By Traci Pantuso, ND, MS

Adjunct Faculty, Bastyr University, Seattle; and Owner Naturopathic Doctor, Harbor Integrative Medicine, Bellingham

Dr. Pantuso reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • A higher intake of α-linolenic acid was correlated with a decreased risk of cerebral infarcts.
  • There was no correlation between seafood consumption and neuropathology among those who were APOE ε4 negative.
  • There were no significant correlations found between fish oil supplementation and any Alzheimer’s disease neuropathology.

SYNOPSIS: This cross-sectional study of older adults who were part of the Rush Memory and Aging Project demonstrated that moderate seafood consumption was correlated with a decreased level of brain Alzheimer’s disease neuropathology in APOE ε4 carriers. Higher brain levels of mercury were correlated with higher seafood consumption. However, these levels were not correlated with brain neuropathology.

SOURCE: Morris MC, Brockman J, Schneider JA, et al. Association of seafood consumption, brain mercury level, and APOE e4 status with brain neuropathology in older adults. JAMA 2016;315:489-497.

Observational studies have demonstrated that increased intake of omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in seafood and other foods, have been associated with slowing cognitive decline and a decreased risk of Alzheimer’s disease (AD) and dementia in older adults.1,2 However, seafood consumption also can lead to increased levels of mercury, a known neurotoxin.1,2 The APOE gene encodes instructions for making apolipoprotein A, which combines with lipids to form lipoproteins. The APOE gene variant APOE ε4 is associated with an increased risk of AD.3 APOE ε4 is present in 25-30% of the population and 40% of people with late onset AD.3 Individuals with the double allele have a 10-fold increased risk of late onset AD.3

To further understand the role of dietary seafood intake and brain neuropathology, Morris et al examined 286 brains from deceased older adult participants enrolled in the larger Rush Memory and Aging Project (MAP) study who died between 2004 and 2013. The MAP study is an ongoing study being conducted in Chicago with predominately white, non-Hispanic participants residing in retirement communities and subsidized housing. The adults in the MAP study did not have dementia at the time of enrollment and completed a dietary assessment before death. The autopsied brains were evaluated for AD neuropathology, including both diffuse and neuritic amyloid plaques as well as neurofibrillary tangles. Counts of chronic macroscopic cerebral infarctions and microinfarcts were performed along with Lewy body staging. Brain selenium and mercury metal concentrations were determined by instrumental neutron activation analysis and were measured in the inferior temporal and midfrontal cortical regions and in the cerebellum. Linear regression models (statistical significance, P < 0.05) were used to investigate the associations of dietary variables and brain metal concentrations with AD neuropathology.

The participants in this study are representative of 51.6% of all deceased MAP participants. The mean age of death was 89.9 years and 67% were women. The mean educational attainment was 14.6 years, and 22.7% were positive for the APOE ε4 allele. In the highest tertile of dietary n-3 PUFA intake, there were more women, and in the lowest tertile of dietary n-3 PUFA intake, there was a higher likelihood of being APOE ε4 positive.

To measure dietary consumption of seafood intake, a semiquantitative food frequency questionnaire previously validated for use in older Chicago residents was administered annually starting in 2004. The questionnaire featured four seafood items that were measured to calculate weekly seafood consumption. To calculate daily PUFA intake, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid amounts were multiplied by the nutrient content of all food items by frequency of consumption and then summed. The questionnaire also asked about fish oil supplements, which were then averaged over all valid food frequency questionnaires obtained before death.

Participants who noted that they used fish oil supplements on one of the food frequency questionnaires were considered to be supplementing with fish oil. Forty-nine participants reported taking fish oil supplements and of these, 31 participants only positively reported supplementation on one visit survey.

APOE ε4 individuals who consumed one or more seafood meals per week had decreased AD neuropathology compared to APOE ε4 individuals who consumed less than one meal per week. There was no correlation between seafood consumption and neuropathology among those who were APOE ε4 negative. There were no significant correlations found between fish oil supplementation and any AD neuropathology for either group.

Increased dietary α-linolenic acid was found to be correlated with a decreased risk of cerebral microinfarcts (P = 0.03) and macroinfarcts (P = 0.04), while EPA and DHA did not demonstrate this effect. However, in APOE ε4 individuals, there was a correlation between decreased risk of macroinfarcts and fish oil supplementation (P for interaction = 0.05)

The researchers analyzed 203 cases for brain concentrations of mercury and selenium in the inferior temporal and midfrontal cortical region of the brain, centers of the brain known to be involved in AD, as well as in the cerebellum (less likely to be affected by AD neuropathology). The mean (SD) for brain mercury concentrations in the inferior temporal region was 0.25 (0.78), 0.26 mcg/g in the midfrontal region and 0.87 (1.80) mcg/g in the cerebellum. Cortical brain mercury levels were positively correlated with cortical selenium levels (ρ, 0.35; P < 0.001) and with the number of seafood meals consumed per week (ρ, 0.16; P = 0.02). No significant correlation (P = 0.07) was found between brain mercury levels and AD neuropathology. Brain mercury levels were significantly correlated with lower odds of macroinfarcts and microinfarcts (P = 0.05 and P = 0.01, respectively), and brain selenium levels were not correlated with neuropathologic markers, except for neurofibrillary tangle severity in which higher selenium levels were correlated with higher tangle severity (P = 0.04).

Table 1: Alzheimer's Disease Neuropathology and Dietary Intake of Seafood Between Seafood Intake Groups ( > 1 meal/week vs. < 1 week) and APOE ξ4 Status

AD Neuropathology

APOE ξ4 positive

APOE ξ4 negative

Global AD Pathology

β (95% CI)

n = 65

-0.77 (-1.53 to -0.01)

n = 221

0.13 (-0.30 to 0.55)

Neuritic Plaque Density

β (95% CI)

n = 65

-0.69 (-1.34 to -0.04)

n = 218

0.26 (-0.14 to 0.65)

Neurofibrillary Tangle Severity

β (95% CI)

n = 65

-0.77 (-1.52 to -0.02)

n = 218

0.20 (-0.19 to 0.59)

Alzheimer Disease Diagnostic Score

β (95% CI)

n = 65

-0.53 (-0.96 to -0.10)

n = 218

0.20 (-0.04 to 0.43)

AD = Alzheimer's disease; 95% CI = 95% confidence interval

ADAPTED FROM: Morris MC, Brockman J, Schneider JA, et al. Association of seafood consumption, brain mercury level, and APOE ξ4 status with brain neuropathology in older adults. JAMA 2016; 315:489-497.

COMMENTARY

It is estimated that more than five million Americans are suffering from AD, an incidence that is expected to rise to 13.8 million by 2050.2-5 AD is the most common cause of dementia. The etiology of AD is not clearly understood and further research into both causative and protective factors is needed.2,4,5 There are numerous risk factors for AD, the main ones being increasing age, APOE status, and female sex.2,4,5 Other risk factors for AD include nutritional factors, low levels of physical activity, reduced cognitive stimulation, socioeconomic status and educational attainment, poor sleep quality, air pollution, smoking, intake of metals, pesticides and insecticides, and metabolic-related dysfunction.2,4,5

This study adds to the body of evidence demonstrating a beneficial effect of dietary patterns emphasizing vegetables and fish, such as the Mediterranean dietary pattern, with better cognitive health and a decreased risk of AD and/or dementia. According to the authors, this is the first published study that investigated the relationship between diet, brain neuropathology, and brain concentrations of mercury. Also, this study included a large amount of brain autopsy data. The lack of association (positive or negative) between fish oil consumption and AD neuropathology is an important finding, not unlike a recent Cochrane review, which also found a lack of evidence to support n-3 PUFA supplementation as a treatment for mild-to-moderate dementia.4

Limitations of this study include the observational study design, which does not allow for determination of causality. The food frequency questionnaire is validated. However, it is a subjective measurement of the dietary intake of EPA, DHA, and α-linolenic acids. The participants in this study were mostly non-Hispanic white older adults who lived in Chicago and ate a moderate amount of seafood, so the findings cannot be generalized to other populations with higher seafood consumption or with high mercury exposure. The authors also mentioned that there was insufficient statistical power to detect small correlations of n-3 PUFA on neuropathology in the APOE ε4 positive group.

Another limitation of this study is the lack of data of other genetic mutations that are known to increase the risk of AD. Although the APOE ε4 allele increases the risk of developing AD, it is not predictive of developing AD.6 Individuals without the APOE ε4 allele who have a first-degree relative with AD still have a two- to four-fold increase in risk of developing AD. The American College of Medical Genetics (ACMG) recommends genetic testing of a number of genes involved in AD if the patient is symptomatic.6 However, APOE genetic testing is not routinely recommended because it has a poor predictive value alone. The ACMG recommends that patients who are symptomatic or have a family history of AD should be referred to a genetic counselor. Direct-to-consumer APOE genetic testing is not recommended.6

Recommending a diet with moderate fish consumption may be beneficial to aging patients. Counseling patients about the benefits of eating sustainable fish with lower mercury levels is also important when recommending moderate fish consumption. Such data are provided by Seafood Watch.7 Mercury in fish exists mostly in the form of methyl mercury and has been found to be highly variable even within a given fish species.8 More studies evaluating the levels of mercury and other contaminants in seafood found throughout the world are needed to better estimate the levels of mercury in imported seafood and its effects on human health.8 Although this study demonstrates benefit with eating one or more seafood meals per week, more research is required to further understand the role of n-3 PUFAs in cognitive health and AD neuropathology, as a number of other factors, including nutritional factors, low levels of physical activity, reduced cognitive stimulation, socioeconomic status and educational attainment, poor sleep quality, air pollution, smoking, intake of metals, pesticides and insecticides, and metabolic-related dysfunction, have demonstrated risk. Recommending a Mediterranean dietary pattern with adequate physical activity, increased cognitive stimulation, adequate sleep, avoidance of smoking, and avoiding intake of metals, pesticides, and insecticides may be beneficial in decreasing cognitive decline and AD. Referring patients showing symptoms of AD or asymptomatic patients with a first-degree relative with AD or dementia to a genetic counselor is warranted.

REFERENCES

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  6. Pistollato F, Ohayon EL, Lam A, et al. Alzheimer disease research in the 21st century: Past and current failures, new perspectives and funding priorities. Oncotarget 2016; doi: 10.18632/oncotarget.9175 [Epub ahead of print].
  7. Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 2011;13:597-605.
  8. Seafood Watch. About Us. Available at: http://www.seafoodwatch.org/about-us. Accessed June 6, 2016.
  9. Karimi R, Fitzgerald T, Fisher NS. A quantitative synthesis of mercury in commercial seafood and implications for exposure in the United States. Environ Health Perspect 2012;120:1512-1519.