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NEUROLOGY 2008;71:1072-1079
© 2008 American Academy of Neurology

Serum cystatin C and the risk of Alzheimer disease in elderly men

J. Sundelöf, MD, J. Ärnlöv, MD, PhD, E. Ingelsson, MD, PhD, J. Sundström, MD, PhD, S. Basu, MSc, PhD, B. Zethelius, MD, PhD, A. Larsson, MD, PhD, M. C. Irizarry, MD, MPH, V. Giedraitis, PhD, E. Rönnemaa, MD, M. Degerman-Gunnarsson, MD, B. T. Hyman, MD, PhD, H. Basun, MD, PhD, L. Kilander, MD, PhD and L. Lannfelt, MD, PhD

From the Departments of Public Health/Geriatrics (J. Sundelöf, J.A., E.I., S.B., B.Z., V.G., E.R., M.D.-G., L.K., L.L.) and Medical Sciences (J. Sundström, A.L.), Uppsala University, Uppsala, Sweden; Massachusetts General Hospital (M.C.I., B.T.H.), Boston, MA; and Astra Zeneca (H.B.), Södertälje, SwedenI. is now affiliated with WW Epidemiology, GlaxoSmithKline, Research Triangle Park, NC.

Address correspondence and reprint requests to Dr. Johan Sundelöf, Uppsala University, Department of Public Health/Geriatrics, Uppsala Science Park, Dag Hammarskölds väg 14B, 751 85 Uppsala, Sweden johan.sundelof{at}pubcare.uu.se

Background: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD).

Methods: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects.

Results: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-β protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 µmol/L] vs highest [>1.30 µmol/L] tertile = 2.67, 95% CI 1.22–5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-µmol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03–1.63, p < 0.03).

Conclusions: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.

GLOSSARY: Aβ40 = amyloid-β protein 40; Aβ42 = amyloid-β protein 42; AD = Alzheimer disease; BMI = body mass index; GFR = glomerular filtration rate; HR = hazard ratio; ICD = International Classification of Diseases; ULSAM = Uppsala Longitudinal Study of Adult Men.

Supplemental data at www.neurology.org

*These authors contributed equally.

Supported by Wallenberg Consortium North, Hjärnfonden, Bertil Hållstens forskningsstiftelse, Alzheimerfonden, The Swedish Research Council (2003-5546 and 2006-6555), Stiftelsen Gamla Tjänarinnor, Capios Forskningsstiftelse, Gun och Bertil Stohnes Forskningsstiftelse, Swedish Heart-Lung Foundation, Swedish Lions Research Foundation, Erik, Karin och Gösta Selanders Stiftelse, Loo och Hans Ostermans stiftelse, NIH 1T32NS048005-01, AG05134 (Massachusetts AD Research Center), AFAR Beeson Award (to M.C.I.), J.D. French Alzheimer’s Foundation, and Astra Zeneca with an unrestricted grant. The funding sources did not play any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. There are no conflicts of interest for any of the authors.

Disclosure: The authors report no disclosures.

Received January 7, 2008. Accepted in final form June 10, 2008.






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