Dietary choices and their consequences may certainly influence cognitive function

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Dietary choices and their consequences may certainly influence cognitive function. A new study led by investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, along with outside collaborators expands on previously published work (focused on Puerto Rican individuals in the U.S.) by including additional races and ethnicities.

The team found that certain plasma metabolites—substances created when the body breaks down food—were associated with global cognitive function scores across the diverse set of races and ethnicities.

Their results are published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“Our study has huge strengths in expanding the sample size and in adding demographics compared to what previous research has done,” said Tamar Sofer, PhD, and director of the Biostatistics Core Program in Sleep Medicine Epidemiology and a member of the Division of Sleep and Circadian Disorders at the Brigham.

“It also illustrates that studies that begin by focusing on minorities can give rise to insights that may be beneficial to other populations. We hope our findings will help people in making specific nutritional choices and in improving their cognitive health.”

Nowadays, researchers can discover biomarkers associated with health changes and diseases by utilizing approaches like metabolomic profiling, which can survey thousands of metabolites within blood samples. An initial study in Boston looking at older adults of Puerto Rican descent found a series of metabolites that were associated with measured cognitive functions.

Building off that work, Brigham researchers tested metabolite-cognitive function associations in 2,222 U.S. Hispanic/Latinx adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), and in 1,365 Europeans and 478 African Americans from the Atherosclerosis Risk In Communities (ARIC) Study.

They then applied Mendelian Randomization (MR) analyses to determine causal associations between the metabolites and cognitive function, as well as between a Mediterranean diet and cognitive function.

The team discovered that six metabolites were consistently associated with a lower global cognitive function across all of the studies. Four of them were sugars or derivatives of sugars. Another metabolite, beta-cryptoxanthin, was associated with a higher global cognitive function in the HCHS/SOL and is also strongly correlated with fruit consumption.

“It is possible that these metabolites are biomarkers of a more direct relationship between diet and cognitive function,” said lead author Einat Granot‐Hershkovitz, PhD, who worked on this study as a postdoctoral fellow in Sofer’s lab at the Brigham.

Diet itself can be an important source of many metabolites, including some with positive or negative associations with cognitive function. In this study, the Mediterranean diet score was associated with higher levels of beta-cryptoxanthin, which was positively associate with cognitive function.

The Mediterranean diet was also negatively associated with the levels of other metabolites, which were associated with lower cognitive function. Previous research has also shown that adherence to the Mediterranean diet is associated with cognitive benefits.

While the study did have limitations like its cross-sectional, observational design which limited conclusions about the potential influence of modifying metabolite levels on cognitive function (causal inference), the researchers attempted to use MR analyses to account for unmeasured confounding and establish some level of causal inference.

Their results showed weak causal effects between specific metabolites and global cognitive function.

The researchers recommend that future studies assess metabolite associations with cognitive function and work to evaluate whether observed associations indeed indicate that changes in diet – manifesting in changing metabolite levels – can improve cognitive health.

“While the causal effect seen in our study may be weak, repeated research has shown that the Mediterranean diet is associated with better health outcomes, including cognitive health,” said Sofer.

“Our study further supports the importance of a healthy diet towards safeguarding cognitive function, consistent across races and ethnicities.”

Disclosures: Co-author Bruce Kristal is the inventor of general metabolomics-related IP that has been licensed to Metabolon via Weill Medical College of Cornell University and for which he receives royalty payments via Weill Medical College of Cornell University. He also consults for and has a small equity interest in the company. Metabolon offers biochemical profiling services and is developing molecular diagnostic assays detecting and monitoring disease. Metabolon has no rights or proprietary access to the research results presented and/or new IP generated under these grants/studies.

Funding: The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (HHSN268201300001I / N01-HC-65233, HHSN268201300004I / N01-HC-65234, HHSN268201300002I / N01-HC-65235, HHSN268201300003I / N01- HC-65236, HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. Additionally, this work was supported by the National Institute on Aging (R21AG070644, R01AG048642, RF1AG054548, RF1AG061022, and R21AG056952, P30AG062429 and P30AG059299). Support for metabolomics data was provided by the JLH Foundation (Houston, Texas). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services under contract numbers (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I).


Figure 2. Venn diagram for metabolite classes associated with memory and gait. Legend: Red indicates upregulated metabolites with memory or gait performance. Blue indicates downregulated with memory or gait performance. * = reported cross-sectional associations; † = reported longitudinal associations. Please refer to Table S1 for individual metabolites that were associated with memory only and gait only.

In this review, we found five shared metabolite classes associated with both memory performance and gait speed. The majority of metabolites associated with memory and gait were sphingolipids and fatty acids. Metabolites from several classes, including sphingolipids, fatty acids, and amino acids, showed similar directions of the associations with memory and gait (both upregulated or downregulated).

Metabolites from classes of amino acids and biogenic amines showed some differences in directions of the associations with memory and gait. The novelty of this work is to systematically identify shared metabolites and pathways related to both memory and gait impairments. A comprehensive review on related metabolites may provide insight into mechanisms underlying dual decline in relation to high dementia risk. To address the specific topic of the dual decline in memory and gait, we focused on reported metabolite classes that were associated with both memory and gait impairments. Here we discuss the shared metabolite classes and relevant pathways and focus on two main classes–sphingolipids and fatty acids.

Metabolites from sphingolipids and the sphingolipid metabolism pathway were found to be shared between memory and gait, many of which were long-chain ceramides. This is in line with previous humans and animal studies which suggest that alterations to the ceramide/sphingosine-1-phosphate rheostat ratio may contribute to the aging process, where ceramides contribute to cellular  senescence and sphingosine-1-phosphate delays it [51,52].

Additional evidence suggests a balance between long (e.g., C16:0, C18:0, C20:0) and very-long-chain (e.g., C24:0 and C24:1) ceramides is important for regulating intrinsic cell apoptosis and proliferation [53,54]. Further, ceramide accumulation has been implicated in pro-inflammatory actions and can increase skeletal muscle insulin resistance [55,56].

Notably, elevated levels of ceramide promote β-amyloid production [57], and β-amyloid can, in turn, promote ceramide formation [58]. β-amyloid is not only a hallmark of Alzheimer’s disease but is also associated with impaired mobility in older adults [59–61]. We hypothesize that impaired sphingolipid metabolism may be a potential mechanism for memory and gait decline.

The biosynthesis of the unsaturated fatty acids pathway may also play a key role in both memory and gait decline. We found that various types of unsaturated fatty acids, such as poly-unsaturated fatty acids and omega-3 fatty acids, were associated with memory and gait. Previous studies have suggested that omega-3 fatty acids, namely DHA and EPA, may have independent and complementary neuroprotective effects in aging and AD, such as controlling apoptotic mechanisms, combatting amyloid-β production and plaque deposition, and anti-inflammatory derivatives [62–64].

Arachidonic acid and its derivatives are largely pro-inflammatory, opposing the effects on inflammatory signaling by omega-3 fatty acids [65,66]. This is in line with several rodent studies showing dietary-induced deficiencies in omega-3 fatty acids and elevations in the AA/(EPA + DHA) ratio leading to increased pro-inflammatory cytokines [67,68].

Besides sphingolipids and fatty acids, amino acids and the kynurenine pathway may also play key roles in both memory and gait decline. For instance, amino acids are the build- ing blocks for protein synthesis. Since amino acids are involved in multiple physiological processes in the body, such as the cell building and synthesis of neurotransmitters, they play key roles in skeletal muscle function and brain function [69,70].

The kynurenine-tryptophan metabolism pathway contributes to mitochondrial dysfunction and inflammation which may affect aging phenotypes. Kynurenine and related metabolites are associated with impaired mitochondrial function and oxidative stress, which can lead to cellular damage and increase inflammation [71–73].

In conclusion, existing data suggests that five metabolite classes (amino acids, biogenic amines, fatty acids, PCs, and SMs) are implicated in both memory and gait impairments, with sphingolipids having the largest number of metabolites. Notably, some metabolite classes, such as triacylglycerols, were only studied in gait impairment. Since these classes have not been studied in both impairments, whether they are informative in delineating the metabolomic signature of dual decline remains unclear. Future studies should consider establishing a rigorous scientific protocol across multiple aging cohorts to understand which metabolites and pathways underlie dual decline in memory and gait.

Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/metabo12040356/s1. Table S1: Associations between metabolites


Original Research: Closed access.
“Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition” by Granot-

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