Hunger Hormone Protective Against MCI, Alzheimer's?

Batya Swift Yasgur, MA, LSW

February 15, 2019

Higher levels of cholecystokinin (CCK), a little-studied amino acid involved in appetite regulation, specifically satiety, is linked to a lower risk of mild cognitive impairment (MCI) or Alzheimer's disease (AD), new research suggests.

Investigators used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the levels of CCK in close to 300 individuals and found that those with higher levels of CCK had a 65% decreased risk of developing either MCI or AD.

However, when they measured p-tau and tau proteins, they found that as tau levels increased, higher CCK was no longer associated with less memory decline.

"We found that higher levels of CCK were related to having a reduced likelihood of having AD, better memory and overall cognitive skills, and more blood sugar use, nutrient absorption, and healthier neurons in the hippocampus and other brain regions affected by AD," senior author Auriel Willette, PhD, assistant professor in the Department of Food Science and Human Nutrition at Iowa State University in Ames, told Medscape Medical News.

"We hope that clinicians might look at CCK levels and several related hormones to understand the degree to which nutrient absorption and energy balance are OK or perturbed in a patient," said Willette, "and if levels are low, that might prompt individualized diet- or exercise-based therapies to help raise CCK levels."

The study was published online January 29 in Neurobiology of Aging.

First Look at CCK and Memory

CCK is a 33-amino acid satiety hormone secreted in the intestines during digestion, which binds to CCK-A receptors, the authors write.

It plays a role in allowing the uptake of nutrients, specifically fat uptake and the metabolism of fatty acids, and its main function is to slow gastric emptying to allow time for proper digestion, they add.

Many patients with AD experience changes in food preference; appetite and eating patterns; malnutrition; weight loss; and a decline in body mass index (BMI), possibly due to muscle wasting or decreased food uptake, suggesting a potential association between AD and food-related issues.

CCK receptors are found not only in the gut but also in the brain, as CCK-B receptors.

In fact, CCK is the must abundant neuropeptide in the brain, with receptors located particularly in the hippocampus, a brain region that is integral to memory formation and adversely affective early in AD.

Studies in animal models have suggested a role for CCK in improving or protecting memory.

"Until our study, no one had examined if CCK could track problems with the hippocampus and memory formation in AD, a disease that is characterized by rapid deterioration of the hippocampus and forming new memories," Willette said.

"If CCK was a good predictor, or what we call a 'biomarker,' of tracking these clinical problems, it could be used in the clinic to help doctors," he said.

To investigate the question, the researchers drew on the ADNI database, focusing on participants with MCI and those with AD.

Data was also obtained from the ADNI Biomarkers Consortium Project, which "investigated the extent to which the selected peptides, measured with mass spectrometry, could discriminate among disease states."

CCK levels were assayed in the cerebrospinal fluid (CSF) proteomics panel.

Additional information collected concerned levels of Aβ1-42, p-tau-181, and total tau. Participants also were genotyped and categorized as being either non-APOE4 (ie, zero APOE ε4 alleles) or APOE4 (ie, 1-2 APOE ε4 alleles).

Participants completed a battery of neuropsychological tests as well as undergoing MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) testing.

Useful Metabolic Biomarker

Although years of education, percentage of APOE4 carriers, and age were not significantly different between participants diagnosed as cognitively normal (CN) vs those diagnosed as MCI or AD, the CSF CCK levels were significantly lower in AD (P < .001), as compared to participants with MCI or AD.

When the researchers used logistic regression to examine whether higher CSF CCK predicted decreased likelihood of being MCI or AD (vs being CN), they found that higher CSF CCK levels predicted a lower odds ratio (OR) for being MCI or AD (likelihood ratio Χ = 27.563, P < .001; OR Wald = 13.437, β = -1.039, Exp(B) = 0.354, P < 0.001).

"These results suggest that a per ng/mL increase in CSF CCK corresponded to a roughly 65% less likelihood of being diagnosed with AD versus CN or MCI," the authors write.

Higher levels of CSF CCK were not related to increased risk when comparing CN vs MCI, CN vs AD, or MCI vs AD individually, they note.

However, among MCI participants, a per unit increase in CCK was related to a 61.7% less likelihood (Wald = 6.708, P = .010) of progressing to AD (i.e., MCI-P) vs remaining stable with MCI.

The researchers performed regression model analyses using age, sex, BMI, baseline diagnosis, and APOE4 status as covariates.

Although they did not find a significant association with Aβ1-42, they found that higher levels of CSF CCK were significantly associated with higher levels of CSF total tau (β±SE = 37.857±4.799, F = 62.237, P < .001) and CSF p-tau181 (β±SE = 10.046±1.630, F = 37.992, P < .001).

Higher CSF CCK was also found to be associated with better global cognition scores on several neurocognitive tests, as well as better memory and executive function factors.

Total tau and ptau-181 both acted as mediators or partial mediators, reducing the influence of CCK on several neurocognitive tests — for example, higher total tau reduced the influence of CCK by 24% on the Alzheimer's Disease Assessment Scale-Cog (ADAS-Cog) 11, and p-tau181 reduced the influence of CCK by 26% on the Mini-Mental State Exam (MMSE).

Both acted as partial mediators for the memory factor and CCK.

For MCI, total tau reduced the influence of CCK on the memory factor by 49.6%, and the total tau also reduced the direct effect of higher CCK on better memory scores by 40.9%.

Similarly, both total tau and p-tau181 reduced the influence of CCK on the memory factor by 50%.

A voxel-wise analysis found that higher levels of CSF CCK were significantly associated with greater gray matter volume in a large cluster of voxels, primarily spanning the cingulate cortex, parahippocampal gyrus, thalamus, superior temporal sulcus, and medial prefrontal cortex parts of the brain.

Higher CSF CCK, however, was not associated with increased FDG-PET glucose uptake.

"We hypothesized that CCK may serve as a useful metabolic biomarker for predicting AD outcomes," the authors write.

"These results suggest that higher CCK levels are related to better cognitive outcomes."

Causal Link Unclear

Commenting on the study for Medscape Medical News, Keith Fargo, PhD, director of Scientific Programs & Outreach at the Alzheimer's Association, said the results "suggest that higher levels of the hormone cholecystokinin may predict better outcomes on cognitive tests in this study group."

However, "at this point, we cannot say anything beyond that," he cautioned, noting that more research is needed "to understand about how and why they are connected and if the link is causal."

Fargo, who was not involved with the study, called 2019 an "exciting time in Alzheimer's research" and noted that the Alzheimer's Association "is encouraged to see researchers taking innovative approaches to help us better understand the causes, development, and progression of AD."

Willette said that future research planned by his group will "continue examining the relationships between nutrient- and energy-regulation hormones like CCK and what is happening to people with and without AD."

His group, he says, takes "a multifaceted approach by looking at the brain, cognition, emotional health, and levels of toxic proteins related to AD specifically."

This study was funded in part by an NIH grant to the College of Human Sciences at Iowa State University and by the Alzheimer's Association. Other sources of funding are listed on the original paper. Willette, his coauthors, and Fargo have disclosed no relevant financial relationships.

Neurobiol Aging. Published online January 29, 2019. Abstract

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