Type II diabetes has long been known as a risk factor in the eventual development of Alzheimer's disease. But prior research efforts to correlate blood glucose levels and Alzheimer's brain pathology have proved fruitless. Now, NIH researchers have published a study that finds a correlation between glucose levels in the brain, the associated cellular metabolic activity, and the severity of Alzheimer's disease pathology and symptoms.

The research, which was recently published in Alzheimer's & Dementia, the journal of the Alzheimer's Association, suggests that sustained high blood glucose levels over time work to increase brain glucose levels, which in turn were associated with more severe Alzheimer's disease (AD) pathology as well as the expression of its symptoms.

"Previous studies did not show any relationship between brain pathology and blood glucose. So, we asked, 'Is there a relationship between brain glucose and blood glucose levels before death?' As individuals grow older, the higher the blood glucose levels in life, then the higher the glucose levels in the brain," Madhav Thambisetty, the study investigator and chief of the Unit of Clinical and Translational Neuroscience in the NIA's Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA) that is part of the National Institutes of Health (NIH), told BioWorld.

"As a risk for Alzheimer's, over a period of time increases in blood glucose may trigger pathology. Our study clearly shows there seems to be a relationship with how blood glucose levels increase over time and brain glucose levels at death," he added.

Thambisetty said his research underscores existing advice aimed at type II diabetes patients, as well as those with prediabetes. Efforts to control and stabilize blood glucose, including regular activity, a healthy diet and good sleep, could help to prevent the damage to the brain tied to disordered glucose metabolism.

Earlier research efforts to tie the mechanisms that underlie diabetes and Alzheimer's disease have focused on insulin signalling abnormalities, which occur both in diabetes and Alzheimer's patients. Thambisetty sees this research as relevant for his work, but also distinct since insulin is not necessary for glucose to enter the brain – making the glucose metabolism abnormalities he observed not directly dependent on insulin activity.

This earlier line of research into the similarities in insulin signalling problems resulted in the colloquial reference to Alzheimer's disease as "type 3 diabetes." But Thambisetty sees this term as somewhat misleading and has actively avoided it, focusing instead on more precisely defining how the mechanisms work in diabetes and Alzheimer's disease in order to more effectively pursue prevention and treatment.

Glucose and the brain

The study, which started in 2013, used brain tissue samples from the Baltimore Longitudinal Study of Aging (BLSA) that has been running since 1958. More than 3,000 subjects have been evaluated on neurological, physical and psychological data over time and, after death, are also autopsied.

Prior research focused on linking Alzheimer's disease to blood glucose levels and even those employing a positron emission tomography (PET) brain scan had been unable to find a direct relationship.

This time around, however, researchers focused specifically on measuring brain glucose levels as well as the metabolomics of the brain.

They measured glucose levels in each of several different regions of the brain, some that are known to be susceptible to Alzheimer's disease pathology, such as the frontal and temporal cortex, as well as some, like the cerebellum that are resistant to it.

The study also looked at a trio of brain categories from: patients who exhibited Alzheimer's symptoms in life and had confirmed disease pathology; healthy control individuals; and those who did not exhibit Alzheimer's symptoms, but did have significant levels of postmortem Alzheimer's pathology. Brain pathology related to Alzheimer's was defined as beta-amyloid protein plaques and neurofibrillary tangles on autopsy.

The researchers found abnormalities in glycolysis, the main process by which the brain breaks down glucose, alongside Alzheimer's pathology. In fact, lower rates of glycolysis were seen with higher rates of brain glucose levels. And, in turn, these correlated with the severity of Alzheimer's pathology. The most severe reductions in brain glycolysis were also tied to the expression of Alzheimer's disease symptoms.

"In patients where there were appreciable levels of Alzheimer's pathology at death, who didn't show symptoms in life – it was important to include these individuals to allow us to detect the risk factors. They do, in fact, look like an intermediate group between those with Alzheimer's disease and healthy controls," Thambisetty said.

He noted that both in measures of brain glucose and in the assessment of glycolysis, this is the case. Thambisetty is continuing his research by examining potential triggers for these abnormalities in brain glycolysis, such as environmental or genetic factors.

Chain reaction?

Symptomatic Alzheimer's disease patients had high brain glucose, alongside low levels of glycolysis. Healthy controls showed the opposite, while asymptomatic individuals with Alzheimer's pathology fell in between the healthy and symptomatic groups.

In addition to measuring brain glucose levels, researchers also evaluated the ratios of the three glycolytic amino acids: serine, glycine and alanine, which are key to the process. The enzyme activity was found to be lowest in symptomatic Alzheimer's disease patients.

Next, they conducted a proteomics analysis, measuring levels of the protein GLUT3, a glucose transporter protein, in neurons. GLUT3 levels followed a similar pattern, lowest in symptomatic.

All three measures, higher brain tissue glucose concentration, reduced glycolytic flux and lower GLUT3 were found to be associated with the greater severity of Alzheimer's pathology and expression of the disease's symptoms.

Finally, the study also established that increases over the preceding decades in fasting plasma glucose levels were associated with a higher concentration of glucose in brain tissue. That specific link could encourage physicians and patients to more proactively and minutely manage blood glucose levels, particularly in older patients, perhaps via technologies such as continuous glucose monitors, insulin pumps and even the automated closed-loop systems that incorporate them both.

All of those have been approaches have been shown to be useful in the maintenance of lower, more consistent blood glucose levels. Their use had been confined largely to the type 1 diabetes population, which requires insulin, but has started moving more into the insulin-dependent type 2 diabetes population and even those who have not progressed to insulin.

This comes as payers have begun to broaden the definition of the reimbursable population for this tech into insulin-dependent type 2 diabetes patients and as the technology itself is becoming radically cheaper, more accurate and more widely available.

"For some time, researchers have thought about the possible links between how the brain processes glucose and Alzheimer's," said NIA Director Richard Hodes. "Research such as this involves new thinking about how to investigate these connections in the intensifying search for better and more effective ways to treat or prevent Alzheimer's disease."