In an encouraging development in Alzheimer’s disease research, impaired brain glucose metabolism is finally getting the attention it deserves. A paper published in JAMA last month provides a nice overview of why Alzheimer’s disease (AD) is now often referred to as “type 3 diabetes”—a phrase coined twelve years ago. It has been known since at least 1994 that glucose metabolism in the brain is compromised in AD: a study employing PET scans determined that some AD patients have up to a 45% reduction in cerebral glucose utilization. Considering that under normal circumstances glucose is the primary fuel for the brain, that large an energy deficit would have catastrophic consequences for cognitive function.

Indeed, researchers recognize the dire implications of an interruption in fuel supply or impairment of fuel utilization in the brain:

“Neurons are largely intolerant of inadequate energy supply, and thus the high energy demand of the brain predisposes it to a variety of diseases if energy supplies are disrupted. […] Although neurodegenerative diseases are not classically thought to be caused by disturbed metabolism, bioenergetic defects are emerging as important pathophysiological mechanisms in several disorders. One of the earliest signs of Alzheimer’s disease (AD) is a reduction in cerebral glucose metabolism.” (Mergenthaler et al., 2013)

“When the brain’s energy supply is insufficient to meet its metabolic needs, the neurons that work hardest, especially those concerned with memory and cognition, are among the first to exhibit functional incapacity (e.g., impairment of memory and cognitive performance).” (Hashim & VanItallie, 2014)

The authors of the 1994 PET study went so far as to say that reduced cerebral glucose use was “the predominant abnormality in incipient late-onset Alzheimer’s disease” (emphasis added). However, while problems with glucose metabolism may be at the heart of this disease, alterations in insulin signaling may precede this. Indeed, individuals who have hyperinsulinemia but who are not diabetic (high insulin but normal glucose) have substantially elevated risk for AD compared to individuals who are not hyperinsulinemic.

Metabolic syndrome, which is driven by chronically elevated insulin, is so closely associated with AD that researchers are looking at “the insulin brain state,” and in addition to “type 3 diabetes,” AD is also called “metabolic-cognitive syndrome.” With this in mind, and considering that nearly every purported blockbuster drug for AD has ultimately been a disappointment, turning toward interventions that address insulin signaling and glucose metabolism may prove more fruitful: “…targeting the insulin signaling pathway during early AD cognitive impairment represents a viable therapeutic opportunity based upon solid empirical evidence that insulin resistance, AD pathology and related cognitive decline are mechanistically interrelated.” (Dineley, Jahrling, Denner, 2014)

Until recently, decades of research efforts and millions of dollars were focused on the amyloid hypothesis—the idea that the pathological buildup of insoluble plaques made of amyloid protein fragments in the brain was responsible for the disease. However, as we explored in a past article, the amyloid hypothesis has several weaknesses and fails to satisfactorily fit the evidence in AD. Researchers note, “The amyloid cascade hypothesis is no longer supported by the majority of experimental evidence,” amyloid does not contribute to the primary pathogenesis of the disease, and “amyloid-centric therapies will continue to fail.”

If the main problem in AD is impaired brain glucose metabolism, it’s crucial to note that ketones can serve as an alternative fuel to glucose in the brain and central nervous system. One of the most promising developments in AD research is evidence that despite problems with glucose uptake, brain ketone uptake remains normal even in moderately advanced AD. Research in human subjects with AD shows that ketone uptake and utilization is not impaired in the Alzheimer’s brain, leading one of the world’s leading experts in this field, Stephen Cunnane, PhD, to state:

“…treatments that ignore the brain energy (glucose) deficit in AD would be predicted to fail, but treatments that attempt to rescue brain fuel availability via ketones would be predicted to have a better chance of succeeding.”

“…those interested in developing a treatment for Alzheimer’s disease should think about nutritional ketosis. Deteriorating brain glucose metabolism is clearly present in older people who are still cognitively normal. Deteriorating brain glucose uptake is also present in young people with insulin resistance, which shows that insulin sensitivity is perhaps the most important modifiable factor to consider in relation to Alzheimer risk. Insulin resistance puts pressure on glucose utilization by the brain long before the cognitive capacity of the aging brain deteriorates. Ketones and exercise are emerging as the best solutions to this problem.”

“There will be no miracle drugs for Alzheimer’s, no one-size-fits-all treatment. It will require a multi-modal solution in which brain energy requirements are being met with ketones in some form or other, plus other interventions including nutrients like DHA, exercise to improve glucose metabolism and cognitive stimulation.”

Indeed, raising ketone levels via supplementation with ketone esters (beta-hydroxybutyrate) or through implementing a ketogenic diet has shown extraordinary promise in improving cognitive function in patients with AD. A fascinating 2019 case study documents a 68-year old male heterozygous for the APOE4 gene and who also had type 2 diabetes, whose cognitive function improved from mild AD to normal (based on Montreal Cognitive Assessment Score, or MoCA) after 10 weeks of following a ketogenic diet with time-restricted eating and moderate intensity exercise. This echoed findings from an earlier study in which a younger man (38 years old) with metabolic syndrome and early-stage memory problems (and a family history of AD) followed a ketogenic diet plus high-intensity exercise and weightlifting and experienced substantial improvements in metabolic syndrome markers, such as a 58% reduction in HOMA-IR, a whopping 71% reduction in triglycerides, a 55% reduction in fasting insulin, and a 77% reduction in the triglyceride-to-HDL ratio. (Not to mention a 14% reduction in body weight and a 71% reduction in VLDL.) Moreover, this individual’s MoCA score improved from 22 (indicative of mild cognitive impairment) to a perfect 30 out of 30, indicating no cognitive dysfunction. It’s possible that these are not unrelated. While more research needs to be done in much larger cohorts, it is unlikely to be a mere coincidence that when an intervention dramatically improves metabolic syndrome, it also improves metabolic-cognitive syndrome.

On a final note, the JAMA paper also addresses the issue of the APOE4 gene, with APOE4 being the strongest known genetic risk factor for AD. One researcher noted that the APOE4 brain “is not as efficient as the other 2 brains [APOE2, & APOE3] in terms of utilizing of glucose.” We looked more closely at the APOE4 issue in a past article. It’s interesting to consider that the ε4 allele of the APOE gene is believed to have been selected against in human populations with a long historical exposure to agriculture, and grain-based agriculture in particular. This suggests that people who carry the ε4 allele may not be evolutionarily well-suited to a high-carbohydrate diet, which may be playing a role in the hyperinsulinemia that is increasingly implicated in this disease.

We have written numerous times in the past about the beneficial role of medium-chain triglycerides (which are readily converted into ketones) for supporting cognitive function, and the exciting potential for ketogenic diets as a supportive avenue to explore in Alzheimer’s disease. It’s heartening to see more attention finally being given to the crucial role of impaired brain glucose metabolism in this condition, and new clinical trials exploring ketogenic diets as novel interventions to move away from the highly flawed and failing anti-amyloid approach.