Do we have the right mechanisms for understanding Alzheimer’s disease?

We have just completed a study to analyze the contribution of known biological pathways to the dysfunction that is Alzheimer’s. Our work, published in Frontiers in Aging Neuroscience, found that most biological pathways can be related to AD pathogenesis. It was surprising that the most studied pathways in Alzheimer’s are in fact not not genetically enriched with AD genes.

Alzheimer’s disease (AD) is a really complex neurodegenerative disorder. There must be many underlying dysfunctional mechanisms that result in the eventual loss of cognition. Using 206,324 dementia publication abstracts we found that 91% of Kyoto Encyclopedia of Genes and Genomes biological pathways are associated via at least 5 studies.

The same set of top-ranked pathways have been consistently related to AD for 30 years, including AD pathway, immune systemmetabolic pathwayscholinergic synapselong-term depressionproteasomediabetescancer, and chemokine signaling.

AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results can be explored at www.adpathways.org.

What does this mean to those suffering from Alzheimer’s dementia?

First, we clearly have underestimated the breadth and reach of the disease. The lack of understanding of the process of the disease is its most powerful block to getting drugs that actually reduce the loss of memory and cognition that occurs as the synapses between the neurons in the brain die.

Second, we need to acknowledge that animal models drive us to bias our understanding into animal functions – animal models allow us to do experiments that work well in animals, and the experiments that work well are the ones that animals can best recapitulate in the disease. For instance, many studies focus on biological pathways that are well understood in animals.

Third, we need to take a fresh look at choosing potential drug targets. Although this is now a well accepted problem, this study reiterates the folly of drug targeting against AD related pathology in the brain. Drug studies have not targeted the well studied biological pathways in AD. The breadth of functional scope of the disease needs to be reconsidered.

Finally, this work points out that understanding what prevents the onset of cognitive loss in Alzheimer’s may be the most fruitful way to develop drug therapies. Looking at individuals who have Alzheimer’s related pathology in their brains – amyloid plaques and neurofibrally tangles but have not lost any of their cognitive ability is a potential strategy. These ‘resilient’ individuals may be controlling the impact of AD related pathology on their brains health – if we can find how they control that resilience, perhaps we can emulate it in the form of a drug that changes the activity of AD related pathways in the brain.

Looking for motivated researchers

Our laboratory works with some of the best Alzheimer’s researchers out there. We are so fortunate to have their expertise to guide our studies into the systems that drive AD.

Come join us! We are looking for people who really want to train to become future leaders in complex disease translational research. We are particularly interested in candidates who are from under represented minorities.

Advertisement

About winhide

I develop and use computational biology approaches to impact global public health in research such as understanding of stem cell biology, systematics of cellular profiling and complex diseases.
This entry was posted in Uncategorized. Bookmark the permalink.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s