An emerging risk factor for cognitive decline

ELDERLY SUBJECTS WITH THE METABOLIC SYNDROME ARE AT HIGHER RISK OF COGNITIVE DECLINE OVER 4 YEARS

Yaffe K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline.JAMA 2004;292:2237-42.

Hypertension, hyperlipidaemia, and diabetes have been individually reported to increase the risk of cognitive decline and might play a role in the pathogenesis of vascular dementia and Alzheimer’s disease. In addition, subclinical inflammation is thought to be an underlying feature of the metabolic syndrome, and a role of inflammatory mechanisms in the pathogenesis of cognitive impairment is suspected. Taken together, these data suggest that elderly people with the metabolic syndrome might have an increased risk of cognitive decline. Yaffe et al conducted a 4-year prospective study, which was the first to test this hypothesis. Subjects were participants of the Health, Aging and Body Composition (ABC) study. This study was conducted from 1997 to 2002 in 3075 elderly subjects aged 70 to 79 years living in two US communities. To investigate a possible association between the metabolic syndrome and cognitive decline, well-functioning subjects were selected if they had no clinical dementia (DSM-IV criteria) and no history of treatment for cancer in the previous 3 years. Well-functioning was defined as having no difficulty in walking a quarter of a mile or going up 10 steps without resting. Baseline assessments included an evaluation of cognitive function using the Teng Modified Mini-Mental State Examination (3MS; best score, 100) and blood measurements of two inflammatory markers, interleukin-6 (IL-6) and C-reactive protein (CRP). High inflammation was defined as having both CRP levels >2.0 mg/l and IL-6 levels >2.0 pg/ml. Cognition was again assessed at 3 and 5 years. The 2632 subjects included in the analyses (mean age: 73.6 y, 52% women, 40% blacks, 60% whites) had at least one cognitive follow-up assessment. The metabolic syndrome was detected using the NCEP ATP III criteria, and cognitive impairment was defined as a decline in 3MS score >5 points.

Statistical comparisons were performed to evaluate the relative risk of cognitive impairment in subjects with the metabolic syndrome and those without at baseline, and to analyse the association between the metabolic syndrome and 4-year change in cognition. Measurements of inflammatory markers were included in the statistical models. Compared with those without the metabolic syndrome (n=1616), elderly subjects with the metabolic syndrome (n=1016) were more likely to have cognitive impairment at baseline (26% vs 21%, multivariate adjusted RR, 1.20; CI 95%, 1.02-1.41). A similar pattern of increased risk of cognitive impairment (adjusted RR, 1.35) was found when subjects with diabetes, hypertension, or hyperlipidaemia were excluded from the analysis. This shows that risk of cognitive impairment may be present in subjects without clinically evident manifestations of the syndrome. However, the risk increase was no longer significant (IC 95%, 0.83-2.19), which the authors explain by a lack of power of the analysis after exclusion of these subjects.

The relative risk of cognitive impairment was higher in subjects with the metabolic syndrome and high inflammation (multivariate adjusted RR, 1.66; 95% CI, 1.19-2.32). Most remarkably, the risk of cognitive impairment was not increased in subjects with the metabolic syndrome and low inflammation (multivariate adjusted RR, 1.08; 95% CI, 0.89-1.30). Similar results were found in blacks and whites when subjects were stratified by race. The interaction between inflammation and the metabolic syndrome was further confirmed by long-term results showing a greater 4-year decline on 3MS (P=0.04) in subjects with the metabolic syndrome and high inflammation compared with those without the syndrome. Again, a higher risk was not observed in subjects with the metabolic syndrome and low inflammation (Figure).

Figure. Risk of developing cognitive decline over 4 years in elderly subjects with
the metabolic syndrome compared with those without.
The increased risk was primarily present in subjects with the metabolic syndrome
and high levels of both CRP and IL-6. Vertical bars represent 95% CI.

* Risk ratios adjusted for age, education, race, baseline cognitive score,
depression, alcohol use, stroke, and statin use.

Another interesting finding was that in people with the metabolic syndrome and high inflammation, the risk of cognitive decline did not vary with the number of metabolic syndrome components. Although they did not assess the pathophysiology underlying these findings, the authors emphasise that the metabolic syndrome contributes to accelerated atherosclerosis, thus eliciting an inflammatory response. Either atherosclerosis or inflammation or both, can contribute to cognitive decline. They also propose that, in metabolic syndrome patients, the level of inflammation might be a marker of active pathological process. The same authors have previously shown an accelerated cognitive decline in people with elevated CRP and IL-6.