The present study assessed the association of phenotypes defined using BMI categories and metabolic status with cognitive function and decline. Our results show that cognition at baseline and cognitive decline over the 10-year follow-up were similar in the metabolically normal-obese (or metabolically healthy-obese) and the metabolically abnormal-obese individuals. In the metabolically normal group, lower BMI was associated with better cognition at baseline and similar cognitive decline as a function of BMI, suggesting that baseline differences were maintained but did not increase over time. In the metabolically abnormal group, there were no differences in cognitive performance at baseline as a function of BMI. However, the longitudinal analysis in this group, statistically significant only for the global measure, suggests faster cognitive decline over 10 years with increasing BMI.
The results at baseline provide no support for an accumulation of risk arising from the presence of both obesity and metabolic abnormality. Thus, either obesity or metabolic abnormality is sufficient to affect cognition, and these factors seem not to exert additive influences on cognition. The longitudinal analyses appear to suggest some accumulation of risk, with the decline being somewhat greater in individuals with both metabolic abnormalities and obesity. We note that this trend is evident for all tests but statistically significant only for the global cognitive score. Because measurement error is minimized in this type of global score,28
there appears to be some evidence of accumulation of risk concerning cognitive decline. However, there was no evidence that the metabolically normal obese group had a better cognitive profile than the metabolically abnormal obese group.
In relation to cardiovascular disease, some17–19
but not all, previous studies20–22
have reported better outcomes for metabolically healthy obese than for metabolically unhealthy obese individuals. Our results show this not to be the case for cognitive function. Some of the attempts to examine obesity phenotypes have constructed 4 groups: normal weight, overweight, obese healthy, and obese unhealthy.30
However, it is clear from previous results31
and our data that the normal and overweight groups are not homogeneous in terms of metabolic health. Our results show that among normal-weight and overweight individuals, an adverse metabolic profile was associated with poorer cognitive function. In our sample, 18% of the normal-weight individuals had metabolic abnormalities, a somewhat lower figure than the 21.1% in women and 30.1% in men reported for North American data using slightly different criteria to define metabolic abnormalities.12
The poorer cognition in the normal weight-metabolically abnormal group in our data cannot be attributed to these individuals having become obese at the end of the follow-up. BMI data from the end of the follow-up, concurrent with the cognitive testing, showed that a similar proportion of individuals in the normal weight-healthy and normal weight-unhealthy group (1.8% vs 1.6%) had become obese at the end of the follow-up.
Because age is known to modify the association between adiposity and cognitive outcomes,2,7
we examined this association in individuals whose mean age was 56 years at the start of the cognitive testing. The magnitude of the effect at baseline was important; for example, in metabolically normal individuals, the difference in global cognitive score for obese individuals (0.16 SD, ) was comparable to 3.8 years of cognitive decline (the 10-year decline being 0.42 SD in this group, ). However, the longitudinal analyses show faster decline as a function of BMI status only in the metabolically abnormal group. The cross-sectional and longitudinal analyses taken together suggest that the effects of BMI and metabolic status persist over time, with some suggestion of a faster decline in those with an adverse BMI and metabolic profile.
There is considerable evidence from single studies and meta-analyses to suggest that obesity in midlife is associated with poorer cognition9,10
and greater risk of dementia in later life.1,2,5,6
The extent to which these associations are causal remains unclear. Cognitive reserve,32
or fetal exposures34
could also underlie these associations. Because our results were robust to adjustment for education and other markers of reserve such as height and occupation (results not shown), cognitive reserve is an unlikely explanation for our findings. Besides examining the effect of genetic factors and putative fetal exposures, further research also needs to take into account the duration of obesity and metabolic status and perhaps assess cognitive decline over a longer follow-up to allow better understanding of the association between obesity and cognition.
There are several plausible mechanisms underlying the association between obesity and adverse cognitive outcomes. Vascular pathologies (white matter lesions, lacunar infarcts, hypoperfusion, blood vessel inflammation, and cerebrovascular disease) are seen to be the primary mechanism underlying this association.2
Other possible mechanisms relate to secretions of adipose tissue, leptin, and adiponectin in particular, which affect the aging brain.2,6
Previous studies have shown high BMI to be associated with poor performance in multiple cognitive domains.8,10,35
Our results show associations at baseline across the cognitive domains examined.
There is considerable evidence to show adverse effects of obesity on health.14–16
As obesity becomes more prevalent (400 million adults were obese in 2005 with the figure projected to rise to more than 700 million by 2015),36
questions are raised about the ubiquity of its impact on health. The idea of an obesity spectrum suggests that the severity and duration of obesity are important.37
Recent analysis using data from nearly 900,000 individuals show that each 5 kg/m2
higher BMI was associated with approximately 30% higher overall mortality.16
There is also emerging evidence of the effect of duration of obesity, every 2 obese-years increasing mortality risk by 6%.38
In addition, it is known that early life measures of obesity predict late life measures, which provides evidence of longitudinal stability or tracking.39
Thus, to estimate the impact of obesity on cognition, the number of years lived with obesity is likely to be important.
The main strengths of this study include the large sample size, comprehensive assessment of cognition, and the 5-year delay between the assessment of the exposure and the first cognitive measure, ruling out, to some extent, reverse causation biases. We used a battery of cognitive tests and present results using the global cognitive score, allowing replication across studies in the future. The most important limitation of the study is that participants of the Whitehall II study are mainly office-based civil servants, not fully representative of the British population because the study does not include the unemployed or individuals in blue collar professions.
In sum, given the rapid increase in obesity levels globally, it is important to estimate its impact on health from a public health point of view. If the concept of MHO holds, then the estimation of the negative impact of obesity on health needs to be revisited. Our data suggest no such heterogeneity in the impact of obesity on cognitive performance in early old age, because obese individuals who are otherwise metabolically healthy have a risk of poor cognition similar to that of their obese metabolically unhealthy counterparts.