0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease Results From the Framingham Heart Study FREE

Thomas M. van Himbergen, PhD; Alexa S. Beiser, PhD; Masumi Ai, MD; Sudha Seshadri, MD; Seiko Otokozawa, MT; Rhoda Au, PhD; Nuntakorn Thongtang, MD; Philip A. Wolf, MD; Ernst J. Schaefer, MD
[+] Author Affiliations

Author Affiliations: Lipid Metabolism Laboratory, Human Nutrition Research Center on Aging, Tufts University (Drs Van Himbergen, Ai, Thongtang, and Schaefer and Ms Otokozawa), Department of Neurology, School of Medicine (Drs Beiser, Seshadri, Au, and Wolf), and Department of Biostatistics, School of Public Health (Dr Beiser), Boston University, and the National Heart, Lung, and Blood Institute Framingham Heart Study (Drs Beiser, Seshadri, Au, and Wolf), Boston, Massachusetts.


Arch Neurol. 2012;69(5):594-600. doi:10.1001/archneurol.2011.670.
Text Size: A A A
Published online

Objective To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.

Design Prospective cohort study.

Setting Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia.

Participants Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.

Main Outcome Measures We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ϵ4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.

Results Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median.

Conclusion In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Dementia is a progressive neurodegenerative disorder that is clinically characterized by loss of memory and cognitive decline. According to the World Alzheimer Report, currently about 36 million people worldwide are affected by dementia and it is estimated that this number will nearly double over the next 20 years. Of all forms of dementia, Alzheimer disease (AD) is the most common, comprising up to 80% in the elderly population.

In addition to the well-established risk factors for AD, ie, age, family history, and the presence of the APOE ϵ4 allele,13 previously, a high plasma homocysteine level was found to be an independent risk factor for dementia,4 while high plasma levels of docosahexaenoic acid (DHA) significantly reduced the risk for developing dementia.5 Furthermore, data suggest that the management of cardiovascular risk factors, such as type 2 diabetes (T2D), high blood pressure, and obesity, may also reduce cognitive decline, although their impact on the risk of development of clinical AD is less certain.6

Insulin resistance and inflammation are important hallmarks of T2D and could provide a potential mechanism explaining the association between T2D and dementia.7 Although a central role for insulin in the pathology of AD and dementia has been suggested,8,9 and intervention trials using insulin-sensitizing drugs to slow down cognitive decline are ongoing,10 there remains uncertainty regarding the role of insulin and glucose intolerance. Similarly, although the inflammatory marker lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with the risk of incident dementia,11 and there is evidence suggesting that C-reactive protein (CRP) is associated with cognitive decline1215 and risk of dementia,16 other reports failed to find such an association.1719 To our knowledge, no prior studies have simultaneously related measures of glucose homeostasis and markers of inflammation to the risk of incident dementia in a single elderly community-based cohort followed up for up to 2 decades.

An additional potential factor that may contribute to the onset of AD and all-cause dementia is adiponectin. Adiponectin is a hormone derived from visceral fat, which sensitizes the body to insulin, has anti-inflammatory properties, and plays a role in the metabolism of glucose and lipids.20 Higher levels of adiponectin have been shown to lower the risk for T2D,21 and there is widespread expression of the adiponectin receptor gene throughout the body, including in the brain.22 Despite the fact that increased adiponectin levels have been shown to have a beneficial effect on the signaling of insulin and the management of T2D, higher levels of adiponectin also have been related to an increased risk of all-cause mortality.23,24 Furthermore, visceral or central obesity has been linked to smaller brain volumes and a higher risk of AD.25 Adiponectin levels are also inversely correlated with levels of leptin and brain-derived neurotrophic factor, both of which have been associated with a lower risk of incident dementia and AD.26

We hypothesized that factors that underlie T2D (ie, insulin signaling and inflammation) may also contribute to the development of all-cause dementia and AD. Furthermore, based on the role adiponectin plays in insulin signaling and the presence of adiponectin receptors in neurological tissue, we hypothesized that adiponectin contributes to or serves as a risk marker for the development of all-cause dementia and AD. To investigate this hypothesis, we measured levels of plasma adiponectin, glucose, glycated albumin, and insulin (as measures of glucose homeostasis) and levels of plasma Lp-PLA2 and CRP (as measures of inflammation) in a prospective cohort study in which the subjects were followed up for incident all-cause dementia and AD (the Framingham Heart Study).

SUBJECTS AND THE DIAGNOSIS OF AD AND ALL-CAUSE DEMENTIA

The Framingham Heart Study is a longitudinal population-based study in which subjects have been examined every 2 years.27 The dementia cohort consists of 3349 participants who were determined to be cognitively intact at examination cycle 14 when participants underwent a neuropsychological test battery (age range, 55-88 years).1 At the 19th biennial examination (1985-1988), 2337 participants from this cohort were alive and free of dementia. Of these, 1370 (69.8%) underwent the 19th examination and had at least 1 year of follow-up data. Plasma adiponectin level was measured in 826 subjects (60.3% of those examined); 2 participants with moderate renal failure (serum creatinine level >2 mg/dL [to convert to micromoles per liter, multiply by 88.4]) were excluded. The study sample of 840 subjects consisted of 541 women and 299 men, with a mean age of 72 years. Seventy percent were high school graduates. Informed consent was obtained from all of the participants. The study was approved by the institutional review board for human research at the Boston University School of Medicine.

Members of the dementia cohort have been monitored for the development of stroke and dementia since their inclusion in the cohort. Participants were routinely administered a screening Mini-Mental State Examination at each biennial examination.28 Persons who scored less than education-based cutoffs or who experienced a decline of 3 or more points on the Mini-Mental State Examination from the most recent previous examination were called back for a neurological and neuropsychological examination. For each case of possible dementia, a detailed case review was undertaken by a panel consisting of at least 1 neurologist (including P.A.W. and S.S.) and a neuropsychologist (R.A.). The panel determined the type of dementia and the date of diagnosis using serial neurological and neuropsychological assessments, a telephone interview with a family member or a caregiver, medical records, and imaging study results. The diagnosis of dementia was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.29 Alzheimer disease was diagnosed when subjects met the criteria of the National Institute of Neurological Disorders and Stroke–Alzheimer's Disease and Related Disorders Association for definite, probable, or possible AD.30 Subjects who had an interim stroke during the follow-up period were not excluded. All confirmed cases of dementia after the 19th biennial examination (through December 31, 2009) were included, providing longitudinal follow-up of up to 24 years.

LABORATORY ANALYSES

Blood was obtained in 0.1% EDTA at the 19th examination. Apolipoprotein E genotyping was performed using DNA isolated from blood cells and carried out as previously described.3 Total plasma homocysteine concentrations were determined with the use of high-performance liquid chromatography with fluorometric detection,4 and creatinine concentrations were estimated using the modified Jaffe method as described elsewhere.31 The DHA concentrations were measured as previously described.5 Insulin and glucose levels were measured as previously reported.32,33 Glycated albumin, Lp-PLA2, high-sensitivity CRP (hsCRP), and adiponectin levels were measured in plasma on an Olympus AU400 with enzymatic reagents (Olympus America Inc) as reported elsewhere.3436 Interassay coefficients of variation were less than 5% for all assays.

ADDITIONAL RISK FACTORS

Risk factors that could potentially confound the relation between the plasma markers and dementia or AD were defined based on data collected at the 19th biennial examination. Educational status was dichotomized at the level of high school completion. Diabetes mellitus was defined by a recorded casual blood glucose level of at least 200 mg/dL (to convert to millimoles per liter, multiply by 0.0555), a previous diagnosis of diabetes mellitus, or the use of a hypoglycemic agent or insulin. Systolic blood pressure and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) were treated as continuous variables. Weight change was defined as change in weight from that recorded at 1 of the prior biennial examinations. This period averaged 4.3 years (range, 2-6 years) prior to examination 19.

STATISTICAL ANALYSIS

The population distributions of plasma adiponectin, insulin, glycated albumin, glucose, and hsCRP levels were positively skewed. The use of natural-log–transformed values provided the best-fitting model for analyses, in which these markers were treated as a continuous variable. Cox proportional hazards regression models were used to examine the relation between the study marker levels and the incidence of all-cause dementia and AD. The risk of dementia is more likely to change as a function of age than of time; we thus used age as the time scale, adjusting for left truncation at entry. Survival age was defined as age at diagnosis of dementia if the individual had dementia or age at death if the individual did not have dementia at death; the remaining participants were censored at the last age known to not have dementia. In analyses of AD, participants with incident non-AD dementia were censored at the date of diagnosis of dementia. Primary analyses were adjusted for age and sex. Supplementary analyses were additionally adjusted for BMI, weight change, APOE genotype (with or without an APOE ϵ4 allele), DHA concentrations, and educational level. An additional subset analysis was performed in 550 subjects who also had serum creatinine and plasma homocysteine measurements available. Plasma adiponectin levels were also evaluated with a median cutoff–based analysis. Testosterone selectively inhibits the secretion of adiponectin from adipocytes resulting in lower levels of circulating adiponectin in men. To take this into account, we investigated interactions by sex and additionally performed analyses stratified by sex. Subjects who had a stroke during the study period were not excluded, since such an event could lie along the causal pathway between elevated plasma levels of the study markers and the development of dementia. All statistical analyses were performed with the use of SAS software (SAS Institute).

The cohort was followed up for a median of 13 years. One hundred fifty-nine subjects developed dementia during the follow-up period (including 125 cases of AD). The baseline characteristics of the sample (at the 19th biennial examination) are shown in Table 1.

Table Graphic Jump LocationTable 1. Baseline Subject Characteristics and Adiponectin Levels at Examination Cycle 19

Age- and sex-adjusted hazard ratios (HRs) for all-cause dementia and AD for every 1-SD increase in adiponectin, insulin, glycated albumin, glucose, Lp-PLA2, and hsCRP concentrations are presented in Table 2. Baseline levels of adiponectin, insulin, glycated albumin, glucose, and Lp-PLA2 were not associated with all-cause dementia or AD in a model adjusted for age and sex. A high plasma hsCRP level, however, was associated with a reduced risk for both all-cause dementia (HR, 0.78; 95% confidence interval [CI], 0.66-0.93; P = .004) and AD (HR, 0.79; 95% CI, 0.65-0.95; P = .01).

Table Graphic Jump LocationTable 2. Age- and Sex-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Concentrations

Multivariate-adjusted HRs for a 1-SD increase in hsCRP concentrations are presented in Table 3. A high plasma hsCRP level remained protective against all-cause dementia and AD after adjusting for BMI and weight changes (HR, 0.78; 95% CI, 0.65-0.93; P = .006 and HR, 0.82; 95% CI, 0.67-1.00; P = .048, respectively). However, the associations were no longer statistically significant after adjustments were made for the other risk factors (HR, 0.83; 95% CI, 0.67-1.03; P = .09 for all-cause dementia and HR, 0.86; 95% CI, 0.86-1.10; P = .23 for AD).

Table Graphic Jump LocationTable 3. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in hsCRP Concentrations

Significant sex interactions were observed for adiponectin (P < .05) (Table 2) and further analyses in men and women revealed that among women, higher baseline adiponectin levels significantly predicted higher risk for all-cause dementia and AD (HR, 1.31; 95% CI, 1.07-1.61; P = .009 and HR, 1.32; 95% CI, 1.06-1.65; P = .02, respectively) (Table 4).

Table Graphic Jump LocationTable 4. Age- and Sex-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Adiponectin Concentrations

Age-adjusted correlations of adiponectin level with measures of body composition and weight loss are presented in Table 5. There was an inverse association between plasma adiponectin levels, BMI, and waist to hip ratio in both men and women. These associations were mainly due to a strong correlation observed in women (r = −0.36 and r = −0.37; P < .001 for BMI and waist to hip ratio, respectively). The correlation between plasma adiponectin levels and weight change was weaker and only significant in women (r = −0.11; P < .01).

Table Graphic Jump LocationTable 5. Age-Adjusted Correlations of Adiponectin With Measures of Weight Loss and Body Composition at Examination Cycle 19a

Results of subsequent analyses regarding adiponectin level performed on women only are given in Table 6 and Table 7. Although adjustments for BMI and weight change did have a small effect on the HR, plasma adiponectin level remained a marginally significant risk factor for both all-cause dementia and AD in the fully adjusted model (HR, 1.29; 95% CI, 1.00-1.66; P = .054 and HR, 1.33; 95% CI, 1.00-1.76; P = .050, respectively). Among women with nonmissing creatinine and plasma homocysteine concentrations, additional adjustment for these variables did not alter the HRs, indicating that there was no confounding by creatinine or plasma homocysteine level (data not shown). Results of quartile analyses of adiponectin level in women showed a threshold at the median. Women with a baseline adiponectin concentration more than the (sex-specific) median had a significantly higher risk of all-cause dementia and AD even in the fully adjusted model (HR, 1.63; 95% CI, 1.03-2.56; P = .04 and HR, 1.87; 95% CI, 1.13-3.10; P = .01, respectively) (Table 7).

Table Graphic Jump LocationTable 6. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Adiponectin Concentrations in Women
Table Graphic Jump LocationTable 7. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia More Than vs Less Than Median Adiponectin Concentrations in Women

To determine if survival bias played in our analysis, we did additional analysis stratified by median age (72 years) for the association of dementia with a 1-SD increase in hsCRP or adiponectin concentrations (eTable 1 and eTable 2). The direction of the effect estimates were the same for both age groups for both hsCRP and adiponectin levels. This was also true for the analysis comparing women with an adiponectin concentration more than and less than the median value (eTable 3).

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 cerebrospinal 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

Correspondence: Ernst J. Schaefer, MD, Lipid Metabolism Laboratory, Tufts University, 711 Washington St, Boston, MA 02111-1524 (ernst.schaefer@tufts.edu).

Accepted for Publication: June 20, 2011.

Published Online: January 2, 2012. doi:10.1001/archneurol.2011.670

Author Contributions: Study concept and design: Beiser, Seshadri, and Schaefer. Acquisition of data: Van Himbergen, Beiser, Ai, Seshadri, Otokozawa, Au, Wolf, and Schaefer. Analysis and interpretation of data: Van Himbergen, Beiser, Ai, Seshadri, Otokozawa, and Thongtang. Drafting of the manuscript: Van Himbergen, Seshadri, Thongtang, and Schaefer. Critical revision of the manuscript for important intellectual content: Van Himbergen, Beiser, Ai, Seshadri, Otokozawa, Au, Thongtang, Wolf, and Schaefer. Statistical analysis: Van Himbergen, Beiser, and Thongtang. Obtained funding: Seshadri. Administrative, technical, and material support: Ai, Otokozawa, Au, Thongtang, Wolf, and Schaefer. Study supervision: Seshadri.

Financial Disclosure: Dr Van Himbergen was supported by a research grant from Unilever Food and Health Research Institute, Unilever R&D, Vlaardingen, the Netherlands. Dr Ai and Ms Otokozawa were supported by research fellowships from Denka Seiken Co, Tokyo, Japan, and Kyowa Medex Co, Tokyo.

Funding/Support: Dr Thongtang was supported by a research fellowship from Siriraj Hospital, Mahidol University, Bangkok, Thailand. Dr Schaefer was supported by grants R01 HL-60935, HL 74753, and PO50HL083813 from the National Institutes of Health and contract 53-3K-06 from the US Department of Agriculture Agriculture Research Service. This work was also supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract N01-HC-25195 and by National Institute of Neurological Disorders and Stroke grant R01 NS17950 and National Institute on Aging grants R01 AG16495, AG08122, AG033040, AG033193 and AG031287, and P30AG013846.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of Unilever, the National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute on Aging, or National Institutes of Health.

Additional Information: The Framingham Dementia Study was planned and is being carried out by Drs Wolf, Au, Beiser, and Seshadri. The selection of the assays for this were made by Dr Schaefer, and the assays for this study were measured by Dr Ai and Ms Otokozawa.

Bachman DL, Wolf PA, Linn R,  et al.  Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study.  Neurology. 1992;42(1):115-119
PubMed   |  Link to Article
Strittmatter WJ, Weisgraber KH, Huang DY,  et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.  Proc Natl Acad Sci U S A. 1993;90(17):8098-8102
PubMed
Myers RH, Schaefer EJ, Wilson PW,  et al.  Apolipoprotein E epsilon4 association with dementia in a population-based study: the Framingham study.  Neurology. 1996;46(3):673-677
PubMed
Seshadri S, Beiser AS, Selhub J,  et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;346(7):476-483
PubMed
Schaefer EJ, Bongard V, Beiser AS,  et al.  Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study.  Arch Neurol. 2006;63(11):1545-1550
PubMed
Giordano V, Peluso G, Iannuccelli M, Benatti P, Nicolai R, Calvani M. Systemic and brain metabolic dysfunction as a new paradigm for approaching Alzheimer's dementia.  Neurochem Res. 2007;32(4-5):555-567
PubMed
Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia.  Curr Neurol Neurosci Rep. 2007;7(5):373-380
PubMed
Watson GS, Craft S. Insulin resistance, inflammation, and cognition in Alzheimer's disease: lessons for multiple sclerosis.  J Neurol Sci. 2006;245(1-2):21-33
PubMed
Biessels GJ, Kappelle LJ.Utrecht Diabetic Encephalopathy Study Group.  Increased risk of Alzheimer's disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?  Biochem Soc Trans. 2005;33(pt 5):1041-1044
PubMed
Luchsinger JA, Gustafson DR. Adiposity, type 2 diabetes, and Alzheimer's disease.  J Alzheimers Dis. 2009;16(4):693-704
PubMed
van Oijen M, van der Meer IM, Hofman A, Witteman JCM, Koudstaal PJ, Breteler MMB. Lipoprotein-associated phospholipase A2 is associated with risk of dementia.  Ann Neurol. 2006;59(1):139-144
PubMed
Yaffe K, Lindquist K, Penninx BW,  et al.  Inflammatory markers and cognition in well-functioning African-American and white elders.  Neurology. 2003;61(1):76-80
PubMed
Roberts RO, Geda YE, Knopman DS,  et al.  Association of C-reactive protein with mild cognitive impairment.  Alzheimers Dement. 2009;5(5):398-405
PubMed
Schuitemaker A, Dik MG, Veerhuis R,  et al.  Inflammatory markers in AD and MCI patients with different biomarker profiles.  Neurobiol Aging. 2009;30(11):1885-1889
PubMed
Noble JM, Manly JJ, Schupf N, Tang MX, Mayeux R, Luchsinger JA. Association of C-reactive protein with cognitive impairment.  Arch Neurol. 2010;67(1):87-92
PubMed
Engelhart MJ, Geerlings MI, Meijer J,  et al.  Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study.  Arch Neurol. 2004;61(5):668-672
PubMed
Kravitz BA, Corrada MM, Kawas CH. High levels of serum C-reactive protein are associated with greater risk of all-cause mortality, but not dementia, in the oldest-old: results from the 90+ Study.  J Am Geriatr Soc. 2009;57(4):641-646
PubMed
Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P. Serum inflammatory proteins and cognitive decline in older persons.  Neurology. 2005;64(8):1371-1377
PubMed
Tan ZS, Beiser AS, Vasan RS,  et al.  Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.  Neurology. 2007;68(22):1902-1908
PubMed
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.  J Clin Invest. 2006;116(7):1784-1792
PubMed
Li S, Shin HJ, Ding EL, van Dam RM. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis.  JAMA. 2009;302(2):179-188
PubMed
Yamauchi T, Kamon J, Ito Y,  et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;423(6941):762-769
PubMed
Laughlin GA, Barrett-Connor E, May S, Langenberg C. Association of adiponectin with coronary heart disease and mortality: the Rancho Bernardo study.  Am J Epidemiol. 2007;165(2):164-174
PubMed
Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure.  Arch Intern Med. 2007;167(14):1510-1517
PubMed
Debette S, Beiser A, Hoffmann U,  et al.  Visceral fat is associated with lower brain volume in healthy middle-aged adults.  Ann Neurol. 2010;68(2):136-144
PubMed
Lieb W, Beiser AS, Vasan RS,  et al.  Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging.  JAMA. 2009;302(23):2565-2572
PubMed
Dawber TR. The Framingham Study: the Epidemiology of Atherosclerotic Disease. Cambridge, MA: Harvard University Press; 1980
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12(3):189-198
PubMed
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.  Neurology. 1984;34(7):939-944
PubMed
Seshadri S, Wolf PA, Beiser AS,  et al.  Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study.  Arch Neurol. 2008;65(5):642-649
PubMed
Kamei T, Tuji N, Taketani K, Nakamoto M. Evaluation and clinical significance of latex immunoassay (LIA) of insulin using the routine biochemical autoanalyzer.  Japanese Journal of Clinical Chemistry. 2006;35(1):48-53
Akomolafe A, Beiser AS, Meigs JB,  et al.  Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study.  Arch Neurol. 2006;63(11):1551-1555
PubMed
Kouzuma T, Usami T, Yamakoshi M, Takahashi M, Imamura S. An enzymatic method for the measurement of glycated albumin in biological samples.  Clin Chim Acta. 2002;324(1-2):61-71
PubMed
Rawlins ML, La’ulu SL, Moon N, Roberts WL. Performance characteristics of an immunoturbidimetric assay for lipoprotein-associated phospholipase A2.  Clin Chim Acta. 2009;406(1-2):66-70
PubMed
Nishimura A, Sawai T. Determination of adiponectin in serum using a latex particle-enhanced turbidimetric immunoassay with an automated analyzer.  Clin Chim Acta. 2006;371(1-2):163-168
PubMed
Haan MN, Aiello AE, West NA, Jagust WJ. C-reactive protein and rate of dementia in carriers and non carriers of apolipoprotein APOE4 genotype.  Neurobiol Aging. 2008;29(12):1774-1782
PubMed
Une K, Takei YA, Tomita N,  et al.  Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer's disease.  Eur J Neurol. 2011;18(7):1006-1009
PubMed
Sattar N, Nelson SM. Adiponectin, diabetes, and coronary heart disease in older persons: unraveling the paradox.  J Clin Endocrinol Metab. 2008;93(9):3299-3301
PubMed
Wedick NM, Barrett-Connor E, Knoke JD, Wingard DL. The relationship between weight loss and all-cause mortality in older men and women with and without diabetes mellitus: the Rancho Bernardo study.  J Am Geriatr Soc. 2002;50(11):1810-1815
PubMed
Roubenoff R, Parise H, Payette HA,  et al.  Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study.  Am J Med. 2003;115(6):429-435
PubMed
Vasseur F, Helbecque N, Dina C,  et al.  Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.  Hum Mol Genet. 2002;11(21):2607-2614
PubMed
Hara K, Boutin P, Mori Y,  et al.  Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.  Diabetes. 2002;51(2):536-540
PubMed
Xu A, Chan KW, Hoo RLC,  et al.  Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes.  J Biol Chem. 2005;280(18):18073-18080
PubMed
Nishizawa H, Shimomura I, Kishida K,  et al.  Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.  Diabetes. 2002;51(9):2734-2741
PubMed
Kamogawa K, Kohara K, Tabara Y,  et al.  Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study.  Dement Geriatr Cogn Disord. 2010;30(5):432-439
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Subject Characteristics and Adiponectin Levels at Examination Cycle 19
Table Graphic Jump LocationTable 2. Age- and Sex-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Concentrations
Table Graphic Jump LocationTable 3. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in hsCRP Concentrations
Table Graphic Jump LocationTable 4. Age- and Sex-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Adiponectin Concentrations
Table Graphic Jump LocationTable 5. Age-Adjusted Correlations of Adiponectin With Measures of Weight Loss and Body Composition at Examination Cycle 19a
Table Graphic Jump LocationTable 6. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia by 1-SD Increase in Adiponectin Concentrations in Women
Table Graphic Jump LocationTable 7. Multivariate-Adjusted HRs for Alzheimer Disease and All-Cause Dementia More Than vs Less Than Median Adiponectin Concentrations in Women

References

Bachman DL, Wolf PA, Linn R,  et al.  Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study.  Neurology. 1992;42(1):115-119
PubMed   |  Link to Article
Strittmatter WJ, Weisgraber KH, Huang DY,  et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.  Proc Natl Acad Sci U S A. 1993;90(17):8098-8102
PubMed
Myers RH, Schaefer EJ, Wilson PW,  et al.  Apolipoprotein E epsilon4 association with dementia in a population-based study: the Framingham study.  Neurology. 1996;46(3):673-677
PubMed
Seshadri S, Beiser AS, Selhub J,  et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;346(7):476-483
PubMed
Schaefer EJ, Bongard V, Beiser AS,  et al.  Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study.  Arch Neurol. 2006;63(11):1545-1550
PubMed
Giordano V, Peluso G, Iannuccelli M, Benatti P, Nicolai R, Calvani M. Systemic and brain metabolic dysfunction as a new paradigm for approaching Alzheimer's dementia.  Neurochem Res. 2007;32(4-5):555-567
PubMed
Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia.  Curr Neurol Neurosci Rep. 2007;7(5):373-380
PubMed
Watson GS, Craft S. Insulin resistance, inflammation, and cognition in Alzheimer's disease: lessons for multiple sclerosis.  J Neurol Sci. 2006;245(1-2):21-33
PubMed
Biessels GJ, Kappelle LJ.Utrecht Diabetic Encephalopathy Study Group.  Increased risk of Alzheimer's disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?  Biochem Soc Trans. 2005;33(pt 5):1041-1044
PubMed
Luchsinger JA, Gustafson DR. Adiposity, type 2 diabetes, and Alzheimer's disease.  J Alzheimers Dis. 2009;16(4):693-704
PubMed
van Oijen M, van der Meer IM, Hofman A, Witteman JCM, Koudstaal PJ, Breteler MMB. Lipoprotein-associated phospholipase A2 is associated with risk of dementia.  Ann Neurol. 2006;59(1):139-144
PubMed
Yaffe K, Lindquist K, Penninx BW,  et al.  Inflammatory markers and cognition in well-functioning African-American and white elders.  Neurology. 2003;61(1):76-80
PubMed
Roberts RO, Geda YE, Knopman DS,  et al.  Association of C-reactive protein with mild cognitive impairment.  Alzheimers Dement. 2009;5(5):398-405
PubMed
Schuitemaker A, Dik MG, Veerhuis R,  et al.  Inflammatory markers in AD and MCI patients with different biomarker profiles.  Neurobiol Aging. 2009;30(11):1885-1889
PubMed
Noble JM, Manly JJ, Schupf N, Tang MX, Mayeux R, Luchsinger JA. Association of C-reactive protein with cognitive impairment.  Arch Neurol. 2010;67(1):87-92
PubMed
Engelhart MJ, Geerlings MI, Meijer J,  et al.  Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study.  Arch Neurol. 2004;61(5):668-672
PubMed
Kravitz BA, Corrada MM, Kawas CH. High levels of serum C-reactive protein are associated with greater risk of all-cause mortality, but not dementia, in the oldest-old: results from the 90+ Study.  J Am Geriatr Soc. 2009;57(4):641-646
PubMed
Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P. Serum inflammatory proteins and cognitive decline in older persons.  Neurology. 2005;64(8):1371-1377
PubMed
Tan ZS, Beiser AS, Vasan RS,  et al.  Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.  Neurology. 2007;68(22):1902-1908
PubMed
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.  J Clin Invest. 2006;116(7):1784-1792
PubMed
Li S, Shin HJ, Ding EL, van Dam RM. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis.  JAMA. 2009;302(2):179-188
PubMed
Yamauchi T, Kamon J, Ito Y,  et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;423(6941):762-769
PubMed
Laughlin GA, Barrett-Connor E, May S, Langenberg C. Association of adiponectin with coronary heart disease and mortality: the Rancho Bernardo study.  Am J Epidemiol. 2007;165(2):164-174
PubMed
Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure.  Arch Intern Med. 2007;167(14):1510-1517
PubMed
Debette S, Beiser A, Hoffmann U,  et al.  Visceral fat is associated with lower brain volume in healthy middle-aged adults.  Ann Neurol. 2010;68(2):136-144
PubMed
Lieb W, Beiser AS, Vasan RS,  et al.  Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging.  JAMA. 2009;302(23):2565-2572
PubMed
Dawber TR. The Framingham Study: the Epidemiology of Atherosclerotic Disease. Cambridge, MA: Harvard University Press; 1980
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12(3):189-198
PubMed
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.  Neurology. 1984;34(7):939-944
PubMed
Seshadri S, Wolf PA, Beiser AS,  et al.  Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study.  Arch Neurol. 2008;65(5):642-649
PubMed
Kamei T, Tuji N, Taketani K, Nakamoto M. Evaluation and clinical significance of latex immunoassay (LIA) of insulin using the routine biochemical autoanalyzer.  Japanese Journal of Clinical Chemistry. 2006;35(1):48-53
Akomolafe A, Beiser AS, Meigs JB,  et al.  Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study.  Arch Neurol. 2006;63(11):1551-1555
PubMed
Kouzuma T, Usami T, Yamakoshi M, Takahashi M, Imamura S. An enzymatic method for the measurement of glycated albumin in biological samples.  Clin Chim Acta. 2002;324(1-2):61-71
PubMed
Rawlins ML, La’ulu SL, Moon N, Roberts WL. Performance characteristics of an immunoturbidimetric assay for lipoprotein-associated phospholipase A2.  Clin Chim Acta. 2009;406(1-2):66-70
PubMed
Nishimura A, Sawai T. Determination of adiponectin in serum using a latex particle-enhanced turbidimetric immunoassay with an automated analyzer.  Clin Chim Acta. 2006;371(1-2):163-168
PubMed
Haan MN, Aiello AE, West NA, Jagust WJ. C-reactive protein and rate of dementia in carriers and non carriers of apolipoprotein APOE4 genotype.  Neurobiol Aging. 2008;29(12):1774-1782
PubMed
Une K, Takei YA, Tomita N,  et al.  Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer's disease.  Eur J Neurol. 2011;18(7):1006-1009
PubMed
Sattar N, Nelson SM. Adiponectin, diabetes, and coronary heart disease in older persons: unraveling the paradox.  J Clin Endocrinol Metab. 2008;93(9):3299-3301
PubMed
Wedick NM, Barrett-Connor E, Knoke JD, Wingard DL. The relationship between weight loss and all-cause mortality in older men and women with and without diabetes mellitus: the Rancho Bernardo study.  J Am Geriatr Soc. 2002;50(11):1810-1815
PubMed
Roubenoff R, Parise H, Payette HA,  et al.  Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study.  Am J Med. 2003;115(6):429-435
PubMed
Vasseur F, Helbecque N, Dina C,  et al.  Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.  Hum Mol Genet. 2002;11(21):2607-2614
PubMed
Hara K, Boutin P, Mori Y,  et al.  Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.  Diabetes. 2002;51(2):536-540
PubMed
Xu A, Chan KW, Hoo RLC,  et al.  Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes.  J Biol Chem. 2005;280(18):18073-18080
PubMed
Nishizawa H, Shimomura I, Kishida K,  et al.  Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.  Diabetes. 2002;51(9):2734-2741
PubMed
Kamogawa K, Kohara K, Tabara Y,  et al.  Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study.  Dement Geriatr Cogn Disord. 2010;30(5):432-439
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Supplemental Content

van Himbergen TM, Beiser AS, Ai M, et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease: results from the Framingham Heart Study. Arch Neurol. Published online January 2, 2012. doi:10.1001/archneurol.2011.670.

eTable 1. Multivariate Adjusted Hazard Ratios for Alzheimer’s Disease and All-cause Dementia by one SD Increase in hsCRP Concentrations.

eTable 2. Multivariate Adjusted Hazard Ratios for Alzheimer’s Disease and All-cause Dementia Above versus Below Median Adiponectin Concentrations in Women.

eTable 3. Multivariate Adjusted Hazard Ratios for Alzheimer’s Disease and All-cause Dementia Above versus Below Median Adiponectin Concentrations in Women.

eTable 4. Characteristics of Studied Subjects in Exam 19 and Exam 22 of the Framingham Dementia Study.

eFigure. Flow Chart Showing all Inclusion and Exclusion Criteria Along with Numbers of Subjects in the Framingham Dementia Study for Exam 19 and Exam 22.

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

2,653 Views
29 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
PubMed Articles
Jobs
JAMAevidence.com

Care at the Close of Life: Evidence and Experience
Alzheimer Disease: "It's OK, Mama, If You Want to Go, It's OK"

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Supplemental Content

×