In July 2022, Weill Cornell Medicine scientists and the Alzheimer’s Disease Metabolomics Consortium published a paper detailing a new study that observed metabolic changes in Alzheimer’s patients, which confirmed existing and found new AD pathways.
Alzheimer’s is the most common type of dementia that leads to memory loss and other decline in mental functions, eventually leading to death due to the degeneration of brain cells and connections.
Corresponding author Prof. Jan Krumsiek, physiology and biophysics, worked with his research associate Richa Batra and several Consortium members to analyze metabolites and their levels in post-mortem brain samples from 500 participants from the Rush Memory and Aging Project.
The team focused on 667 metabolites—small molecules that are used and made during metabolism—in order to investigate metabolism, the chemical processes for creating energy, a central process in virtually all living organisms.
The research revealed that AD is a highly metabolic disease, meaning that the brains of AD patients experienced significant changes in brain metabolism.
“The genome and epigenome are the capabilities of the system and the transcriptome and proteome, in simple terms, is what the cell or biological system is trying to achieve, like making new building blocks and tools, but metabolism is what has already happened,” Krumsiek said.
“If you see the metabolic changes, you know a difference was made.”
Despite being unable to choose specific metabolites for study due to equipment limitations, Krumsiek explained that there was a general trend among the metabolites being measured.
The team highlighted eight specific AD components such as their diagnosis, level and trajectory of decline of cognition and beta amyloid and tau proteins which accumulate in the brains of AD patients, etc.
Analyzing these traits with levels of the metabolites showed that almost half of the metabolites measured correlated with at least one of the eight traits.
“This means that there is a massive dysregulation at a very global scale of metabolism in the brain for people who either have symptoms or some sort of brain pathology of this disease,” Krumsiek said.
“This is significant because there are some diseases that show metabolic changes, but only within a handful of metabolites.”
Interestingly, the study saw that metabolic dysregulation was less pronounced in amyloid beta than what was observed with the tau protein.
Amyloid beta is a protein that forms deposits of plaques around brain cells and tau is another protein that forms tangles between brain cells. These two proteins are key features of the disease.
Although it cannot be concluded whether beta amyloid is the appropriate target for AD drug treatment, results from the study reveal a potential new field of research that could be used in future treatments.
Researchers also focused on four specific pathways associated with AD: change in cholesterol metabolism, bioenergetic changes, inflammation and osmoregulation.
While changes in cholesterol metabolism, energy homeostasis and inflammation is fairly well known among those in the field, osmoregulation, is relatively new.
Osmosis is the cellular mechanism of the movement of water and is tightly regulated because of the significant impacts of pressure changes. This is particularly concerning because changes in osmosis and water homeostasis may influence protein folding.
Research has shown that misfolded amyloid beta proteins have been linked to AD where the misfolded proteins accumulate to form plaques. This has categorized AD as a proteopathy— a protein misfolding disease.
Krumsiek will continue research on potential treatments for AD through a NIH grant, using computational drug repositioning which is to use an existing drug in the treatment of a different disease. This is possible because the drug is not treating a disease but rather targeting certain pathways, a molecule or a gene.
“Alzheimer’s and drug research is in a complicated state. There’s been a lot of failures and question marks, but one of the data sources to find these unexpected connections is this paper because we found how Alzheimer’s talks to metabolism.”
For Krumsiek, the results of the paper show potential in such areas which have not been frequently explored.
“You can now check how metabolism talks to genes, and realize that maybe some of these genes are affected by drugs we have never thought about in that way. It is a more innovative way of using this screening type of experiment for finding new therapeutics, for example.”