Serum inflammatory proteins and cognitive decline in older persons M.G. Dik, PhD; C. Jonker, MD, PhD; C.E. Hack, MD, PhD; J.H. Smit, PhD; H.C. Comijs, PhD; and P. Eikelenboom, MD, PhD Abstract—Objective: To assess whether serum levels of the inflammatory proteins  1 -antichymotrypsin (ACT), C-reactive protein (CRP), interleukin-6 (IL-6), and albumin are associated with cognitive decline in older persons. Methods: The study sample consisted of 1,284 participants in the Longitudinal Aging Study Amsterdam, aged 62 to 85 years. Cognition was assessed on general cognition (Mini-Mental State Examination [MMSE]), memory (Auditory Verbal Learning Test), fluid intelligence (Raven’s Colored Progressive Matrices), and information-processing speed (Coding Task) at baseline and at 3-year follow-up. Results: The highest tertile of ACT was associated with an increased risk of decline on the MMSE (age-, sex-, education-adjusted odds ratio [OR] 1.60; 95% CI: 1.05 to 2.43) but not on any other cognitive test score. CRP, IL-6, and albumin were not associated with cognitive decline on any cognitive test in our study. Conclusions: This population-based study showed that the serum inflammatory protein  1 -antichymotrypsin is associated with cognitive decline in older persons, whereas C-reactive protein, interleukin-6, and albumin are not. NEUROLOGY 2005;64:1371–1377 There is increasing evidence that inflammatory mechanisms are involved in the pathogenesis of Alz- heimer disease (AD). Immunopathologic studies have shown that amyloid plaques are associated with clusters of activated microglial cells expressing proinflammatory cytokines, mainly interleukin (IL)-1 and IL-6, and by deposition of acute-phase reactants such as  1 -antichymotrypsin (ACT), com- plement factors, and C-reactive protein (CRP). These immunohistochemical data suggest the view that amyloid plaques are closely associated with a chronic inflammatory response. 1,2 Recent neuropathologic and neuroradiographic findings show that the neu- roinflammatory response is a relatively early patho- genic event that precedes the process of neuropil destruction in patients with AD. 3-5 The neuropathologic studies indicating the involvement of inflammatory mechanisms in the pathogenesis of AD are supported by clinical studies showing increased serum and CSF levels of IL-6, 6 ACT, 7-9 and CRP 10 and decreased serum levels of the negative acute-phase protein albumin 11-13 in patients with late-onset AD vs controls. However, these cross-sectional studies do not allow conclusions regarding the temporal relationship between elevated plasma levels of acute-phase reactants and AD. To in- vestigate the hypothesis that inflammatory reactions contribute to AD pathology rather than being a conse- quence of AD, longitudinal studies early in the disease process before AD diagnosis are necessary. Recently, a few longitudinal population-based studies showed an association between the inflam- matory markers IL-6 and CRP and cognitive decline in older persons. 14-16 Data from the Honolulu-Asia Aging Study showed that increased CRP levels may precede clinical dementia by 25 years, suggesting that inflammatory processes occur long before clini- cal symptoms appear. 17 Only one study 18 thus far included ACT and showed that serum levels of ACT were to a greater extent associated with dementia than CRP. Our study in an independent older cohort expands on these studies and concentrates on cogni- tive decline before dementia diagnosis. To allow comparison of the strength of the associ- ations between several inflammatory markers and cognitive decline on several cognitive tests, this lon- gitudinal population-based study included four in- flammatory markers most likely to be important for neurodegeneration (i.e., ACT, IL-6, CRP, and albu- min) and decline on a broad spectrum of cognitive functions (i.e., on the Mini-Mental State Examina- tion [MMSE], information-processing speed, mem- ory, and fluid intelligence). Methods. Study subjects participated in the Longitudinal Aging Study Amsterdam (LASA), an ongoing interdisciplinary cohort study on predictors and consequences of changes in autonomy and well-being in the aging population in the Netherlands. 19 The sam- pling and data collection procedures have been described in more detail elsewhere. 20,21 Briefly, a sample of older men and women (aged 55 to 85 years), stratified by age and sex according to ex- From the Institute for Research in Extramural Medicine (EMGO Institute) (Drs. Dik, Jonker, and Comijs) and the Departments of Psychiatry (Drs. Jonker, Smit, Comjis, and Eikelenboom), Clinical Chemistry (Dr. Hack), and Social Sciences (Dr. Smit), VU University Medical Center, Amsterdam, the Netherlands; and Department of Immunopathology (Dr. Hack), Sanquin Research at the CLB, Amsterdam, the Netherlands. The Longitudinal Aging Study Amsterdam is funded by the Dutch Ministry of Health, Welfare, and Sports and the Vrije Universiteit. The study on inflammation and cognition is supported by the Internationale Stichting Alzheimer Onderzoek (grant no. 01501), and the Alzheimer Center of the VU University Medical Center. Received September 10, 2004. Accepted in final form December 30, 2004. Address correspondence and reprint requests to Dr. M. G. Dik, VU University Medical Center, LASA H-065, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands; e-mail: mg.dik@vumc.nl Copyright © 2005 by AAN Enterprises, Inc. 1371