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Differential modulation of plasma ß-amyloid by insulin in patients with Alzheimer disease

From the Geriatric Research, Education, and Clinical Center (J.J.K., D.G.C., G.S.W., M.A.R., L.D.B., S.R.P., K.R., S.C.), VA Puget Sound Health Care System, and Departments of Psychology (J.J.K.), Medicine (P.S.G., D.G.C., S.R.P.), Pharmacology (D.G.C.), and Psychiatry and Behavioral Sciences (G.S.W., L.D.R., L.D.B., K.R., S.C.), University of Washington, Seattle, WA; William S. Middleton Memorial Veteran's Hospital and Department of Medicine (S.A.), University of Wisconsin, Madison; and Department of Immunology (P.D.M.), Institute for Basic Research in Developmental Disabilities, Staten Island, NY.

Address correspondence and reprint requests to Dr. S. Craft, VAPSHCS, S-182-GRECC, 1660 S. Columbian Way, Seattle, WA 98108; e-mail: scraft{at}u.washington.edu

Background: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid ß-peptide (Aß) in vitro in neuronal cultures and in vivo in the CSF of normal older adults.

Objective: To determine whether insulin affected plasma Aß levels and whether such effects differed for patients with AD compared with normal older adults.

Methods: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU · kg^–1 · min^–1) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU · kg^–1 · min^–1) and higher (1.67 mU · kg^–1 · min^–1) rate. Plasma insulin and Aß were measured after 120 minutes of infusion.

Results: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Aß levels at the middle (1.0 mU · kg^–1 · min^–1) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Aß levels at the two higher doses (1.0 and 1.67 mU · kg^–1 · min^–1).

Conclusions: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid ß-peptide (Aß) elevation. Abnormal regulation of peripheral Aß by insulin may contribute to AD risk.

Supported by the Department of Veterans Affairs, NIA RO1 AG-10880, and the Alzheimer's Association.

Disclosure: The authors report no conflicts of interest.

Received August 17, 2005. Accepted in final form February 17, 2006.

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