Review
Does insulin dysfunction play a role in Alzheimer's disease?

https://doi.org/10.1016/S0165-6147(02)02037-0Get rights and content

Abstract

Age-related changes in hormone levels are determinants of a variety of human diseases. Insulin is known to affect numerous brain functions including cognition and memory, and several clinical studies have established links between Alzheimer's disease (AD), insulin resistance and diabetes mellitus. These are reinforced by biological studies that reveal the effects of insulin on the molecular and cellular mechanisms that underlie the pathology of AD. For example, insulin regulates phosphorylation of tau protein, which underlies neurofibrillary lesions in the brains of AD patients. Insulin also affects the metabolism of β-amyloid, the main constituent of AD amyloid pathology. Here, we discuss clinical and biological data that highlight potential targets for therapeutic intervention.

Section snippets

Insulin, DM and AD

DM consists of a group of metabolic disorders that are characterized by hyperglycemia resulting from a defect in either insulin secretion or insulin action. The most common forms are type 1 diabetes [also known as insulin-dependent diabetes mellitus (IDDM)] and type 2 diabetes, which is characterized by insulin resistance [also known as non-insulin-dependent diabetes mellitus (NIDDM)]. In addition to complications that affect the eyes, kidneys, heart, blood vessels and nerves, DM is associated

Insulin activity in the brain and AD: cellular and molecular mechanisms

The role of insulin in the CNS has been little documented compared with its role in muscle and adipose tissue. However, there is evidence that insulin has important functions in brain, including metabolic, neurotrophic, neuromodulatory and neuroendocrine actions. Both insulin and the insulin receptor (IR) are present in the brain, and insulin is actively transported across the blood–brain barrier and might also be produced locally in the brain [24]. IRs are abundant in rodent and human brains

Insulin and AD: a matter of debate

Various aspects of the effects of insulin on the brain remain puzzling. Although several clinical and epidemiological studies indicate a positive effect of insulin on cognitive performance and an increased risk of AD in patients with DM, how insulin modulates cerebral functions, particularly cognitive functions, and the mechanisms that underlie such effects remain largely unexplored. In particular, whether the association between AD and DM is causal or results from shared risk factors such as

Possible therapeutic interventions

The clinical and biological data reviewed here indicate a possible beneficial role of insulin in cognitive function and AD. The possibility that antidiabetic drugs currently used in NIDDM therapy could potentially affect AD pathology has been little explored. It is reported that tolbutamide, a sulfonylurea hypoglycemic agent, might promote amyloid formation by interfering with the binding of Aβ to proteins in the plasma and CSF [63]. Because Aβ and tolbutamide bind to the same site on albumin,

Acknowledgements

We thank E. Ongini (Nicox Research Institute, Milan, Italy) for critical reading of the manuscript. This work was supported by NIH grant AG09464 to P.G. and H.X., and the Alzheimer's Association, the American Health Assistance Foundation and the Ellison Medical Foundation to H.X.

References (68)

  • K. Vekrellis

    Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme

    J. Neurosci.

    (2000)
  • D.C. Solano

    Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway

    FASEB J.

    (2000)
  • D.G. Bruce

    Dementia and its association in type 2 diabetes mellitus: the Fremantle diabetes study

    Diabetes Res. Clin. Pract.

    (2001)
  • G.M. Pieper

    Review of alterations in endothelial nitric oxide production in diabetes. Protective role of arginine on endothelial dysfunction

    Hypertension

    (1998)
  • A. Perez

    Degradation of soluble amyloid β-peptides 1–40, 1–42, and Dutch variant 1–40Q by insulin degrading enzyme from Alzheimer disease and control brains

    Neurochem. Res.

    (2000)
  • G.K. Gouras

    Intraneuronal Aβ42 accumulation in human brain

    Am. J. Pathol.

    (2000)
  • A. Mochizuki

    Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease

    Lancet

    (2000)
  • S.W.J. Lamberts

    The endocrinology of aging

    Science

    (1997)
  • S. Gandy et al.

    Post-menopausal estrogen deprivation and Alzheimer's disease

    Exp. Gerontol.

    (2000)
  • W.H. Gispen et al.

    Cognition and synaptic plasticity in diabetes mellitus

    Trends Neurosci.

    (2000)
  • D. Knopman

    Cardiovascular risk factors and cognitive decline in middle-aged adults

    Neurology

    (2001)
  • K.F. Mortel

    Analysis of familial and individual risk factors among patients with ischemic vascular dementia and Alzheimer's disease

    Angiology

    (1993)
  • C.L. Leibson

    Risk of dementia among persons with diabetes mellitus: a population-based cohort study

    Am. J. Epidemiol.

    (1997)
  • A. Ott

    Association of diabetes mellitus and dementia: the Rotterdam study

    Diabetologia

    (1996)
  • A. Ott

    Diabetes mellitus and the risk of dementia: the Rotterdam study

    Neurology

    (1999)
  • J.A. Luchsinger

    Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort

    Am. J. Epidemiol.

    (2001)
  • J.D. Curb

    Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance

    Neurology

    (1999)
  • K. Landin

    Low blood pressure and blood glucose levels in Alzheimer's disease. Evidence for a hypometabolic disorder?

    J. Intern. Med.

    (1993)
  • J. Heitner et al.

    Diabetics do not have increased Alzheimer-type pathology compared with aged-matched control subjects – a retrospective postmortem immunocytochemical and histofluorescent study

    Neurology

    (1997)
  • A. Heyman

    Alzheimer's disease: a study of epidemiological aspects

    Ann. Neurol.

    (1984)
  • L. Ferini-Strambi

    Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: a case control study

    Neuroepidemiology

    (1990)
  • E. Kokmen

    Impact of referral bias on clinical and epidemiological studies of Alzheimer's disease

    J. Clin. Epidemiol.

    (1996)
  • S. Craft

    Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease

    Neurology

    (1998)
  • L. Frolich

    Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

    J. Neural Transm.

    (1998)
  • Cited by (276)

    View all citing articles on Scopus
    View full text