Alzheimer's may be a metabolic disease where a broken energy shuttle starves neurons. An enzyme called IDO1 drives this damage by blocking astrocytes from feeding neurons lactate. A cancer drug called PF068 that blocks IDO1 restored memory in animal models and human cells.
What causes Alzheimer's disease? This is a complex question without a linear answer. However, what I can say with relative confidence is that Alzheimer's disease is a metabolic disease characterized by dysfunctions in how brain cells, neurons, and their partner cells called astrocytes process and produce energy in the brain. And chronic progressive failure in brain energy metabolism can result in dementia, including Alzheimer's disease. Now, new research in the prestigious journal Science has identified a key node in brain metabolism that acts as a convergence point of the classical amyloid and tau pathologies in the Alzheimer's brain. And this new finding opens up an unexpected way to target this node to rescue brain metabolism from dementia. But to truly understand these exciting novel findings, why I'm so excited, I need to first arm you with some brain metabolism background. A moment ago I mentioned astrocytes, These are a type of glial support cell in the brain which support neurons. And one way in which astrocytes support neurons is by providing energy substrate to neurons in the form of the molecule lactate. So simply, astrocytes turn glucose via glycolysis and fermentation into lactate, and then the lactate can be passed from astrocytes to neurons for energetic support. And failure of this astrocyte-neuron lactate transport shuttle undermines neurons' ability to generate energy and undermines their ability to carry out critical neuronal functions, which is simply put, not good. So now let's introduce that node I mentioned in the brain metabolism network. It's an enzyme called indoleamine-2,3-dioxygenase, or IDO1 for short. IDO1 is an enzyme that converts the amino acid tryptophan into a molecule called kynurenine, or kyn for short. Now, What researchers of the study find is that the classical amyloid and tau pathologies in Alzheimer's disease each converge on and increase the activity of the IDO1 enzyme, which increases Kyn levels, thereby inhibiting astrocyte glycolysis, decreasing lactate transfer to neurons, starving neurons of energy. And I'll repeat that because it's very important to understand, and I appreciate it's a little complex. The hallmarks Alzheimer's disease, amyloid and tau, each can activate IDO1 enzyme in astrocytes, and this increases levels of a metabolite, kyn, which leads to inhibition of lactate production by astrocytes. Therefore, astrocytes can't provide neurons with as much lactate, and this leads to energetic starvation in neurons and brain metabolic failure. And impressively, in this paper, they found that this pathway was relevant in 3 independent animal models of Alzheimer's and has parallels in human brains, in human brain cells where human astrocytes from patients with the most common form of Alzheimer's disease, late onset Alzheimer's disease, also had lower tryptophan and higher kyn levels, and that inhibiting IDO1 normalized these levels, basically revealing that this pathway is active in the human Alzheimer's brain as well. And that brings me to the solution part of the video. It's quite possible to inhibit IDO1 and in so doing restore normal astrocyte glycolysis and lactate production to feed neurons and support brain metabolism. Indeed, they found that inhibiting IDO1 restored astrocyte glycolysis and lactate production. It improved metabolic function in the brain, improved neuronal function and markers, functional markers of learning like long-term potentiation, and improved memory. And these effects were replicatable across models. Granted, one can't actually do these particular experiments in live humans, at least not yet. Although the effects were replicatable in human cells as far as metabolic bulk rescue was concerned. So really, the question now is, how could we today attack this pathway in live humans with Alzheimer's disease? And the answer is, there's actually already a cancer drug that targets IDO1, uncreatively named PF068 in this paper. But this raises the possibility of repurposing a cancer metabolism therapy for Alzheimer's disease. And what's more, the IDO1-KYN pathway is also involved in other forms of neurodegenerative diseases like Parkinson's disease, leading to the possibility that targeting this pathway could have positive effects on dementia and neurodegenerative diseases beyond just Alzheimer's. Now, that constitutes the thrust of what I wanted to share with you on these particular new data. That said, I am catching on, and in anticipation of a question I know I'll receive in the comments— what can I do to decrease my risk of Alzheimer's disease today?— here are my high-level suggestions for protecting yourself against dementia and Alzheimer's disease. First, exercise. What's good for the body is good for the brain. This is in part due to indirect effects of exercise and overall health, but is also due to direct effects whereby exercise can increase levels of certain brain protective neurotrophic factors like BDNF, which support good brain health. Two, and this is quite obvious but bears repeating, get adequate sleep. The amount needed varies from person to person, but generally 7 to 9 hours is adequate for most. Sleep is really important for clearing the metabolic debris out of your brain, the debris that built up over the course of a day. Third, get long-chain omega-3 fatty acids in your diet, EPA and DHA. Personally, I like consuming these from fatty fish, the SMASH fish: salmon, mackerel, anchovy, sardine, and herring. You can get them from supplements as well, but there may be benefits beyond the omega-3s of actually eating real fatty fish, and this includes the presence of certain potentially neuroprotective forms of selenium. And if you want more on that, check out this video linked below. Furthermore, for those specifically with the APOE4 risk allele for Alzheimer's disease, the literature continues to suggest eating a lower carb, higher fat fat and potentially ketogenic, although not necessarily, diet might be particularly beneficial. I'll link to more resources on that below because it's something I've done quite a deep dive on. And finally, enjoy life. While I'm by no means a socio-neurobiologist, it really appears that social connection and life purpose have powerful effects on lifespan and healthspan. So don't forget to enjoy the ride. It might just help you not forget.
