. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010 Aug 31;75(9):764-70. PubMed.


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  1. Insulin is not required for glucose to enter brain cells. Alzheimer's disease, then, is not a type 3 diabetes. Later in the disease, the oxidation of glucose transporters does reduce glucose levels in brain cells (Mark et al. 1997).

    Insulin resistance does contribute to Alzheimer's disease as it initially increases the amount of glucose in the brain because the glucose is not being "absorbed" in other parts of the body (Jacob et al., 2002). This results in high levels of myo-inositol, the precursor molecule to Alzheimer's disease (Hauser and Finelli 1963; Huang et al., 1995) and to the activation of phospholipase C gamma-gamma, an enzyme implicated in triggering Alzheimer's disease, primarily via the platelet-derived growth factor receptor (Dequin et al., 1998; Okuda et al., 1996). Polyphenols in various fruits, vegetables, and spices, and polyunsaturated fats such as fish oil partially inhibit phospholipase C gamma and thus provide some protection against the disease (Godichaud et al. 2006; Kang et al., 2003; Sanderson and Calder, 1998; Valente et al., 2009).

    View all comments by Lane Simonian
  2. Careful reading of a very similar work (see Peila et al., 2002) reveals that there is limited new data in this paper by Matsuzaki et al. Like the latter paper, Peila et al. investigated a large population of individuals (i.e., Japanese-Americans) participating in a longitudinal study (i.e., the Honolulu-Asia aging study) on diabetic factors in aging. Peila et al. specifically tested the hypothesis that 1) diabetes is a risk factor for dementia generally and for Alzheimer disease (AD) and vascular dementia in particular; 2) that such risk is enhanced in carriers of at least one copy of the ApoE4 allele; and 3) that diabetes alone or in combination with an ApoE4 allele is associated with increased neuritic plaques and neurofibrillary tangles in the cerebral cortex and/or hippocampus. The last two hypotheses are the focus of this news study, which is in most respects a replication of the study by Peila et al. (2002) on a different population of Japanese origin.

    In a few respects, however, Matsuzaki et al. provide some new information. First, they establish that only relatively high levels of insulin resistance (measured in three different ways, see their Fig. 1) are associated with neuritic plaque densities in the brain. Second, this association is present even in cases without AD. Third, unlike Peila et al., they found that elevated insulin resistance is associated with elevated neuritic plaque densities even in the absence of ApoE4 alleles (see Matsuzaki et al., Fig. 2), though the presence of even one such allele greatly increases the association of insulin resistance and plaque densities as found by Peila et al. (2002).

    Why did Matsuzaki et al. find an association of high insulin resistance with neuritic plaques, but not with neurofibrillary tangles?

    Peila et al. (2002), by studying a large number of autopsied cases (216 vs. 135 in Matsuzaki et al.) tested closer to the time of death (Unger et al., 1989) and insulin-sensitive glucose transporter 4 in the brain (El-Messari et al., 1998).

    But Matsuzaki et al. provide no data on the density of plaques or tangles in specific brain areas. It is implied that they calculated a composite score for neuritic plaques and for neurofibrillary tangles from semi-quantitative scores (+ to +++) in each of at least 12 brain areas in the cerebral cortex, limbic system, basal ganglia, basal forebrain, thalamus, midbrain, and pons. It is not explained how they calculated such composite semi-quantitative scores. With such scores, the authors only tested the hypothesis that global levels of neuritic plaques and neurofibrillary tangles are strongly associated with high insulin resistance. Their data is insufficient to detect weaker, but significant associations globally or in specific brain areas. Detection of such associations requires more objective quantitative measures of neuritic plaques (amyloid load) and neurofibrillary tangle densities in each brain area sampled. Peila et al. also used only semi-quantitative methods, but they present data for specific brain areas.

    Matsuzaki et al. have consequently only shown that the association of high insulin resistance with global levels of neuritic plaques is stronger than with neurofibrillary tangles. This is not inconsistent with Peila et al., who did not assess global levels of those pathologies. It is possible that there is an association with neurofibrillary tangles in certain brain areas. The global findings are, nevertheless, consistent with our unpublished data that a major hippocampal abnormality in AD associated with impaired insulin signaling (i.e., elevated serine phosphorylation of insulin receptor substrate 1 [IRS-1]: see Talbot et al., Alzheimer's and Dementia 2, suppl. 1: S54, 2006) is not elevated with neurofibrillary tangles without an elevation in neuritic plaques (e.g., in corticobasal degeneration [CBD]; Talbot et al., in preparation).

    What might explain the association between high insulin resistance and neuritic plaque levels?

    One of the more interesting and novel findings of Matsuzaki et al., noted above, was that high insulin resistance was associated with higher global neuritic plaque levels even in the absence of AD. This is consistent with the view, gaining increasing acceptance, that insulin resistance precedes clinical onset of that disorder, a view supported by many epidemiological studies finding that type 2 diabetes (characterized by insulin resistance) is a clear risk factor for AD (Biessels et al., 2006). It is not widely appreciated, however, that the risk goes beyond those with a history of diabetes: it is estimated that among those 60-74, in which the incidence of AD shows a clear increase, 66.7 percent are insulin resistant (Cowie et al., 2009). Indeed, more than 80 percent of the AD cases studied by Janson et al. (Janson et al., 2004) were insulin resistant, either in a diabetic or a pre-diabetic state. That the brain itself is often insulin resistant in AD, even without a history of diabetes, is suggested by our finding that about 90 percent of such AD cases we have studied postmortem display large numbers of hippocampal neurons with abnormally phosphorylated insulin signaling molecules consistent with insulin resistance (Talbot et al., in preparation). Many of these abnormalities were seen to a lesser extent in a type of mild cognitive impairment likely to progress to AD. The abnormalities are very highly correlated with memory impairments of the cases studied and are consistent with reduced levels of insulin signaling found in our ex vivo stimulation experiments on hippocampal tissue from AD cases. These findings are being prepared for submission next month.

    It should not be assumed, as Matsuzaki et al. do, that insulin resistance necessarily leads to neuritic plaque formation. The available data are only correlational and thus leave open the possibility that both phenomena are the consequence of other factors. Among these are soluble oligomers of amyloid-β (Aβ), which are better able to account for the cognitive impairments of AD than plaques, due to the affinity of such oligomers for synapses. Aβ oligomer levels rise even in mild cognitive impairment and are generated before plaques appear. They are known to trigger all the mechanisms that lead to inactivation of the insulin receptor and serine phosphorylation of IRS-1. The latter effect is mediated (at least in part) by Aβ oligomer activation of a stress molecule known as JNK, activation of which is highly correlated with levels of IRS-1 serine phosphorylation in hippocampal neurons of our AD cases.

    All of this points to the importance of finding the roots of neuronal insulin resistance in AD cases and mild cognitive impairments leading to AD, because this is an important risk factor suggesting promising new treatments for the disorder.


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