Insulin dose–response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype
Introduction
Raising plasma insulin levels to 85 μU/ml by infusing exogenous insulin improves memory in patients with Alzheimer’s disease (AD) (Craft et al., 1996, Craft et al., 1999a, Craft et al., 1999b). Normal adults do not demonstrate such improvement, raising the question of whether they have a different dose–response curve for insulin effects. Dose–response differences are suggested by studies examining the effects of glucose administration on immediate memory for new information (also termed ‘declarative memory’) for adults with and without AD. In such studies, adults with AD show memory facilitation at plasma glucose levels of about 225 mg/dl, whereas normal adults show memory facilitation at plasma glucose levels of about 150 mg/dl (Craft et al., 1992, Craft et al., 1993, Manning et al., 1993). Craft et al. demonstrated that hyperglycemic memory facilitation in AD is likely to be dependent on the endogenous rise in insulin levels that accompanies hyperglycemia (Craft et al., 1999a). The fact that patients with AD require higher levels of glucose and correspondingly higher levels of endogenous insulin for memory facilitation than do normal adults suggests the presence of insulin resistance, a condition in which higher insulin levels are required to induce its physiologic effects.
Insulin resistance may contribute to the pathophysiology of AD via several mechanisms. For example, increasing insulin lowers soluble amyloid precursor protein (APP) levels in plasma (Boyt et al., 2000), raising the possibility that insulin resistance may interfere with normal processing of APP. Recent evidence suggests that insulin may inhibit degradation of the APP intracellular domain fragment (AICD) produced by γ-secretase cleavage, and thereby interfere with the putative nuclear signaling function of this fragment (Edbauer et al., 2002). Insulin also inhibits degradation of the beta amyloid protein (Aβ) derived from APP, as well as reducing intraneuronal accumulation of Aβ via a PI3-K-activated mechanism (Edbauer et al., 2002, Gasparini et al., 2001, Qiu et al., 1998, Vekrellis et al., 2000). Thus, chronic high levels of insulin associated with insulin resistance may result in corresponding chronic elevations of Aβ. Conversely, Aβ acts as a competitive substrate with insulin, reducing insulin binding and receptor phosphorylation necessary for signaling to occur (Xie et al., 2002). This interference may impact insulin’s numerous direct and indirect effects on energy metabolism, neurotransmitter synthesis, and neurophysiology of the hippocampal/medial temporal region, an area that is critical for memory and affected at the earliest stages of AD (Craft et al., 1999b).
Given the accruing evidence of insulin resistance in AD, we hypothesized that normal adults would demonstrate memory facilitation at lower insulin doses than would patients with AD. In addition, AD patients who are apolipoprotein E-ε4 homozygotes (ε4 homozygotes), a genotype that increases susceptibility to the development of AD, show less insulin resistance than other patients with AD (Craft et al., 1998, Craft et al., 1999b). This somewhat surprising finding suggests that AD patients of varying apoE genotypes may have different dose–response patterns. This finding also raises the exciting possibility that insulin resistance may be part of a novel class of risk factors for sporadic AD in adults who are not ε4 homozygotes. To test the hypothesis of apoE-related insulin dose response differences in AD, we examined cognitive performance in normal adults and adults with AD at five plasma insulin levels. We also examined insulin effects on plasma APP levels.
Section snippets
Subjects
This study was approved by the Human Subjects Committee of the University of Washington. Written informed consent was obtained from all subjects and from the legal representatives of the patients with AD after the procedures had been fully explained. Subjects were 22 patients with AD and 17 normal adults. Subjects for the present study were divided into three groups: AD patients homozygous for the apoE-ε4 allele (ε4 homozygotes, n=5), AD patients who were non-homozygous for the ε4 allele
Cognitive measures
As predicted, normal adults and ε4 homozygotes showed memory facilitation at lower levels of insulin than did non-ε4 homozygotes, producing an insulin level by diagnosis interaction, F(4,32)=2.68, P<0.0488. As can be seen in Fig. 1, ε4 homozygotes and normal adults showed marked improvement in memory in the 25 μU/ml insulin condition relative to baseline/10 μU/ml, F(1,4)=34.94, P<0.0041 and F(1,14)=11.07, P<0.0050. In fact, ε4 homozygotes showed the greatest proportional increase in memory in
Discussion
As predicted, normal adults and AD patients who were ε4 homozygotes demonstrated memory facilitation and decreased plasma APP levels at lower insulin doses than did non-ε4 homozygotes. Normal adults showed memory facilitation at the lowest dose of insulin suggesting that insulin plays a role in normal memory processing. The finding of memory facilitation at higher insulin doses for non-ε4 homozygotes is consistent with the presence of insulin resistance in these patients, in which higher levels
Acknowledgments
This study was supported by the Department of Veteran Affairs, NIA AG-10880 (S.C.) and AG-05136 (G.S), and Alzheimer’s Association IIRG 95-1151 (SC). Preliminary results of this study were presented at the Vascular Factors in Alzheimer’s Disease International Conference in Newcastle, UK, May 1999. The authors would like to thank Cassin Lofgreen, R.N., Lindell Cubberly, R.N., Karla Grimwood, M.S., Shannon Boldt, and Robert Beckham III for their excellent technical assistance. Direct
References (36)
- et al.
The amyloid precursor protein of Alzheimer’s disease is released by human platelets
Journal of Biological Chemistry
(1990) - et al.
Memory improvement following induced hyperinsulinemia in dementia of the Alzheimer type
Neurobiology of Aging
(1996) - et al.
Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated a2-macroglobulin in adipocytes
Journal of Biological Chemistry
(1993) - et al.
Genotyping and sequence analysis of apolipoprotein E isoforms
Genomics
(1988) - et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhal
Journal of Lipid Research
(1990) - et al.
LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation
Cell
(1995) - et al.
Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer’s type
Neurobiology of Aging
(1993) The left frontal lobe of man and the suppression of habitual responses in verbal categorical behavior
Neuropsychologia
(1974)- et al.
Insulin-degrading enzyme regulates extracellular levels of amyloid B-protein by degradation
Journal of Biological Chemistry
(1998) - et al.
Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats
Peptides
(1990)