Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults

Abstract

Background: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

Objective: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.

Methods: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

Results: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

Conclusion: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

Keywords: Aging; Alzheimer’s disease; cognition; dementia; diet; fatty acids.

Figure 1.. Mean difference in annual rate of cognitive decline 3MSE scores for 1-IQR unit difference in plasma phospholipid fatty acids.

Legend: Positive values indicate slower decline, while negative values suggest faster decline in cognitive function. Mean values were estimated using Tobit Models adjusted for baseline age, sex, race (white or nonwhite), study site, education (years of education through 12th grade, any education beyond 12th grade), income (<$12,000, $12,000-$24,999, $25,000-$49 999, or >$50 000/year), time-varying study time (years), study time2 (years2), smoking status (never, current or former smokers), alcohol intake (drinks/week), leisure-time physical activity (kcal/week), intakes of vegetables (servings/day) and fruits (servings/day), plus multiplicative interaction terms for follow-up time as continuous variable with each covariate. Abbreviations: AA, arachidonic acid; ALA, alpha-linolenic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid.

Figure 2. Multivariable-adjusted hazard ratios (and 95% confidence intervals) of total dementia (n=3,564) for 1-IQR unit of circulating AA in older US adults free of dementia and stroke at baseline. Solid lines and shaded area represent the HR estimate and 95% confidence interval overtime, respectively.

Legend: Long-term exposure was assessed by using cumulative average of serial fatty acid measures, i.e., FA levels in 1992 were related to risk from 1992–98; the average of FA levels in 1992 and 1998, to risk from 1998–2005; and the weighted average of FA levels in 1992, 1998, and 2005, to risk after 2005, with 50% weight assigned to the most recent measurement, and 25% assigned to each previous measurement. The solid line and grey area represent hazard ratios and 95%CI estimated using $\widehat{HR}=\exp \left({\widehat{\beta }}_1+\widehat{\delta }t\right)$ and $95\%\text{CI}=\exp \left({\widehat{\beta }}_1+\widehat{\delta }t\pm 1.96\sqrt{(s_{{\beta }_1}^2+t^2{s}_{\delta }^2+2t\widehat{\mathrm{cov}}({\widehat{\beta }}_1,\widehat{\delta }}\right)$, where ${\widehat{\beta }}_1$ is the estimated coefficient for 1-IQR unit of AA, and $\widehat{\delta t}$ is the estimated coefficient for the multiplicative interaction term (i.e. AA x log(time)), t is years of follow-up, $s_{{\beta }_1}^2,s_{\delta }^2$ and $\widehat{\mathrm{cov}}\left({\widehat{\beta }}_1,\widehat{\delta }\right)$ are estimated variances and covariance for ${\widehat{\beta }}_1$ and $\widehat{\delta }$. Time-varying covariates were updated at each fatty acid measurement. Multivariable model included adjustment for sex, race (whites or nonwhite), enrollment site (4 sites), education (years of education through 12th grade, any education beyond 12th grade), income (<$12 000, $12 000-$24 999, $25 000-$49 999, or >$50 000/year), APOE status (at least one ε−4, none, unknown), time-varying information on age (years), age-squared, smoking status (never, current or former smokers), alcohol intake (drinks/week), leisure-time physical activity (kcal/week), vegetable (servings/day), fruit intake (servings/day), and a multiplicative interaction term AA as linear variable with log of time.