MIND Diet and Cognitive Function over Eight Years in Puerto Rican Older Adults

Background Healthy diets have been associated with better cognitive function. Socio-economic factors including education, poverty and job complexity may modify the relationship between diet and cognition. Methods We used adjusted linear mixed models to examine the association between long-term adherence to the Mediterranean-Dietary Approaches to Stop Hypertension - Intervention for Neurodegenerative Delay (MIND) diet and cognitive function over 8 years of follow-up in Puerto Rican adults residing in the Boston, MA area (aged 45 to 75 years at baseline). We also examined whether the MIND diet – cognition association was confounded or modified by socioeconomic measures. Results In both cross-sectional and longitudinal analyses the highest, vs lowest, MIND quintile was associated with better cognition function (ß = 0.093; 95% CI: 0.035, 0.152; P trend = 0.0019), but not with cognitive trajectory over 8 years. Education <=8 th grade (ß = -0.339; 95% CI: 0.394, -0.286; P < 0.0001) and income-to-poverty ratio <120% (ß = -0.049; 95% CI: -0.092, -0.007; P = 0.024) were significantly associated with lower cognitive function, while higher job complexity (ß = 0.008; 95% CI: 0.006, 0.011; P < 0.0001) was associated with better cognition function. These variables acted confounders, but not effect modifiers of the MIND-diet – cognitive function relationship. Conclusion Adherence to the MIND diet was associated with better cognitive function at baseline and over 8 years of follow-up, however MIND diet was not associated with 8-year cognitive trajectory. More studies are needed to better understand whether the MIND diet is protective against long-term cognitive decline.

Vigorous physical activity and cognitive trajectory later in life: prospective association and interaction by apolipoprotein E e4 in the Nurses’ Health Study

Background The apolipoprotein E (APOE) e4 allele is a well-established genetic risk factor of brain ageing. Vigorous physical activity may be particularly important in APOE-e4 carriers, but data have been inconsistent, likely due to differences in the timing of the physical activity assessment, definition of cognitive decline and/or sample size. Methods We prospectively evaluated the association between vigorous physical activity and cognition assessed at least 9 years later, according to APOE-e4 carrier status. Biennially from 1986, Nurses’ Health Study participants reported their leisure-time physical activities. Starting in 1995-2001 and through 2008, participants (aged 70+ years) underwent up to four repeated cognitive telephone assessments (6 tasks averaged together using z-scores). Results Among 7,252 women, latent process mixed models identified three major patterns of cognitive change over 6 years: high-stable, medium-stable, and decline. Taking the high-stable cognitive trajectory as the outcome reference in multinomial logistic regressions, highest tertile of vigorous physical activity (≥5.9 metabolic-equivalent[MET]-hours/week) compared to lowest tertile (≤0.9 MET-hours/week) was significantly associated with subsequent lower likelihood of the medium-stable trajectory in the global score (OR[95%CI]=0.72[0.63,0.82]), verbal memory (OR[95%CI]=0.78[0.68-0.89]) and telephone interview of cognitive status score (OR[95%CI]=0.81[0.70-0.94]). Vigorous physical activity was also associated with lower likelihood of decline in category fluency (OR[95%CI]=0.72[0.56,0.92]). We observed some evidence (p-interaction=0.06 for the global score) that the association was stronger among APOE-e4 carriers than non-carriers (OR[95%CI]=0.60[0.39,0.92] versus 0.82[0.59,1.16]). Conclusion Midlife vigorous physical activity was associated with better cognitive trajectories in women in their seventies, with suggestions of stronger associations among APOE-e4 carriers.

Simulating the Effects of Common Comedications and Genotypes on Alzheimer’s Cognitive Trajectory Using a Quantitative Systems Pharmacology Approach

Background: Many Alzheimer’s disease patients in clinical practice are on polypharmacy for treatment of comorbidities. Objective: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. Methods: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer’s disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531, and APOE genotypes and with benzodiazepines, antidepressants, and antipsychotics, all together 9,585 combinations. Results: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. Conclusion: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials.

Modeling the Cognitive Trajectory in CADASIL

Background: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. Objective: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. Methods: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. Results: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. Conclusion: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.