In our population-based cohort of elderly persons, high % carbohydrate intake was associated with an increased risk of MCI. In contrast, high % fat and high % protein intake were associated with a reduced risk of MCI or dementia. These findings suggest that dietary patterns consisting of a high intake of energy derived from carbohydrates and a relatively low intake from fat and protein may have adverse implications for development of MCI. In contrast, an optimal balance in the proportions of daily calories derived from carbohydrate, fat, and protein, may maintain neuronal integrity and optimal cognitive function in the elderly.
A possible explanation for the association of carbohydrate intake with MCI is that elderly subjects with a high % carbohydrate intake may consume more foods with a high glycemic index. Indeed, subjects in our study with the highest % carbohydrate intake also had the highest intake of sugars and fruit (which are high in sugar content) but not vegetables, and the lowest intake of fat and protein. Glucose is a major source of energy for brain metabolism, and glucose administration typically enhances cognitive performance [33
]. However, in elderly persons, a dietary pattern high in carbohydrate intake and in simple sugars may disrupt glucose and insulin metabolism [8
]. High insulin levels may be detrimental to cognitive function [38
]. Persistence of the association of high % carbohydrate with MCI risk after simultaneous adjustment for fat and protein suggests that high intake of carbohydrate may be a key promoter of the increased risk, and relative intakes of protein and fat may also play a role.
High carbohydrate and sugar intake may adversely affect cognition through several mechanisms. Hyperglycemia and diabetes may contribute to increased formation of advanced glycation endproducts (AGE), upregulation of the soluble receptors for AGEs, and may generate oxidative stress which in turn, enhances AGE formation [39
]. AGEs and oxidative stress have also been associated with greater cognitive decline and with AD through effects on amyloid and tau metabolism [39
The increased risk of MCI with lower intake of fats and proteins may involve non-energy related pathways [33
]. Fat and protein intake may be required for the integrity of neuronal membranes and fats for the integrity of the myelin sheaths in the brain. Although we did not observe significant trends with increasing quartiles of % MUFA and % PUFA intake, the hazard ratios were reduced for higher intake. These unsaturated fatty acids, and in particular essential PUFAs, may maintain cognitive function through effects on structural, functional, and synaptic integrity of neurons [42
], reduced amyloid-β levels [42
], improved insulin sensitivity and glucose metabolism [45
], decreased cardiovascular disease [48
] and stroke [49
]. High intake of fish, an important source of omega 3 PUFA, has been associated with a reduced risk of cognitive impairment in elderly persons [50
] since fish is also an important source of vitamin D, the reduced risk of cognitive impairment in individuals with high fish intake may be due to the combined effects of omega 3 PUFA and vitamin D [51
]. Low intake of protein may be associated with low intake of essential proteins that are required for synthesis of neurotransmitters in the brain. For example, tryptophan crosses the blood brain barrier and is a precursor for brain serotonin, an important neurotransmitter. Murine studies suggest that tryptophan transport across the blood brain barrier decreases with ageing [52
]. If this is true in humans, reduced intake of proteins in the elderly may adversely impact neuronal function.
Other factors besides macronutrient intake may contribute to our findings. Subjects with the highest % carbohydrate intake had the lowest total caloric intake which is consistent with the low % fat intake, but is also consistent with low BMI in these subjects, and with previously reported decreased weight loss in the years preceding onset of dementia in elderly persons [53
]. In addition, moderate alcohol intake has been reported to reduce risk of cognitive impairment [3
] and may play a role on MCI risk in our cohort. The dietary patterns observed may be causal or alternately, may be a marker for preclinical disease and risk of cognitive impairment or dementia in elderly persons. These associations need to be examined in other longitudinal studies.
Our findings are consistent with findings from several studies. In one study, subjects with AD and vascular dementia had a high predilection for sugar and sweet foods [56
]. Other investigators suggest that reducing caloric intake through carbohydrate restriction may reduce risk of cognitive impairment, AD [5
], and amyloid-β deposition and pathology [63
]. In a study among non-diabetics, the highest cognitive performance was observed in subjects with the best glucose regulation [37
]. In the National Health and Nutrition Examination Survey, a dietary pattern with a high % fat was associated with better processing speed, learning, and memory; in contrast high % carbohydrate was associated with poor processing speed [65
]. Other studies suggest that phosphatidylcholine, an essential PUFA, improved memory, learning, concentration, and the ability to memorize words in elderly subjects with memory decline [33
], and that protein may enhance cognitive performance [65
] by improving glucose homeostasis [67
]. Decreasing total calories and BMI with increasing % carbohydrate quartile may be markers for imminent cognitive impairment, and are consistent with decreasing weight prior to dementia onset in elderly persons [55
Potential limitations of our findings include recall bias in reporting of dietary nutrients. This effect may be small in part because subjects were cognitively normal at the time the food frequency questionnaire was completed, and because our previously reported cross-sectional findings on diet and cognition [2
] are consistent with several other studies [1
]. Although the validity of food frequency questionnaires has been questioned, this concern may have greater bearing on studies regarding cancer risk [73
]. Other experts suggest that use of the food frequency questionnaire is valid for ranking subjects according to food and nutrient intake as in the present study [74
]. We could not estimate glycemic index (or glycemic load) since this index is impacted by foods eaten together at a meal; the food frequency questionnaire only assessed usual eating habits in the previous 12 months. There is a potential for non-participation bias, but the higher frequency of vascular risk factors in non-participants suggests that the hazard ratios may be are biased toward a null association. The potential impact of reverse causality is unclear, but it is not possible to determine whether preclinical changes of AD, cerebrovascular disease, or other neurodegenerative pathology, contributed to dietary patterns at baseline. Finally, study participants were primarily of northern European ancestry and any generalizability to other ethnicities should be performed with caution.
Several strengths of our study should be noted. The study was specifically designed to investigate risk factors for MCI. The population-based design reduced selection bias and enhanced the external generalizability of the findings to the population [14
]. The comprehensive evaluation of participants for MCI or dementia by 3 independent evaluators increased the internal validity of the findings. We categorized subjects on their usual macronutrient intake using data from a previously validated food frequency questionnaire [23
], and assessed nutrient intakes using an established nutrition database. The prospective study design allowed us to estimate causal associations while taking into account potential confounding factors.