Introduction
Advancing age is the number one risk factor of age-related cognitive impairment and dementia, representing a major public health epidemic among older Americans (1). A systematic review of cross-sectional studies and longitudinal cohorts has identified a relation between diet quality and cognitive health in the aging population (2). A healthy diet covers a variety of dietary patterns such as Mediterranean diet (MeDi) (3, 4), Healthy Dietary Index (HDI) diet (5), Healthy Eating Index (HEI) diet (6), Dietary Approaches to Stop Hypertension (DASH) diet (7), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet (8). In some studies, dietary patterns are derived a posteriori with cluster analysis, factor analysis (e.g., principal component analysis [PCA]), or reduced rank regression (9–13). Though healthy dietary patterns have been diversely defined, they share common components of high intake of fruits, vegetables, whole grains, nuts, seeds, fish, and limited intake of added sugar, sodium, high-fat dairy products, red, and processed meat (2).
Traditionally, habitual dietary intake has been estimated using subjective recall data derived from food frequency questionnaires (FFQ). This approach, despite its direct translation for establishing dietary recommendations, does not account for recall bias, particularly among subjects with varied cognitive performance, and inter-individual variability in the nutrient absorption and metabolism (14). There has been an attempt to overcome these issues by constructing serum nutrient patterns (NP) as a marker of intake among subjects in the Oregon Brain Aging Study (15), and the Illinois Brain Aging Study (16–18). However, given that cognitive processes originate from the human brain, particularly in neocortices, and that nutrient uptake into the central nervous system (CNS) is strictly regulated at the blood-brain barrier (BBB) (19), we need to expand the scope of investigation further into the CNS for a greater apprehension of nutrition's roles in the aging brain.
While the evidence for relations between diet quality and cognitive function has been largely consistent among observational studies, the evidence from clinical trials of dietary supplements has been mixed (20). When investigating the relationship between nutrition and age-related diseases, the importance of examining nutrition as dietary patterns or NPs have been highlighted (21, 22), as most individuals acquire nutrients predominantly from foods, rather than supplements, throughout their lifespan. From a biochemical and molecular perspective, the etiology of age-related dementia, despite its heterogeneity, shares multiple mechanisms including cardiometabolic risk factors, elevated oxidative stress, neuroinflammation, and impaired AMP-activated kinase signaling (23). All of these factors can potentially be regulated by multiple dietary components. The pathology of age-related cognitive impairment is also different from cognitive symptoms caused by a deficiency of a single nutrient that may manifest during a shorter period of time and may be reversible—such as dementia caused by vitamin B12 or niacin deficiency, and Wernicke-Korsakoff syndrome caused by a genetic predisposition “to thiamin” deficiency (24, 25).
Therefore, the present research study was proposed based on the rationale that many fat-soluble nutrients (carotenoids, vitamins A, E, K, and fatty acids [FA]) are present in human brain (26–31), and that they are a part of dietary patterns and serum NPs previously reported to be associated with better cognitive function in multiple aging cohorts (2, 15, 26, 28, 32, 33). This was accomplished by constructing a posteriori NPs of fat-soluble nutrients measured in brain tissues acquired post-mortem from a subset of centenarians (defined as ≥98 years) who were enrolled in the Georgia Centenarian Study (GCS)—the longest running centenarian study in the U.S. to date (34, 35). Subsequently, the relationship between constructed NPs and cognitive performance at the time point closest to death was cross-sectionally investigated. Findings from this novel study may also provide insights into the role of nutrition in cognition in the oldest old, which may be similar or different from lesser aged older adults.