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AAIC 2022 | Intermittent fasting in Alzheimer’s disease
Metabolic dysfunction, arising from impaired glucose metabolism and mitochondrial dysfunction, and neuronal network hyperexcitability are key age-related alterations postulated to be involved in Alzheimer’s disease (AD) pathogenesis. Mark Mattson, PhD, Johns Hopkins University School of Medicine, Baltimore, MD, outlines our understanding of these changes, what underlies them, and how boosting ketone levels is an interesting therapeutic approach to target these alterations. It is thought that when starved of glucose, neurons can still use ketones as an energy source and thus, using intermittent fasting to increase ketone levels may be beneficial. In AD mouse models treated with a dietary restriction regimen, researchers have seen increased resistance to degeneration of hippocampal neurons, delayed onset of cognitive impairment, and reduced Alzheimer’s neuropathology. Supplementing the diet of these mice with a ketone ester suppressed hyperexcitability, prevented seizure development, and enhanced GABA tone. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.
Transcript (edited for clarity)
It’s been known for a long time that patients with mild cognitive impairment and early Alzheimer’s disease have a deficit in the brain’s ability, the cells in the brain’s ability, to use glucose as an energy source. And that is based on PET imaging, Positron Emission Tomography with radiolabeled form of glucose. And then back in the early 1990s, we showed in my laboratory that the amyloid beta peptide when it’s in an aggregating state, can impair the glucose transporter protein that moves glucose into neurons...
It’s been known for a long time that patients with mild cognitive impairment and early Alzheimer’s disease have a deficit in the brain’s ability, the cells in the brain’s ability, to use glucose as an energy source. And that is based on PET imaging, Positron Emission Tomography with radiolabeled form of glucose. And then back in the early 1990s, we showed in my laboratory that the amyloid beta peptide when it’s in an aggregating state, can impair the glucose transporter protein that moves glucose into neurons. That was cell culture work. So we directly exposed the neurons to the amyloid protein and then measured glucose uptake.
However, increasing evidence suggests that neurons can still use ketones as an energy source. At least in mild cognitive impairment, this needs to be looked at in Alzheimer’s disease specifically. So there’s this increased thinking that, from the standpoint of both risk reduction and treatment in the early course of the disease, that interventions that boost ketone levels may be beneficial. Now, one way to do that is with ketogenic diet. Another way is by intermittent fasting.
So during fasting, the glucose stores in your liver are depleted and your body and brain cells start using ketones, which come from fats. And so in our laboratory and animal models of Alzheimer’s disease, where the mice accumulate amyloid beta peptide, and have tau pathology. When we put them on an every other day fasting regimen, this is long term now, it delays the onset of cognitive impairment and mitigates some of the neuropathology.
And then we also showed in these mice, and this is mainly the 3xTg-AD model, which is one of the most widely used models that was developed by Frank LaFerla with our help. And anyway, so we found that if we supplement the diet of these Alzheimer’s mice with a ketone ester, which is essentially the exact same ketone molecule that’s produced from fats when we’re fasting, or on a ketogenic diet. That ketone ester will ameliorate the pathology and some of the cognitive deficits. And then we started looking at neural network activity in the brains of the animals in two ways. One is by EEG recording, electroencephalogram. So that’s a non-invasive way. And we found that these Alzheimer’s mice have hyperexcitability. And then actually, as they get older, they develop seizures, epileptic seizures. But even before they develop observable seizures, they have abnormal hyperexcitability in neurons.
Again, going back to our cell culture work in the 1990s, I think my most highly cited original research article was where I showed, with colleagues, that amyloid beta peptide renders neurons vulnerable to excitotoxicity. So can cause hyperexcitability. And it’s also known that Alzheimer’s patients have a very large increased incidence of epileptic seizures compared to age matched control subjects. So then anyway, in the Alzheimer’s mouse model, the ketone ester suppressed the neural hyperexcitability and prevented the development of seizures, and had beneficial effects.
And then finally, with the intermittent fasting, we found that by recording electrical activity in individual neurons in the hippocampus, we found that the animals adapted intermittent fasting, there’s reduced excitability. And it’s due to enhanced GABA tone. GABA’s the main inhibitory neurotransmitter in the brain. So anyway, the bottom line is, the fasting and the ketones seem to enhance the inhibitory tone, enhance GABA, which constrains the excitability of the glutamatergic neurons, the neurons that use glutamate, which is the main neurons that degenerate in Alzheimer’s disease.