Research Emerging That Links Insulin Resistance to Cognitive Decline

May 26, 2016
Andrew Smith

Evidence-Based Diabetes Management, May 2016, Volume 22, Issue SP7

The earliest studies involving diabetes therapy for Alzheimer’s are recruiting patients.

Retrospective analyses1,2 of patient records have long tended to find an increased risk of incidence of Alzheimer’s disease among patients with type 2 diabetes (T2D). In more recent years, as rates of T2D have soared, rates of Alzheimer’s disease—although far lower, overall—have risen at a similar rate, and a number of studies3,4 have found evidence that suggests Alzheimer’s disease can be slowed or even reversed by increasing either the amount of insulin in the brain or the brain’s ability to respond to existing insulin.

This evidence has convinced many that diabetes can trigger Alzheimer’s disease in many patients who would otherwise have escaped it, or that Alzheimer’s disease is essentially a type of diabetes that affects the brain, sometimes in conjunction with T2D, sometimes on its own. Other observers believe the evidence linking diabetes and Alzheimer’s disease, to date, is interesting, but inconclusive—particularly when one considers study results that find no connection between the 2 conditions.

The symptoms of Alzheimer’s disease can be nearly identical to the symptoms of vascular dementia, a form of cognitive decline, that certainly can result directly from T2D’s effects on the circulatory system or indirectly from T2D-related strokes.5 Indeed, the only sure way to diagnose Alzheimer’s disease is via autopsy, and studies that have looked for T2D after confirming Alzheimer’s disease via autopsy, have not found it nearly as frequently as population-based studies would predict.6,7 According to Geert Jan Biessels, MD, PhD, a professor of Neurology at the Rudolph Magnus Institute, who spoke with Evidence-Based Diabetes Management (EBDM), studies, that have used positron emission tomography (PET) scans to compare amyloid protein levels in patients with and without T2D, have not found diabetic patients to have the sort of protein buildup that would indicate elevated risk of Alzheimer’s disease.8

Many investigators are working to solve the apparent contradictions by focusing their research on the pathways that could connect the 2 diseases, and on the effort to see whether any existing treatment for T2D can also treat Alzheimer’s disease.9 There is hope, looking forward, that such treatments could be a breakthrough in Alzheimer’s care. That said, researchers have been investigating possible links between T2D and Alzheimer’s disease for many years. A review, published by Diabetes Care nearly 2 decades ago,10 gathered evidence from 19 controlled studies on patients with T2D, and noted that 13 of those studies reported that diabetics performed worse than controls on at least 1 aspect of cognitive function. All the remaining studies, the review authors noted, lacked the statistical power to find a relatively strong gap in cognitive abilities.

That review did not find enough evidence to distinguish among vascular dementia, Alzheimer’s disease, or other types of cognitive impairment, but another review,11 published, just 2 years later by Diabetic Medicine, went further. “There is also evidence for an elevated risk of both vascular dementia and Alzheimer’s disease in Type 2 DM albeit with strong interaction of other factors such as hypertension, dyslipidemia and apolipoprotein E phenotype,” the authors wrote. “Both vascular and nonvascular factors are likely to play a role in dementia in diabetes.”

Such conclusions soon led other researchers to look at health record databases in search of further evidence, and their findings varied significantly. International Psychogeriatrics, for example, published a 2002 analysis12 of records from 702 people aged 80 years or more. Among the 187 patients to receive a dementia diagnosis at some point during the study period, 31 began the study with T2D. After adjusting for age, gender, education, smoking habits, and circulatory diseases, the investigators calculated that diabetics were more than twice as likely as other people to develop vascular dementia, but no more likely than others to develop Alzheimer’s disease. On the other hand, a 2004 study that appeared in Archives of Neurology13, followed 824 Catholic nuns, priests, and monks who received thorough clinical evaluations each year, and found that preexisting T2D did predict elevated risk of Alzheimer’s disease. The 127 patients who began the study with T2D had a 65% greater risk of incidence of Alzheimer’s disease than nondiabetic counterparts (95% CI, 1.10-2.47), even after adjusting for age, sex, and education.

Several newer analyses have pulled their data from far larger datasets in hopes of drawing stronger and more accurate conclusions. A 2014 paper that appeared in PLoS One14 used information on 1 million randomly sampled people to compare the 71,433 diabetics in the group with 71,311 nondiabetics matched by age, sex, hypertension, hyperlipidemia and previous stroke history. Incidence of Alzheimer’s disease was rare in both groups (0.48% vs 0.37%, P <.001). Still, over a follow-up period of up to 11 years, T2D patients were far more likely than controls to develop Alzheimer’s disease (hazard ratio [HR], 1.76; 95% CI, 1.50-2.07; P <.001).

Another large study, published by Diabetes Care in 2015,6 concluded that although dementia risk is most elevated in patients with longstanding cases of T2D, that risk begins to go up as soon as patients start demonstrating resistance to insulin. Investigators from Canada used records from Ontario’s health administration databases to match 225,045 seniors with newly-diagnosed T2D and 668,070 controls, and followed them up to 17 years. A fully-adjusted Cox model found the risk of dementia to be significantly higher among diabetic patients (HR, 1.16; 95% CI, 1.15-1.18). Risk of Alzheimer’s disease increased within a month of T2D diagnosis, and it kept rising over time.

“When testing the proportional hazards assumption, we did detect a significant interaction between diabetes status and time,” the study authors wrote. “The HR associated with diabetes status was 1.19 (HR; 95% CI, 1.16-1.22), and this effect increased by about 1% per year (HR for diabetes × year interaction: 1.009; 95% CI, 1.004-1.014). Thus, after 10 years of duration, diabetes was associated with a nearly 30% higher incidence of dementia.”

Collectively, the evidence from the individual population studies has convinced the authors of several meta-studies that T2D patients do face significantly elevated risk of Alzheimer’s disease. A review that appeared in The Lancet Neurology in 2006, found that 8 of 13 included studies linked T2D with Alzheimer’s, while 6 of 9 included studies linked T2D with vascular dementia.1 A 2012 meta-analysis that appeared in Internal Medicine Journal,2 pooled the relative risks found in 19 studies with nearly 45,000 subjects and found that T2D patients, compared to other patients, faced a higher risk of Alzheimer’s disease (relative risk [RR], 1.46; 95% CI, 1.20-1.77), vascular dementia (RR, 2.48; 95% CI, 2.0-2.96), any dementia (RR, 1.51; 95% CI, 1.31-1.74) and mild cognitive impairment (RR, 1.21; 95% CI, 1.02-1.45).

Further evidence that T2D is linked to Alzheimer’s disease comes from research that finds evidence of insulin resistance in the brains of Alzheimer’s patients. A 2012 study, published in The Journal of Clinical Investigation,15 found that markers of insulin resistance increased “commonly and progressively from normal cases to mild cognitively impaired cases to Alzheimer’s disease cases, regardless of diabetes.” Researchers from the University of Pennsylvania tested tissue samples collected by 2 cohort studies that also measured cognitive decline and found that, “Brain insulin resistance thus appears to be an early and common feature of Alzheimer’s disease, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction, potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic Alzheimer’s disease pathology.”

Other studies have found that intranasal insulin can improve memory in older adults with Alzheimer’s disease. A 2006 study, published in Neurobiology of Aging,3 which gave insulin or placebo to 35 controls and 26 memory-impaired subjects (13 with early Alzheimer’s disease; 13 with mild cognitive impairment), reported that insulin facilitated significantly improved recall among Alzheimer’s patients in 2 measures of verbal memory. The Journal of Alzheimer’s Disease reported, 2 years later, how insulin affected another group of 59 controls and 33 memory-impaired adults. Again, insulin produced significant gains only in memory-impaired subjects without the apolipoprotein E epsilon4 allele.4

“There’s a growing body of evidence that Alzheimer’s disease is, at its core, a condition defined by insulin resistance in the brain. The brain is the target of a particular kind of diabetes that some people call, type 3 diabetes. This form of diabetes can obviously occur independently of type 2 diabetes, as many people with Alzheimer’s disease do not have type 2 diabetes, but it also looks very likely that the 2 diseases can arise from the same causes, or that type 2 diabetes can either trigger or worsen Alzheimer’s disease in people who are otherwise prone to it,” said Suzanne de la Monte, MD, MPH, a professor of pathology, laboratory medicine and neurosurgery, at Brown University, in an interview with EBDM.

“It appears, at this point, like there may be some parallels between Alzheimer’s disease and other conditions characterized by localized insulin resistance. Metabolic syndrome is a disease of localized insulin resistance, as is nonalcoholic fatty liver disease. Both of them can exist independent of diabetes, but it’s certainly wise for people who treat diabetic patients to test regularly for them in hopes of spotting them early and treating them before they progress,” de la Monte added. Despite the evidence that Alzheimer’s disease is associated with insulin resistance in the brain, and that insulin can temporarily improve the memory for some patients with the disease, some observers think it’s too early to conclude that T2D can trigger or worsen Alzheimer’s disease, and that it’s way too early to begin thinking of Alzheimer’s disease as a specialized type of diabetes. This resistance stems both from the belief that too little is known about Alzheimer’s disease for so sweeping a statement about its fundamental nature, and by the observation that some types of research tend to find little, if any, connection between T2D and Alzheimer’s disease.

Unlike the retrospective analyses of large health record databases, which have typically found T2D patients far more likely than others to develop Alzheimer’s disease, studies that diagnose Alzheimer’s disease via autopsy rather than medical claims, often find little or no connection. A 1997 study, which appeared in Neurology,16 compared the amount of Alzheimer-type pathology in the postmortem brains of diabetics and agematched control subjects. “There was no significant difference between diabetics and control subjects with respect to severity of Alzheimer-type pathology, on average, or with respect to age,” the study authors wrote. “This finding was true for diabetics with and without insulin dependence.” These conclusions were echoed in a 2004 study published in The Journal of Gerontology.17 Investigators traced 385 consecutive autopsies of residents from a single nursing home (15.8% of whom were diabetic) and found that diabetes was negatively correlated with Alzheimer’s disease neuropathology. “Diabetics had significantly fewer neuritic plaques (P = .008) and NFTs (P = .047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (P = .019).” (They are based, in part, on autopsies that have positively associated T2D with Alzheimer’s disease, 18 but they are in the minority.)

“The results of the autopsy studies are a significant counterweight to the belief that diabetes greatly increases the risk of Alzheimer’s disease because autopsy is the only definitive way to distinguish Alzheimer’s from the vascular dementia that diabetes certainly causes. It is possible to look at the autopsy studies and conclude that a lot of diabetics with vascular dementia are being diagnosed with Alzheimer’s. The other evidence that this may be the case is when we look at levels of amyloid proteins. If diabetes triggered or worsened Alzheimer’s in some significant percentage of patients, we’d expect diabetic patients to have unusually high levels of the amyloid proteins that are so closely associated with Alzheimer’s, but we don’t tend to see that in PET scans or in cerebrospinal fluid,” said Biessels.

“This is not to say that diabetes cannot cause or accelerate Alzheimer’s disease, but if it does, we’re a long way from understanding which pathways connect diabetes and Alzheimer’s— and there probably will be multiple pathways, just as there are multiple phways that we now know to lead from diabetes to vascular dementia,” he said. Researchers are also a long way from understanding which diabetes medications, if any, can provide any value in treating Alzheimer’s disease. A number of studies have found individual diabetes medications that can treat Alzheimer’s disease in mice. The 2 most cited of those are a 2012 study, published in The Journal of Clinical Investigation,15 which found that exendin-4 (exenatide) protected mice from defective insulin signaling associated with Alzheimer’s, and a NeuroMolecular Medicine article that reported that liraglutide had a number of anti-Alzheimer’s effects.19

Researchers began recruiting humans with Alzheimer’s disease for a liraglutide trial more than a year ago,20 but results from that and other trials on other diabetes medications are still years away. There is some evidence from other types of studies—such as a 2008 postmortem study, published in Neurology21—that diabetes medications may reduce Alzheimer’s neuropathy, but other studies have found no comparable effect. Large population studies from Canada and Taiwan, for example, found no connection between diabetes medication and Alzheimer’s progression among diabetic patients.

RELATED COVERAGE: ITCA 650 Results Point to Transformational Method to Deal With Poor Adherence in Type 2 Diabetes

References

1. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5(1):64-74.

2. Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J. 2012;42(5):484-491. doi: 10.1111/j.1445-5994.2012.02758.x.

3. Reger MA, Watson GS, Frey WH 2nd, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27(3):451- 458.

4. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323-331.

5. Kalaria R. Similarities between Alzheimer’s disease and vascular dementia. J Neurol Sci. 2002;203-204:29-34.

6. Haroon NN, Austin PC, Shah BR, Wu J, Gill SS, Booth GL. Risk of dementia in seniors with newly diagnosed diabetes: a population-based study. Diabetes Care. 2015;38(10):1868-1875. doi: 10.2337/dc15-0491.

7. Talbot K, Wang HY, Kazi H. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122(4):1316—1338. doi: 10.1172/JCI59903.

8. Roberts RO, Knopman DS, Cha RH, et al. Diabetes and elevated hemoglobin A1C levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med. 2014;55(5):759-764.

9. Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment. Clin Interv Aging. 2015;10:549-560. doi: 10.2147/CIA.

S74042.

10. Strachan MW, Deary IJ, Ewing FM, Frier BM. Is type 2 diabetes associated with an increased risk of cognitive dysfunction? A critical review of studies. Diabetes Care. 1997;20(3):438-445.

11. Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999;16(2):93-112.

12. Hassing LB, Johansson B, Nilsson SE, et al. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer’s disease: a population-based study of the oldest old. Int

Psychogeriatr. 2002;14(3):239-248.

13. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61(5):661-666.

14. Huang CC, Chung CM, Leu HB, et al. Diabetes mellitus and the risk of Alzheimer’s disease: a nationwide population-based study. PLoS One. 2014;9(1):e87095. doi: 10.1371/journal.

pone.0087095.

15. Bonfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease associated Aβ oligomers. J

Clin Invest. 2012;122(4):1339-1353. doi: 10.1172/JCI57256.

16. Heitner J, Dickson D. Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. Neurology. 1997; 49(5):1306-1311.

17. Beeri MS, Silverman JM, Davis KL, et al. Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci. 2005;60(4):471-475. doi:

10.1093/gerona/60.4.471.

18. Peila R, Rodriguez BL, Launer LJ; Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes.

2002;51(4):1256-1262. doi: 10.2337/diabetes.51.4.1256.

19. Long-Smith CM, Manning S, McClean PL, et al. The diabetes drug liraglutide ameliorates aberrant insulin receptor localization and signaling in parallel with decreasing both amyloid-β

plaque and glial pathology in a mouse model of Alzheimer’s disease. NeuroMolecular Med. 2013;15(1):102-114. doi: 10.1007/s12017-012-8199-5.

20. Donnelly L. Alzheimer’s ‘breakthrough’: Addenbrooke’s Hospital recruits first humans for testing diabetes drug. The Telegraph website. http://www.telegraph.co.uk/news/health/

elder/11552208/Alzheimers-breakthrough-Addenbrookes-Hospital-recruits-first-humans-fortesting-diabetes-drug.html. Published April 21, 2015. Accessed April 21, 2016.

21. Beeri MS, Schmeidler J, Silverman JM, et al. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology. 2008;71(10):750-

757.