28 August 2010. Having diabetes seems to drive up risk for dementia, including Alzheimer disease, but the jury has been out as to how this occurs. Now, Japanese scientists propose a mechanism—insulin resistance—and find that diabetes-related readouts of this condition associate with AD pathology prior to memory loss. As reported online August 25 in Neurology, researchers led by Toru Iwaki, Kyushu University, Fukuoka, determined that insulin-resistant seniors tend to rack up more brain Aβ than people with normal insulin regulation, and that having the ApoE4 allele further heightens the risk for these brain lesions. Given epidemiological data suggesting that some two-thirds of U.S. elderly ages 65 and older are insulin-resistant (Cowie et al., 2009), the impact of this potential risk factor could be significant.
Longitudinal studies have shown that type 2 diabetics don’t fare as well cognitively (Allen et al., 2004), and develop AD at higher rates than the general population (Arvanitakis et al., 2004). However, the relationships are far from absolute. Some diabetics stay mentally sharp, most AD patients do not have diabetes, and diabetes itself develops in numerous ways, one of which is insulin resistance, which has been linked to brain amyloid accumulation (Craft, 2007). In the current paper, first author T. Matsuzaki and colleagues homed in on insulin resistance, and looked at whether it correlated with specific brain lesions in AD, namely amyloid plaques and neurofibrillary tangles. “It’s a tight study,” said Suzanne de la Monte, Brown University, Providence, Rhode Island, who noted that many prior investigations examined the link between diabetes and dementia without addressing underlying mechanisms, or studied associations between diabetes and cognitive impairment without focusing in particular on AD.
Matsuzaki’s team investigated 135 elderly who were among several thousand enrolled in a long-term prospective cohort study in the southern Japanese town of Hisayama. The seniors in the analyzed subset underwent autopsy after they died around the turn of the twenty-first century. They had taken an oral glucose tolerance test as part of a clinical exam 10-15 years prior. They were demographically similar to others in the cohort who were not autopsied, decreasing the possibility of selection bias. The participants were cognitively normal at the time of their glucose test. By the end of the study, only 21 of the 135 had developed AD-type dementia, whereas 88 had plaque pathology.
By three different readouts (i.e., two-hour post-load plasma glucose, fasting insulin, and a homeostatic index called HOMA-IR), insulin resistance correlated with the presence of neuritic plaques, as judged by CERAD criteria, in autopsy brain specimens. Furthermore, the relationship between insulin resistance and plaque pathology was dose dependent. Those with more severe glucose and insulin measures had correspondingly increased risk for plaque pathology. Plaque risk shot up even further in ApoE4 carriers, about 15- to 30-fold, relative to non-carriers with similar extent of insulin resistance.
Methodologically, the study draws praise for its attention to a slew of other factors that could have accounted for the findings, said Konrad Talbot, University of Pennsylvania School of Medicine, Philadelphia, in an interview with ARF. The association between diabetes-related measures and plaque pathology held after the researchers controlled for age, gender, and other potential confounding variables including blood pressure, body-mass index, cholesterol, and exercise—even after excluding the 21 people who developed AD dementia by the time they died. The data suggest “insulin resistance can affect formation of plaques before you see any clinical symptoms,” Talbot said. “It could be something happening very early on.”
Perhaps just as striking as the link between insulin resistance and plaques was the complete lack of relationship with neurofibrillary tangles. Whether or not people had tau pathology, as judged by Braak staging, did not seem to correlate with the magnitude of their hyperglycemia or hyperinsulinemia.
The data run counter to an earlier study of Japanese-American men that found type 2 diabetics had increased risk for both plaques and tangles (Peila et al., 2002). However, the lack of correlation with tau pathology appears consistent with a large-scale study on insulin signaling that Talbot is preparing to submit for publication (see ARF related news story). In that study, aberrant phosphorylation of insulin receptor substrate 1 (IRS1), a key insulin signaling abnormality found in AD patients, is absent in tauopathies that lack plaque pathology, Talbot said.
The current paper also leaves unaddressed another issue, and that is, Which comes first—insulin resistance or plaque formation? The diabetes-related factors can presumably act upstream of the AD pathological cascade, as the authors suggest. A recent study bears out this idea by showing that insulin signaling can protect neurons from Aβ toxicity (De Felice et al., 2009 and ARF related news story). However, it’s also possible that some upstream event could drive both (see ARF Live Discussion), Talbot said, by causing brain neurons to become insulin resistant and, at the same time, more susceptible to Aβ accumulation. In his view, the methods used in the current study make it particularly challenging to make the call. Pathological reads were done some 10-15 years after assessment of insulin resistance, and yet amyloid plaques are known to develop decades in advance of symptoms.
Ultimately, the answer to whether insulin resistance can cause AD may lie in ongoing clinical trials testing insulin sensitizers in patients with mild cognitive impairment, suggested Jose Luchsinger, Columbia University, New York, in an editorial accompanying the Japanese study.—Esther Landhuis.
Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Insulin resistance is associated with the pathology of Alzheimer disease. Neurology. 2010 Aug 25;75:764-770. Abstract