Risk factors for AD and all-cause dementia exhibit overlap with those for cardiovascular disease. One of the important risk factors for cardiovascular disease is T2D and our purpose was to investigate the contribution of markers of glucose homeostasis and inflammation to the development of AD and all-cause dementia. We did not find indications that plasma insulin, glucose, and glycated albumin levels were associated with AD or all-cause dementia. In addition, the inflammatory marker Lp-PLA2
was not associated with AD or all-cause dementia. Higher plasma levels of hsCRP, the other inflammatory marker under investigation, initially appeared to be associated with a lower risk for AD and all-cause dementia. This association, however, was no longer significant after adjusting for the additional risk factors, including the presence of the APOE
ε4 allele. The latter finding is in line with a previous report suggesting that in APOE
ε4 carriers, the elevated plasma levels of CRP reflect a better immune function and are associated with a decreased risk for AD and dementia.37
Alternatively, persons with elevated levels of CRP and APOE
ε4 may have died of alternative causes before the examination round of this study and were therefore not included.
Our data indicated that adiponectin level was an independent risk factor for all-cause dementia and AD in women. One of the main features of adiponectin is that it has been shown to play a role in the sensitization of insulin and therefore may become a therapeutic target for the treatment of T2D. Surprisingly, a higher adiponectin level was found to be a predictor of all-cause and vascular mortality.23,24
In concurrence with the mortality findings, the current investigation shows that an elevated adiponectin level is also an independent predictor for all-cause dementia and AD in women. A recent cross-sectional study from Japan also found that high adiponectin levels were associated with mild cognitive impairment and AD.38
To clarify the positive association of adiponectin with mortality, a number of possibilities have been raised, including the known elevation of plasma adiponectin levels with impaired renal function and weight loss.39
This latter concept may be especially relevant in our study since weight loss is a significant risk factor for mortality in elderly individuals.40,41
In addition, patients with dementia usually have prodromal and subsequent weight loss that would be predicted to increase adiponectin levels. In our study population, we also found a significant correlation between age-adjusted correlation of adiponectin level and weight change in women. However, it did not impact the significance of adiponectin level as a risk factor for AD in women.
Although we did not have data on the entire sample for plasma creatinine or homocysteine levels, we studied these variables in a subset (n = 550) of study participants and found no direct evidence for confounding. Furthermore, adiponectin level remained a significant risk factor for all-cause dementia and AD in women when taking into account the established risk factors, ie, APOE ε4 allele, plasma DHA level, and level of education, suggesting that at least in women, adiponectin level is an independent risk factor or risk marker for all-cause dementia and AD.
A previous study from the Framingham population using samples from examination 22 has shown that elevated levels of leptin were associated with a reduced incidence of dementia and AD and with higher total cerebral brain volumes in asymptomatic older adults.26
To see if selection bias explained the results, we compared the characteristics of the study subjects included in that study with subjects in our study. The flowchart showing all inclusion and exclusion criteria along with subject numbers of the 2 studies is shown in the eFigure
. The characteristics of the subjects included in the 2 studies were similar (eTable 4
). In addition, the majority of the subjects were included in both studies (56.5%; 479 of 848). Therefore, it is unlikely that selection bias would explain our findings. Furthermore, additional analysis stratified by median age also showed that a high adiponectin level was associated with an increased risk of dementia in both age groups. Although the significant differences were found only in the age group 72 years and older, this could be explained by low numbers of subjects with dementia in the age group younger than 72 years. These findings would exclude the survival bias as well.
It is well established that insulin signaling is dysfunctional in the brains of patients with AD,6
and since adiponectin enhances insulin sensitivity, one would also expect beneficial actions protecting against cognitive decline. Our data, however, indicate that elevated adiponectin level was associated with an increased risk of dementia and AD in women. Alternatively, adiponectin levels may have risen as a (protective) response to vascular damage or changes in brain morphology that had not yet been identified at the time of enrollment into the study. To distinguish between these 2 possibilities, studies reporting the correlation between multiple measures of adiponectin and cognitive decline over time, and in addition, mendelian randomization studies linking genetic variation in the adiponectin gene to plasma adiponectin levels and cognitive decline, will be of great interest. To our knowledge, to date, there are no data relating baseline adiponectin levels to changes in cognition. Furthermore, although polymorphisms in the promoter region of the adiponectin gene with direct effects on adiponectin levels have been identified,42,43
no study that we know of has investigated the role of these genetic variants in relation to cognitive end points.
To our knowledge, this is the first prospective study to report that adiponectin level is an independent risk factor for all-cause dementia and AD in women. The strengths of our investigation include its prospective design, the large community-based sample, and the long follow-up period. Some limitations are the predominantly white nature of our study sample; hence, our results require verification in other racial and ethnic samples. Furthermore, the lack of an association between some of the circulating biomarkers tested (such as Lp-PLA2
and insulin levels) and the risk of dementia or AD could be a reflection of the age at which these markers were tested and of our relatively limited sample size. In addition, circulating levels of these markers might not reflect concentrations in the brain parenchyma or in the cerebro-spinal fluid. We have not corrected for multiple testing and would consider our results exploratory, requiring confirmation in other samples. Finally, a limitation of our study is the limited number of male cases; therefore, we cannot rule out the possibility that the absence of an association between adiponectin levels and the risk of dementia in men might reflect inadequate power to detect an effect. On the other hand, animal models have shown that testosterone downregulates adiponectin release from fat cells, and in human population studies, including the current study, women have higher plasma adiponectin levels than men.44,45
The fact that in women we find a threshold effect above which adiponectin level becomes a risk factor for dementia suggests that in men the absence of an effect of adiponectin could reflect that men have adiponectin levels less than a threshold value for increasing the risk of dementia. Thus, the sex dimorphism with regard to adiponectin levels might partially explain the lower risk of AD observed among men in another study.46