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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 71, Number 14, September 30, 2008 All Versions of this Article: 01.wnl.0000310646.32212.3av1 71/14/1065    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rönnemaa, E. Articles by Kilander, L. Search for Related Content PubMed PubMed Citation Articles by Rönnemaa, E. Articles by Kilander, L. Related Collections Related Articles

Impaired insulin secretion increases the risk of Alzheimer disease

From the Departments of Public Health and Caring Sciences/Geriatrics (E.R., B.Z., J. Sundelöf, M.D.-G., L.L., L.K.) and Medical Sciences (J. Sundström, C.B.), Uppsala University Hospital, Uppsala, Sweden.

Address correspondence and reprint requests to Dr. Elina Rönnemaa, Uppsala University, Department of Public Health/Geriatrics, Uppsala Science Park, 751 85 Uppsala, Sweden elina.ronnemaa{at}pubcare.uu.se

Objective: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia.

Methods: The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models.

Results: A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10–1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE 4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05–2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment.

Conclusions: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

Abbreviations: AD = Alzheimer disease; AIR = acute insulin response; HOMA = Homeostasis Model Assessment.

Editorial, page 1046

See also pages 1051 and 1057

e-Pub ahead of print on April 9, 2008, at www.neurology.org.

Supported by grants from Uppsala University Hospital, Hjärnfonden, Bertil Hållstens forskningsstiftelse, Alzheimerfonden, The Swedish Research Council (2003-5546), DIADEM (QLK3-CT-2001-02362), APOPIS (contract no. LSHM-CT-2003-503330), Gamla Tjänarinnor, Emma Petterson, and the Ernfors Family and Sehlander Foundations.

Disclosure: The authors report no disclosures.

Received August 8, 2007. Accepted in final form December 10, 2007.

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