In this cross-sectional study of a group of elderly participants without dementia, we found that higher dietary intake of ω-3 PUFA was associated with decreased plasma Aβ42 levels, independent of age, gender, ethnicity, education, and APOE genotype. For this population, the ω-3 PUFA was most likely from salad dressing, fish, poultry, margarine, and nuts.
Data from transgenic animal models of AD have consistently demonstrated reduced Aβ production/accumulation after treatment with ω-3 PUFA.31–34
In one study, DHA-enriched diets significantly reduced total detergent-insoluble Aβ by more than 70% compared with low-DHA or control chow diets.32
Image analysis of brain sections revealed that overall plaque burden was reduced by 40.3%.32
Other investigators reported that dietary supplementation with DHA in the 3xTg-AD mouse model of AD reduced the intraneuronal accumulation of Aβ.33
In a different study, 6-month-old APP/PS1 mice were fed either a typical Western diet chow containing 1% cholesterol or a DHA-enriched diet for 12 months.34
The mice fed with the DHA-enriched diet had increased regional cerebral blood volume, indicating a larger circulation in the brain, probably due to vasodilatation and a decreased amount of vascular Aβ deposition.34
Thus, our data are consistent with results observed in these animal studies, pointing to a beneficial role of dietary ω-3 PUFA in brain pathology.
In humans, a recent clinical trial evaluated the effect of ω-3 PUFA supplementation on the CSF level of Aβ42 in patients with mild to moderate AD.35
No effect on the CSF Aβ42 levels was noted after treatment with ω-3 PUFA supplement for 6 months (compared with the placebo-treated group).35
However, the null results might have been partly due to the few participants (n = 35), the short period of treatment (6 month), and the inclusion of participants who already have dementia.35
Future clinical trials with larger sample sizes and longer follow-up period are warranted. Alternatively, our study supports the potential of using an observational study design to examine the effects of ω-3 PUFA, in particular those of dietary source, on circulating levels of Aβ.
The results of the present study are also consistent with previous reports from the WHICAP population. We have reported a lower risk of incident AD, incident MCI, and progression from MCI to AD among participants who adhered more to a Mediterranean-type diet, a diet characterized by high intake of fish (a main dietary source of ω-3 PUFA).2–4
We also found that a dietary pattern characterized by (among other nutrients) high ω-3 PUFA was associated with a nearly 40% reduced risk of incident AD.5
Recently, we found that increasing intake of ω-3 PUFAs was associated with a 20−30% lower risk of dementia.36
In this cohort, higher baseline Aβ40 or Aβ42 levels are associated with increased risk of incident AD7,9,15
and faster decline in multiple cognitive domains.10
Taken together, our results support the hypothesis that ω-3 PUFA could be associated with AD at least partially via its association with Aβ; i.e., a higher dietary intake of ω-3 PUFA might lead to lower plasma levels of Aβ42 (and possibly Aβ40)and a subsequent lower risk of AD.
We detected no persistent association for other nutrients, including ω-6 PUFA, MUFA, SFA, antioxidants (vitamin E, vitamin C, and β-carotene), homocysteine-related B vitamins (vitamin B12
and folate), or vitamin D, suggesting that these nutrients might have little or no association with Aβ-related mechanisms. Thus, their potential associations with AD or cognitive decline might involve other pathways, such as antioxidative, vascular, anti-inflammatory, or metabolic. Alternatively, in contrast with ω-3 PUFAs, which have been shown to correlate well with plasma fatty acids biomarkers,37,38
it is possible that the SFFQ nutrient estimates for other nutrients are not reflecting their respective blood levels very well, providing another explanation for the failure to reject the null hypothesis for these nutrients.
Some limitations need to be considered when these results are interpreted. The present study has a cross-sectional design; thus, causal inferences cannot be drawn. Our outcome is not a stable trait but rather a moving target with temporal dynamic changes, because previous studies have consistently shown that blood Aβ levels change during the process of AD development.7,9,12
A single assessment of Aβs may be susceptible to short-term variation. There could also be measurement error of nutrients from the SFFQ, which could bias our results if reporting error is associated with the Aβ measurements. We tried to minimize this possibility by excluding participants with prevalent dementia and subsequently those with incident dementia. Estimation of nutrient intake from a SFFQ may be different and potentially less accurate than nutrient levels measured in blood, which may have more direct biologic relevance.39
However, plasma nutrients can be affected by many other factors such as metabolic rate and genetic factors, are reflective of instantaneous time points (and less of long-term habitual intake of foods), are subject to other types of measurement errors, and are often technically and financially difficult to measure in large-scale epidemiologic studies such as ours. We focused on dietary intake of nutrients in our study because findings regarding dietary intakes can be directly translated into a lifestyle modification measure. We analyzed 10 selected nutrients and may have missed potential associations that other unanalyzed nutrients might have with Aβ peptides. Although ω-3 PUFAs have been shown to correlate well with plasma fatty acid biomarkers37,38
and they remained significantly associated with Aβ42 after controlling for multiple factors, we could not completely rule out the possibility of this association being due to residual confounding. Results from this population may not be directly generalizable to other populations. Finally, because Aβ physiology is not fully understood, the associations of nutrients with plasma Aβ may not be directly interpreted as associations with brain Aβ.
Our study has several strengths. This study includes a large and ethnically diverse community-based population. We used a previously validated instrument to collect dietary data.22
Exclusion of participants with prevalent dementia (and incident dementia in supplementary analyses) allowed us to examine the relationship between dietary nutrient intake and the Aβ levels free from the influence of cognitive impairment in reporting of dietary habits. Measures for multiple potential confounding factors have been carefully recorded and adjusted for in the analyses.
In the current study, we found that higher dietary ω-3 PUFA intake was associated with lower plasma Aβ42 level, suggesting that the potential beneficial effects of ω-3 PUFA intake on AD and cognitive function in the literature might be at least partly explained by an Aβ-related mechanism.