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Dementia risk reduced with higher blood levels of two carotenoids – NIH study

Higher serum levels of two kinds of carotenoids were tied to lower risk of developing dementia over time, with dementia risk associated with blood levels of certain antioxidants., found a  NIH National Institute on Aging study in Neurology.

Higher serum levels of carotenoids lutein+zeaxanthin and beta-cryptoxanthin were tied to the lower risk of incident dementia, said May Beydoun, PhD, MPH, of the NIH National Institute on Aging in Baltimore, Maryland, and colleagues.

Findings were attenuated in adjusted analyses, suggesting socioeconomic status, lifestyle, and diet quality may mediate the associations.

When oxidative stress occurs at an abnormally high level, consuming antioxidants may help protect cells of the body, including brain cells, from damage, Beydoun said.

“Carotenoids, which are the pigments found in orange and yellow plants, are converted by the body into vitamin A. We found that the most important carotenoids in potentially protecting the brain may be lutein+zeaxanthin and beta-cryptoxanthin,” she said.

“Unlike other studies, we did not analyse levels of dietary intakes of antioxidants or carotenoids. Instead, we analysed levels of antioxidants and carotenoids in the blood.

“This is the first nationally representative study to do so in relation to dementia risk,” she said. “This may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume. That simple fact may explain why results from dietary comparison studies for the development of dementia have been mixed.”

While nutrition and diet components may be potential dementia risk targets in the future, observational studies so far have shown inconsistent findings, said Dr Babak Hooshmand and Dr Miia Kivipelto, both of the Karolinska Institute in Stockholm, in an accompanying editorial.

“For example, dietary total carotenoid consumption and in particular lutein+zeaxanthin and lycopene were associated with reduced incidence of Alzheimer’s disease and its neuropathology among 927 older adults from the Rush Memory and Aging Project who were followed up over seven years,” Hooshmand and Kivipelto wrote.

However, several longitudinal studies about dietary components and dementia have reported null findings, they observed. “Possible explanations for the discrepancies are heterogeneities in study designs and populations, differences in antioxidant status and dietary habits, and different consideration of potential confounders,” the editorialists wrote.

Beydoun and colleagues used data from 7,283 participants in the third National Health and Nutrition Examination Survey (NHANES 1988-1994), linking that information with Centers for Medicare & Medicaid Services records to identify incident dementia cases for up to 26 years.

Participants were ages 45-90 at baseline and mean follow-up was 16-17 years. At baseline, participants were dementia-free and had a physical exam, interview, and blood draw.

“The take-home message is that a healthy diet rich in carotenoids and antioxidants from dark leafy greens and orange-pigmented fruits with or without antioxidant supplements may reduce the risk of developing dementia,” Beydoun said. “But the only way to prove the connection between carotenoids and brain protection health is with a long-term, randomised clinical trial with antioxidant supplements to see whether fewer people develop dementia over time.

“Also, importantly, it is not yet known what levels of antioxidants we need to consume each day through food, beverages, and supplements to promote healthy ageing of the brain,” she added. “More research is needed to establish the necessary amount of antioxidants to promote brain health and healthy ageing.”

A limitation of the study is that antioxidant levels were based on one measurement and may not reflect lifetime habitual intakes, the researchers noted. Reverse causality also may have influenced the findings.

Study details

Association of Serum Antioxidant Vitamins and Carotenoids With Incident Alzheimer Disease and All-Cause Dementia Among US Adults

May Beydoun, Hind Beydoun, Marie Fanelli-Kuczmarski, Jordan Weiss, Sharmin Hossain, Jose Atilio Canas, Michele Kim Evans, Alan Zonderman

Published in Neurology on 4 May 2022



Serum antioxidant vitamins and carotenoids may protect against neurodegeneration with age. We examined associations of these nutritional biomarkers with incident all-cause and AD dementia among US middle-aged and older adults.

Using data from the third National health and Nutrition Examination Surveys (1988-1994), linked with Centers for Medicare and Medicaid-Medicare follow-up data, we tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s Disease (AD) and all-cause dementia. Cox proportional hazards regression models were conducted.

After ≤26y follow-up (mean:16-17y, n=7,283 participants aged 45-90y at baseline), serum lutein+zeaxanthin was associated with reduced risk of all-cause dementia (65+ age group), even in the lifestyle-adjusted model (per SD, HR=0.93, 95%CI: 0.87-0.99, p=0.037), though attenuated in comparison to a socio-economic status (SES)-adjusted model (HR=0.92, 95% CI: 0.86-0.93, p=0.013). An inverse relationship was detected between serum β-cryptoxanthin (per SD increase) and all-cause dementia (45+ and 65+), for age and sex-adjusted models (HR=0.86, 95% CI:0.80-0.93, p<0.001 for 45+; HR=0.86, 95% CI:0.80-0.93, p=0.001 for 65+ ), a relationship remaining strong in SES-adjusted models (HR=0.89, 95%CI: 0.82-0.96, p=0.006 for 45+; HR=0.88, 95%CI:0.81-0.96, p=0.007 for 65+), but attenuated in subsequent models. Antagonistic interactions indicate putative protective effects of one carotenoid may be observed at lower levels other carotenoids or antioxidant vitamin.

Incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and β-cryptoxanthin levels. Further studies with time-dependent exposures and randomized trials are needed to test neuroprotective effects of supplementing the diet with select carotenoids.

Classification of Evidence
This study provides Class II evidence that incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and β-cryptoxanthin levels.


Neurology article – Association of Serum Antioxidant Vitamins and Carotenoids With Incident Alzheimer Disease and All-Cause Dementia Among US Adults (Open access)


Neurology accompanying editorial – Antioxidants and dementia: more than meets the eye (accepted, not yet published)


See more from Medicalbrief archives:


MIND diet slows cognitive decline in stroke survivors


Plant-based diet lessens risk of cognitive impairment — 12-year European study


Healthy eating stalls elderly's cognitive decline


Flavonoids may have protective benefits against Alzheimer's and related dementias




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