Limitations of Animal Models in Alzheimer's Disease Research and Prevention

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• Mouse Model Failures in Alzheimer's Research
• The Search for Natural Alzheimer's Disease Models
• Is Alzheimer's a Human-Specific Disease?
• Social Determinants of Dementia Risk
• Protective Factors Against Cognitive Decline
• Future Directions for Alzheimer's Research
• Full Transcript

Mouse Model Failures in Alzheimer's Research

Dr. Steven Austad, MD, PhD, states that research into Alzheimer's disease treatments has been a spectacular failure. He notes that over 300 treatments developed in mouse models have not translated into effective human therapies. This stark reality leads Dr. Austad to a critical conclusion. The mouse is an insufficient model for understanding the complex biology of human Alzheimer's disease.

The Search for Natural Alzheimer's Disease Models

A significant problem in the field is the lack of good animal models. Dr. Steven Austad, MD, PhD, explains that current models are genetic caricatures. Researchers take human genes known to cause Alzheimer's and insert them into mice. Dr. Austad points out that even chimpanzees, which are over 99% genetically identical to humans, do not commonly develop Alzheimer's. This makes them unsuitable for natural model studies.

Is Alzheimer's a Human-Specific Disease?

Dr. Steven Austad, MD, PhD, discusses intriguing alternative models, such as the gray mouse lemur. This tiny primate shows brain lesions similar to those in Alzheimer's disease upon post-mortem examination. However, Dr. Steven Austad, MD, notes a critical difference. These lesions are not located in the same brain regions as in humans. This evidence suggests Alzheimer's might be a uniquely human condition, complicating research efforts.

Social Determinants of Dementia Risk

Human studies are challenging due to uncontrollable variables. Dr. Steven Austad, MD, PhD, emphasizes that people cannot be made to eat the same food or live identical lifestyles. He explains that Alzheimer's disease is profoundly affected by social determinants. Dr. Steven Austad, MD, highlights puzzling correlations that researchers are trying to understand. These include the protective effects of higher education and greater income against developing dementia.

Protective Factors Against Cognitive Decline

Research is beginning to uncover modifiable risk factors for Alzheimer's. Dr. Steven Austad, MD, PhD, identifies physical activity as a key protective behavior. This discovery, combined with the influence of education and socioeconomic status, paints a complex picture. Dr. Austad suggests that these factors collectively illustrate why a simple mouse model cannot capture the entirety of human Alzheimer's disease.

Future Directions for Alzheimer's Research

The interview with Dr. Steven Austad, MD, PhD, underscores a paradigm shift in neuroscience. The consistent failure of mouse models necessitates new approaches. Dr. Austad's insights call for a greater focus on human-specific research and the integration of social science. Understanding the biological mechanisms behind factors like education and exercise is crucial for future breakthroughs in preventing and treating Alzheimer's disease.

Full Transcript

Dr. Anton Titov, MD: Alzheimer's disease and other dementias correlate with aging. What are the innovative approaches to cognitive aging?

Dr. Steven Austad, MD: Alzheimer's disease is fascinating to a comparative biologist like me. We have been spectacularly failing at being able to do anything about Alzheimer's disease. There still aren't any treatments, even though we've had more than 300 treatments that we've developed in mouse models of Alzheimer's disease.

This leads me to think that the mouse is not enough to understand human biology. One of the problems is that we don't have good animal models of Alzheimer's disease. All we've done so far is we've taken some human genes that we know cause Alzheimer's disease, we put them in a mouse, and there's some caricature of Alzheimer's disease.

There don't seem to be any natural models. You would think that chimpanzees that are more than 99% genetically identical to humans would have something like Alzheimer's disease. But so far, we haven't seen it. It's certainly not common enough to study.

So what we need are some better natural models. Now there are a couple that are intriguing and may be helpful. One of them, believe it or not, is a very tiny primate called the gray mouse lemur. It weighs only 100 grams. It seems to show something very similar.

Looking at the brains post mortem, they seem to have similar lesions to Alzheimer's disease. However, they're not in the same places as in humans. This may be something that's a human-specific disease. We're still not sure about that.

But that makes it very, very difficult to study because humans are terrible experimental models. We can't have them all eat the same food and live the same lifestyle. Alzheimer's disease also seems to be affected by so many social determinants.

There's another level of biology that we don't understand. Why does a higher level of education reduce the risk for Alzheimer's disease? Why are people who make more money more protected from Alzheimer's disease?

I think we're starting to learn a little bit because now we understand that physical activity is protective against Alzheimer's disease. So I guess if you put all these things together, it makes us realize the limitations of a mouse for trying to understand a complex human disease like Alzheimer's disease.