Sunday, September 19, 2010

Alzheimer's and Hyperglycemia 2

So we know what Gary Taubes thinks.  Since Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health (Vintage) came out, there has been quite a bit more research into the topic of metabolic syndrome and the risk for Alzheimer's dementia.  I'm going to list some of the papers and the results to show what we're looking at here (there are a TON of studies, so I'm trying to pick a few studies on either side of the issue here):



J Am Geriatr Soc. 2010 Mar;58(3):487-92.  Metabolic syndrome and risk of dementia in older adults.
Forti P, Pisacane N, Rietti E, Lucicesare A, Olivelli V, Mariani E, Mecocci P, Ravaglia G.  Conclusion: MetS measured in late life is not associated with risk of dementia. After age 75, persons with MetS may even be at lower risk for AD.

J Am Geriatr Soc. 2002 Jan;50(1):41-8.Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D; ILSA Working Group.  Conclusion: Incidence of dementia in Italy paralleled that in most industrialized countries. About 150,000 new cases per year are expected. A significant gender effect was evidenced for major dementia subtypes. The burden of VaD, especially in men, offers opportunities for prevention.

Biochim Biophys Acta. 2009 May;1792(5):432-43. Epub 2008 Dec 16.(Pre)diabetes, brain aging, and cognition. S Roriz-Filho J, Sá-Roriz TM, Rosset I, Camozzato AL, Santos AC, Chaves ML, Moriguti JC, Roriz-Cruz M. Abstract: Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of diabetes mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory importance, insulin has significant neurothrophic properties in the brain. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-beta (Abeta) clearance due to competition for their common and main depurative mechanism - the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin than for Abeta, brain hyperinsulinism may deprive Abeta of its main clearance mechanism. Hyperglycemia and hyperinsulinemia seems to accelerate brain aging also by inducing tau hyperphosphorylation and amyloid oligomerization, as well as by leading to widespread brain microangiopathy. In fact, diabetes subjects are more prone to develop extense and earlier-than-usual leukoaraiosis (White Matter High-Intensity Lesions - WMHL). WMHL are usually present at different degrees in brain scans of elderly people. People with more advanced WMHL are at increased risk for executive dysfunction, cognitive impairment and dementia. Clinical phenotypes associated with insulin resistance possibly represent true clinical models for brain and systemic aging.


Biol Psychiatry. 2010 Mar 15;67(6):505-12. Epub 2009 Apr 9. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Profenno LA, Porsteinsson AP, Faraone SV.  (* Emily's note:  This is a paper that ended up in my physical mailbox earlier this year, leading me to be enthusiastic about the diabetes/Alzheimer's link yesterday*).  Conclusion: Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD.

Neurology. 2008 Sep 30;71(14):1065-71. Epub 2008 Apr 9.Impaired insulin secretion increases the risk of Alzheimer disease.Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Berne C, Lannfelt L, Kilander L.  Conclusion: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

Diabetologia. 2009 Aug;52(8):1504-10. Epub 2009 May 20. Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men. Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Lannfelt L, Berne C, Kilander L.  Conclusion: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.


Diabetologia. 2009 Jun;52(6):1031-9. Epub 2009 Mar 12.Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L.  Conclusion: Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.


Neurology. 2010 Aug 31;75(9):764-70. Epub 2010 Aug 25.Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. RESULTS: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR. CONCLUSION: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.


Neuropathol Appl Neurobiol. 2009 Feb;35(1):60-8. Epub 2008 Mar 10.Beta-amyloid deposition in brains of subjects with diabetes.Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H.  Conclusion:  We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.

* * * 


 So what have we got?  Italians who seem to be protected from dementia by metabolic syndrome.  Finnish diabetics whose brains don't seem to have an increase in beta-amyloid plaques despite insulin-degrading enzyme issues, directly disproving Gary Taubes' theory.  Brazilians who found the opposite of the Finns, proving Gary Taubes' theory. Meta-analysis showing independently increased factors for dementia with obesity and diabetes.  Insulin resistance showing increased risk of Alzheimer's 35 years later. 

Sigh.

It's complicated.  That's all right.  There are thin type II diabetics and obese type II diabetics, after all.

But the overall theory isn't as straightforward as Taubes insulin-degrading enzyme being too busy to clean up the amyloid too, though the overall theory is simple in concept - hyperglycemia speeds up aging.  It's like our metabolisms in fast-forward.  Anatomic brain differences have been shown in patients with diabetes (type I and II) consistent with non-diabetic patients > 80 years old.  Also shrinkage of the hippocampus and the amygdala (these are also found to be shrunk in type II DM).  Patient with uncontrolled type II diabetes have worse cognitive function and memory.  Patients with more diabetic complications (suggesting poorer glycemic control) also have more cognitive difficulty.  Studies of the "oldest old" (>85 years) don't seem to show a difference between diabetic and non-diabetic populations, though.  Though at that point almost everyone starts losing weight (possibly improving diabetic control).  Alzheimer's disease is the cause of dementia in 82.5-91% of type II diabetics - which is greater than the general population.  (1)   But insulin degrading enzyme (IDE) is still important - patients with the genetic predisposition for Alzheimer's have decreased expression of IDE in the hippocampus.  Since one of the above studies showed a special link between diabetes and ApoE (in the Japanese), it does make one ponder.  The meta-analysis from Biological Psychiatry makes for interesting reading too - suggesting that diabetes is, indeed, an independent risk factor.

All in all, the primary sources certainly give one less of a warm and fuzzy feeling than the secondary ones.  That is to be expected.  But there's no harm in keeping one's fasting insulin levels low.  And perhaps a lot to be gained.

6 comments:

  1. Emily

    So the best ward against Alzheimer's maybe a good glucometer?

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  2. Unless you are Italian, Finnish, or >85! It is no slam dunk. More thoughts to come in some other entires.

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  3. Jeez, Emily. How do you do this? You got a team of interns working for free?

    1) Heitner J et al. "Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects: a retrospective postmortem immunocytochemical and histofluorescent study." Neurology, 1997; 49: 1306-1311. Autopsy study, No. of subjects not in abstract. They looked for senile plaques and neurofibrillary tangles, etc. The title says it all.

    2) Beeri MS et al. "Type 2 diabetes is NEGATIVELY [emphasis added} associated with Alzheimer's disease neuropathology." J. Gerontol A. Biol Sci. Med. Sci. 2005; 60: 471-475. 385 autopsies. The title again says it all.

    3) Arvanitakis Z, et al. "Diabetes is related to cerebral infarction but NOT [emphasis added] to Alzheimers disease pathology in older persons." Neurology 2006; 67: 1960-1965. Autopsy study of 233 Catholic clergy.

    There does seem to be some concensus that older diabetics DO have impaired cognitive performance compared to matched non-diabetic controls.

    So perhaps it's a mistake to focus just on "Alzheimers Disease." It would make sense for diabetics to have more vascular dementia since they have so many risk factors for atherosclerotic complications. And we do find they have more coronary heart disease. Yet one of your references above indicates that Alheimers is by far the most common type of dementia in older diabetics.

    I wonder if anyone has looked at glucose levels and insulin levels/secretion in middle-aged and older adults who have MCI (mild cognitive impairment). Good project for one of your interns!

    I appreciate your great work here.

    -Steve

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  4. Dr. Deans,
    Just wanted to put in a comment to let you know I am one of your avid followers. I am a lay person with no formal medical training. I rely on clear thinking people like yourself to find my way through the maze of junk science and ill conceived public policy that has led to our astounding decline in general health over the las 50 years. You made a reference in your last blog about the few people that read your blog. Add me to your reader count. I do pass on what I learn from you. Currently in Kuala Terengganu, Malaysia and sailing to worlds oceans in my yacht. You have more followers than you know.

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  5. Steve - no interns! That's a good idea, though. Especially the unpaid part. No, I'm pretty much an obligate homebody if I'm not at work, as I have two little ones. They nap and it's either clean the house or comb the literature. House isn't spotless.

    Xogenisis - thanks! I'm hoping this is the beginning of the guerrilla evo med movement. Have fun on your yacht! Sounds great. It's pleasing to think someone is getting something out of this blog while sailing the oceans.

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  6. this makes a lot of sense...but looking at mainstream people, wouldnt the alzheimers epidemic deifinitely be on the rise then? i see it in my parents now :( and it does hurt to notice, simple things like telling the stories over and over, forgetting random things etc. i would absolutely be devestated to see my parents go through something like the Notebook movie

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