Low-fat dietary pattern and global cognitive function: Exploratory analyses of the Women's Health Initiative (WHI) randomized Dietary Modification trial

Abstract

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function.

Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini-Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611.

Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38-0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35-1.19) and HR of 0.63 (95% CI 0.19-2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16).

Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women.

Funding: Several Institutes of the US National Institutes of Health.

Keywords: Cognition; Dietary modification; Low-fat dietary pattern; Randomized clinical trial; Women's Health Initiative.

Conflict of interest statement

All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Chlebowski reported being a consultant for Novartis, AstraZeneca, Immunomedics, Amgen, Puma and Genentech.

© 2019 Published by Elsevier Ltd.

Figures

Fig. 1

Participant flow diagram for the low-fat dietary intervention phase among the subset of DM trial participants that participated in WHIMS (n = 1606), an age eligible subset (age ≥ 65 years) of the WHI MHT trials. WHIMS = Women's Health Initiative Memory Study; MHT = menopausal hormone therapy; CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate.

Fig. 2

Overall influence of the low-fat dietary intervention on possible cognitive impairment* during the intervention phase among the subset of DM trial participants that participated in WHIMS (n = 1606). The 7-year follow-up is over the dietary intervention phase of the trial (median, 7.2 [interquartile range {IQR}, 6.0–8.0] years). Summary statistics computed from Cox regression models stratified by 5-year age group, race/ethnicity, education, and randomization status in the WHI hormone therapy trials, using time from randomization as the time-scale. Subgroups were investigated, one at a time, by including an interaction term between randomization arm and subgroup with additional stratification of the baseline hazard by corresponding subgroup. P values corresponds to a two-sided score (log-rank) test of the dietary intervention's overall influence, or for the subgroup analysis, a test of interaction between the randomization group and corresponding subgroup. Percentages are annualized. * Possible cognitive impairment defined as transition to Phase 2 of the WHIMS protocol. After completion of Phases 2 and 3, typically within 3 months possible cognitive impairment, participants were classified as probable dementia, mild cognitive impairment, or no cognitive impairment. † Ever used menopausal hormone therapy or randomized to CEE or CEE+MPA arm of WHI hormone trial.  ^ Among women randomized to either WHI hormone therapy trial. WHIMS = Women's Health Initiative Memory Study; HR = hazard ratio; CI = confidence interval.

Fig. 3

Kaplan-Meier estimates of the cumulative hazard for possible cognitive impairment* during the intervention phase among the subset of DM trial participants that participated in WHIMS (n = 1606). The 7-year follow-up is over the dietary intervention phase of the trial (median, 7.2 [interquartile range {IQR}, 6.0–8.0] years). Summary statistics computed from a Cox regression model stratified by 5-year age group, race/ethnicity, education, and randomization status in the WHI hormone therapy trials, using time from randomization as the time-scale. P-value corresponds to a two-sided score (log-rank) test of the dietary intervention's overall influence. Percentages are annualized. * Possible cognitive impairment defined as transition to Phase 2 of the WHIMS protocol. After completion of Phases 2 and 3, typically within 3 months of possible cognitive impairment, participants were classified as probable dementia, mild cognitive impairment, or no cognitive impairment. WHIMS = Women's Health Initiative Memory Study; HR = hazard ratio; CI = confidence interval.