Dementia

This is such an important topic to cover, even for a pediatrician.

This problem is slated to exponentially worsen in the coming decades. And it starts at birth!

​In the intricate landscape of Alzheimer's disease (AD), emerging research underscores a pivotal yet under explored facet for the why?, the brain's energy immunometabolism. A recent study by Patel et al., titled "Global Energy Metabolism Deficit in Alzheimer Disease Brain," delves into this domain, revealing significant metabolic disruptions that may illuminate novel upstream causes and possible therapies.

​ For the better part of the last few decades, all AD research centered on the amyloid and tau plaques as the causative problem. However, billions of dollars and many drugs later, this hypothesis has crashed and burned. Failed therapies coupled to the skyrocketing volume of AD patients in the US over the next few decades will burden the US healthcare system and families alike. Folks, we need better answers and therapies rapidly. Thus, I have been following this information on and off over the years looking for answers. Last month, Dr. David Perlmutter gave an excellent lecture on microglial cells in the brain and their impact on AD and neurocognition in general. One paper that he cited was the Patel paper. Let's look at it.

Dr. Patel conducted a metabolomic analysis on postmortem prefrontal cortical tissues from individuals diagnosed with AD compared to matched controls. Their objective was to discern alterations in canonical energy metabolism pathways, focusing on glycolysis and the pentose phosphate pathway (PPP). The findings were striking: glucose-derived metabolites in both pathways were uniformly diminished in AD brains compared to controls. Additionally, levels of β-hydroxybutyrate (BHBA), a key ketone body, that the brain loves, were markedly reduced. Notably, despite these metabolic deficits, glucose concentrations remained unchanged between the groups, suggesting a specific impairment in glucose utilization rather than availability. ​

In laymen's terms, this means that the brain of an AD person has defective mitochondria and thus defective engines for utilizing glucose for energy as well as building blocks for DNA, RNA and other nucleic structures. This is a big deal as bio energetics are the hallmark of aging when they are faulty. Faulty engines lead to faulty neuronal function leading to the symptoms of AD.

Mitochondria are GROUND ZERO for research and the future of AD.

The brain's reliance on glucose for energy is well-established, with glycolysis and the PPP playing central roles in neuronal function and survival. The brain uses 30%+ of the glucose in circulation at any one time. The observed decrease in glycolytic intermediates indicates a compromised ability to generate adenosine triphosphate (ATP), essential for maintaining synaptic activity and cognitive processes. Furthermore, the PPP's role extends beyond energy production; it is crucial for generating nicotinamide adenine dinucleotide phosphate (NADPH), which supports antioxidant defenses and biosynthetic reactions. A reduction in PPP metabolites suggests heightened vulnerability to oxidative stress and impaired synthesis of nucleotides and fatty acids, potentially exacerbating neuronal degeneration. ​

Again, this means that the mitochondrial dysfunction leads to poor energy production as well as weakened ability to handle oxidation which is the by product of energy production via the burning of glucose and fatty acids. This all leads to cellular damage and senescence over time.

The study also noted diminished levels of BHBA, a ketone, in AD brains, which presents a paradox. Under normal circumstances, when glucose metabolism is impaired, the brain can utilize ketone bodies like BHBA as alternative energy substrates. The reduction of BHBA implies a failure to compensate for glucose metabolic deficits, leading to an overall energy shortfall. This finding aligns with previous research indicating systemic metabolic disturbances in AD, including decreased ketone body availability and utilization. ​

These metabolic impairments are not isolated observations. Studies utilizing animal models, such as intracerebroventricularly administered streptozotocin (ICV-STZ) in mice, have demonstrated similar neurometabolic deficits, reinforcing the concept of energy metabolism disruption in AD pathophysiology. ICV-STZ-treated mice exhibit reduced glucose oxidation rates and compromised synaptic neurotransmission, mirroring the metabolic disturbances observed in human AD brains. (Soni et. al. 2021)(Grieb et. al. 2015)(Fan et. al. 2022)

Moreover, the correlation between diminished cerebral glucose metabolism and cognitive decline has been substantiated through various imaging studies. These studies reveal decreased glucose utilization in specific brain regions associated with memory and cognition, such as the hippocampus and cortical regions: parietal, temporal, and prefrontal cortices. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer's disease. ​(Zhang et. al. 2023)

The study by Patel et al. contributes to a growing body of evidence highlighting global energy metabolism deficits in the AD brain. These findings suggest that therapeutic strategies aimed at enhancing cerebral energy metabolism, improving glucose utilization, and supporting alternative energy pathways may hold promise in mitigating AD progression. As we continue to unravel the complexities of AD, focusing on metabolic interventions could pave the way for more effective treatments and preventive measures.​

Take home point: the function of our mitochondria, the power generators of our cells, are of paramount importance to the prevention of dementia and other neurology based diseases. In the brain, the mitochondria inside glial cells are taking center stage in the damage associated with AD.

It is our job to stop this process by eliminating the upstream causes of this dysfunction. Here are some ideas:

1) Avoid UltraProcessed foods

2) Avoid large volumes of any food that spikes your blood sugar - potatoes, rice, pasta, bread, flour based foods, etc...

3) Avoid toxins in all forms as they over work the antioxidant systems in the body

4) Reduce sleep and mental stress for the same oxidant reasons

5) Increase omega three fatty acids as small oily fish or fish oil

6) Exercise daily - no excuses - likely the greatest lever to reduce AD risk

7) Sweat via exercise, sauna, etc...

8) Get adequate sun exposure at dawn, dusk and during the day for vitamin D, POMC, melanocyte stimulation and immune integrity

9) Time restricted eating and true intermittent fasting - induce ketosis when possible

10) If you have blood sugar issues, consider metformin and the new glp1 agonists until you have the dietary and exercise program under control

11) Increase fiber as food and supplement while considering adding akkermansia as a probiotic

12) Eat lots of antioxidant and polyphenolic compounds daily. Consider a polyphenol supplement

13) Individual research on compounds like Urolithin A, Rapamycin, Lion's Mane mushrooms, sulfurophane and others are emerging

Finally,

Books related to dementia and metabolism: 1) The Ageless Brain and the End of Alzheimers - Dale Bredesen, 2) Drop Acid - David Perlmutter, 3) Nature Wants Us to Be Fat - Rick Johnson

Dr. M

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