab elicits might not be clinically significant. There are also concerns regarding oedema or microhaemorrhages observed in about 21% of the patients who received Lecanemab.

Research into the cause of Alzheimer’s disease and the preclinical testing of therapeutics have relied heavily on animal models: The majority of AD patients (>95%) are afflicted with sporadic Alzheimer’s disease (SAD), which could be a result of both genetic and environmental factors. In research, the most used species that display neuropathology similar to SAD are non-human primates and dogs.

Non-human primates are of interest to scientists due to their genetic similarity to humans, a well-developed prefrontal cortex, and age-related progression of cognitive deficits. However, there is significant variation in the extent of pathological changes among and within non-human primate species. Similarly, while dogs may develop amyloid-related pathology, there is divergence between their comparative brain structures related to sensory perception when compared to humans. It should also be noted that many researchers who use animal models in their research experience some dissonance or discomfort when confronted by research using non-human primates, our closest living relative and canines, who are considered man’s best friend.

Perhaps due to relative ease of use and affordability, the vast majority of animals used for AD research tend to be transgenic mice. However, 99% of clinical trials testing potential AD therapeutics have failed, despite the same therapeutics being successful in preclinical stages where transgenic mice were used. A number of factors help to explain this failure rate:

• Transgenic mice are used to model familial Alzheimer’s disease (FAD) which is caused by autosomal dominant mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the amyloid precursor protein (APP), and accounts for less than 5% of all cases of AD in humans.
• Unlike humans, mice do not develop amyloid plaques as a part of normal aging; their symptoms are induced by the expression of chimeric and/or mutant human [word missing here: “genes” maybe?]. As a result, these animals tend to mimic human pathologies ineffectively. For example, while most transgenic mice display the amyloid accumulation characteristic of AD, that does not always translate to specific memory-associated cognitive decline. Also, they tend to develop amyloid plaques at a very young age (6-9 months), which does not reflect the average age of disease onset (about 80 years) in humans.
• These models do not always display other pathological characteristics endemic to the human disease, such as the development of neurofibrillary tangles or neuronal loss. For example, the accumulation of insoluble tau aggregates results in the formation of neurofibrillary tangles in humans with AD. However, given that no mutation in tau has been linked to AD, AD mouse models with tauopathy carry mutations associated with frontotemporal dementia, thereby not being truly reflective of the tauopathy in a human brain.

These factors contribute to significant gaps in knowledge that is stalling progress in research . While recent efforts have been made to develop mouse models that better mimic the more common (>95% of cases) late onset sporadic AD, these efforts are still in an early stage.

It is critical that AD research pivot from the current standard of animal models towards a more human-centered paradigm. Over the last decade, various research groups have succeeded in the development of 3D, multicellular, cerebral organoids using human stem cells, known as AD organoids. AD organoids have been successful in replicating multiple aspects of AD pathogenesis as seen in humans, in the same system, like amyloid plaque deposition, neurofibrillary tangles, as well as induction of neuroinflammation. These organoids could be spheroids, brains-on-a-chip, 3D bio-printed brain tissues and/or vessels, and combination platforms. Given that these systems are developed using cells from AD patients and their unaffected counterparts, scientists can get a more accurate representation of both familial and sporadic AD. Recent work has demonstrated the potential for brain organoids to be combined with other organoids to create body organoids, producing a more systemic perspective. These features, along with their relative ease of use, cost effectiveness, and potential for extension to high-throughput screening, make them a more desirable and reliable model for studying AD compared to animal models.

Twenty-two years ago, the noted biomedical engineer, Mehmet Toner stated: “If we researchers had always been forbidden from using animals for research, by now we would have found a way to answer all these questions directly in humans”.

Toner’s observation highlights the significant scientific, economic, and human costs incurred because of our historical reliance on animal-model based biomedical research. However, there have been significant breakthroughs in the development of non-animal methods, and now more than ever, we have strong incentives to invest our time, money, and scientific capital in human-based models. As awareness grows regarding the power of human-based models of AD, strategic grant -making should inspire a move away from failing animal models and toward advanced, human-based approaches, to provide the best therapeutic intervention necessary to help AD patients.

What do you think? Please share your thoughts and comments below.