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Paul Clayton

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Mind Your Head

Worldwide, an estimated 50 million people are living with dementia (1). Projections (which I believe are conservative) show this rising to 82 million by 2030 and 152 million by 2050 (1, 2); with global costs currently estimated at $1 trillion and rising fast (3). Alzheimer’s disease accounts for approximately 60%–70% of these cases, with vascular dementias making up most of the rest (1). 

The risk of dementia can be reduced by controlling blood pressure and clotting parameters, but there are no effective treatments for Alzheimer’s.

One reason for this is that Alzheimer’s is not a disease but a syndrome, in the sense that the same clinical symptoms can be generated by different pathologies. There is evidence of at least four sub-types, namely inflammatory, atrophic, toxic (4) and iatrogenic (5), and each of these requires different therapeutic approaches. There is also persuasive evidence that Alzheimer’s in some patients can be stabilised and partly reversed with intensive nutritional strategies (6, 7), but this approach is not widely known and is certainly not accepted by the main stakeholders.

As the mainstream pharmaceutical approach has been a comprehensive failure we need to develop preventative strategies – and there are some obvious things we could do to reduce risk. Unfortunately, as they require social engineering rather than drugs, they will not be promoted by officialdom. Depressive illness (8-14) and the interlinked trio of diabetes (15-18), obesity (19-24) and hypertension (25, 26) are well-established risk factors; but modifying these would require us to design a society less likely to cause depression, diabetes, obesity and hypertension; in other words, a society where the multinational food companies assumed a degree of social responsibility and re-designed their currently toxic products. 

But that’s just a day dream. Depression, diabetes, obesity and hypertension are all increasing.  

The pandemics of dementia and Alzheimer’s will therefore continue to grow. The damaging effects are and will be most pronounced in our children (8-13, 19, 23, 24) but there’s no need to worry about it too much. Odds are you’ll forget about it soon enough.

You could go on a diet but in our obesogenic environment most diets fail, repeatedly. This may well be counter-productive because body weight fluctuations, which increase the risk of insulin resistance, NIDDM and cardiovascular disease (26-30), also appear to increase the risk of Alzheimer’s (31). So perhaps we should try to be more specific, and look to key events in the brain.

Microglia are critically important cells in the central nervous system, where they play multiple roles.

During brain development, microglia secrete neurotrophic factors which promote the growth and development of neurons in the hippocampus and cortex. Throughout life they enable synaptic pruning, a constant refinement of the synaptic tree and a process of creative destruction which is at the heart of learning and adaptation. At all times, they are the major regulators of neuroinflammation; and they play a dual role in Alzheimer’s. If programmed in one way they degrade amyloid β (Aβ), reduce plaque formation and protect against Alzheimer’s. If alternately programmed, they release pro-inflammatory and inflammatory factors which drive neuroinflammation and increase both Aβ and tau pathology. This initiates a vicious cycle, because as more synapses are damaged by Aβ and tau accumulation, the microglia increasingly activate one of their repertoire of behaviours, namely the removal of dysfunctional, under-utilised and damaged neuronal tissue. The pruning process is amplified beyond normal bounds and now leads to progressive cognitive loss (32).

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer’s disease (33). Hippocampal neurogenesis plays an important role in structural plasticity and network maintenance, and when pro-inflammatory and destructive microglia start to damage the hippocampus (34, 35), the stage has been set for global decline. One of the key factors supporting hippocampal health and function is brain-derived neurotrophic factor (BDNF). BDNF synthesis is impaired by the ultra-processed diet (36) and recently, an alarming clinical study found that habitual consumption of such a diet was associated with, and likely caused, hippocampal atrophy (37, 38).

There are various ideas as to what switches microglia from supportive and protective dominance to destructive dominance, and most of these involve inflammatory stress. If this is chronic and excessive, the microglia will tend to go along with this and become themselves chronically pro-inflammatory and destructive (39). As the modern lifestyle and diet have become spectacularly pro-inflammatory, it is not surprising that chronic degenerative conditions, neuroinflammatory disorders, dementia and Alzheimer’s have all increased.

From the mass of available data, it looks as if one way of differentiating between the positive and negative effects of microglia is to divide their functions into innate and adaptive immune responses (38, 39). This might be considered an odd way of considering what are thought to be specialized macrophages, but the microglia play different roles depending on their environment.

Chronic inflammation is harmful in all tissues, including the central nervous system.

By switching microglia away from a damaging chronic inflammatory response back towards an innate (and acute) inflammatory response, they shift towards a protective set of behaviours (39) which enable axonal regeneration (41) and presumably synaptic regeneration also. This can be achieved using yeast-derived 1-3, 1-6 beta glucans (41) which likely act via TREM2, a microglial receptor that identifies both beta amyloid (42) and a number of pathogen-linked molecular patterns found in yeast and other microbes (43, 44).

The evidence indicates that the 1-3, 1-6 beta glucans are best supported by a systemic anti-inflammatory approach (39). This would include the classical omega 3 HUFA / lipophile combination; and as dysbiosis and IBD has recently been found to double the risk of dementia (45), a parallel restoration of the microbiome using blended prebiotic fibers (46-48).

Given the above nutritional factors, it seems overwhelmingly likely that dietary shift since WW2 has driven the increase in Alzheimer’s we see today. The removal of 1-3, 1-6 beta glucans and prebiotic fibers from the food chain and the parallel move from an anti-inflammatory to a pro-inflammatory diet leads directly to neuroinflammation, microglial-mediated damage and rising tides of depression and dementia. Restoring these nutritional inadequacies should push the tides back.

What I am proposing here is no more than an extended version of a nutritional regime that has already been shown to stabilize and reverse early cases of Alzheimer’s (5). Professor Dale Bredesen’s pioneering work has opened a door through which we may all hope to progress.

References:

1. World Health Organization. (2017). Dementia: Fact sheet. Retrieved from http://www.who.int/mediacentre/factsheets/fs362/en/

2. Alzheimer’s Association. (2018). Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 14, 367–429.

3. Prince M et al. World Alzheimer’s Report 2015, The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International

4. Bredesen DE. Inhalational Alzheimer’s disease: an unrecognized – and treatable – epidemic. Aging (Albany NY). 2016 Feb;8(2):304-13.

5. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control StudyJAMA Intern Med. 2019 Aug; 179(8): 1084–1093.

6. Bredesen DE, Amos EC, Canick J, Ackerley M, Raji C, Fiala M, Ahdidan J. Reversal of cognitive decline in Alzheimer’s disease. Aging (Albany NY). 2016 Jun;8(6):1250-8.

7. Shetty P, Youngberg W. Clinical Lifestyle Medicine Strategies for Preventing and Reversing Memory Loss in Alzheimer’s. Am J Lifestyle Med. 2018 May 11;12(5):391-395.

8. Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MM. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology. 2008;70:1258–1264.

9. Dal Forno G, Palermo MT, Donohue JE, Karagiozis, H Zonderman AB, KawasCH.

10. Depressive symptoms, sex, and risk for Alzheimer’s disease. Ann. Neurol. 2005;57:381–387.

11. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology. 2010;75:27–34.

12. Barnes DE, Yaffe K, McCormick M, Schaeffer C, Quesenberry C, Byers AL, Whitmer RA. Mid-life versus late-life depressive symptoms and risk of dementia: differential effects for Alzheimer’s disease and vascular dementia. The Alzheimer’s Association 2010 International Conference on Alzheimer’s Disease; Honolulu, HI. July 10-15, 2010.

13. Green RC, Cupples A, Kurz A, Auerbach S, Go R,  Sadovnick D, Duara R, KukullWA, Chui H, Edeki T, Griffith PA, Friedland RP, Bachman D, Farrer L. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch. Neurol. 2003;60:753–759.

14. Wilson RS, Capuano AW, Boyle PA, Hoganson GM, Hizel LP, Shah RC, Nag S, Schneider JA, Arnold SE, Bennett DA. Clinical-pathologic study of depressive symptoms and cognitive decline in old age. Neurology. 2014 Aug 19;83(8):702-9.

15. Takeda S., Sato N., Uchio-Yamada K., Sawada K., Kunieda T., Takeuchi D., Kurinami H., Shinohara M., Rakugi H., and Morishita R. (2010) Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. Proc. Natl. Acad. Sci. U.S.A. 107, 7036–7041 

16. Han W., and Li C. (2010) Linking type 2 diabetes and Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 107, 6557–6558 

17. Ott A., Stolk R. P., van Harskamp F., Pols H. A., Hofman A., and Breteler M. M. (1999) Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53, 1937–1942 

18. Xu W. L., von Strauss E., Qiu C. X., Winblad B., and Fratiglioni L. (2009) Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study. Diabetologia 52, 1031–1039

19. Singh-Manoux A, Dugravot A, Shipley M, Brunner EJ, Elbaz A, Sabia S, Kivimaki M. Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II StudyAlzheimers Dement. 2018 Feb; 14(2): 178–186

20. Bednarska-Makaruk M, Graban A, Wiśniewska A, Łojkowska W, Bochyńska A, Gugała-Iwaniuk M, Sławińska K, Ługowska A, Ryglewicz D, Wehr H.Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementiaBiogerontology. 2017; 18(4): 561–580.

21. Danat IM, Clifford A, Partridge M, Zhou W, Bakre AT, Chen A, McFeeters D, Smith T, Wan Y, Copeland J, Anstey KJ, Chen R. Impacts of Overweight and Obesity in Older Age on the Risk of Dementia: A Systematic Literature Review and a Meta-Analysis J Alzheimers Dis. 2019; 70(Suppl 1): S87–S99.

22. Ma Y, Ajnakina O, Steptoe A, Cadar D. Higher risk of dementia in English older individuals who are overweight or obeseInternational Journal of Epidemiology, dyaa099, https://doi.org/10.1093/ije/dyaa099

23. Qu Y, Hu HY, Ou YN, Shen XN, Xu W, Wang ZT, Dong Q, Tan L, Yu JT. Association of body mass index with risk of cognitive impairment and dementia: A systematic review and meta-analysis of prospective studies. Neurosci Biobehav Rev. 2020 May 30;115:189-198.

24. Karlsson IK, Lehto K, Gatz M, Reynolds CA, Dahl Aslan AK. Age-dependent effects of body mass index across the adult life span on the risk of dementia: a cohort study with a genetic approach. BMC Med. 2020 Jun 9;18(1):131. 

25. Steinberg M, Hess K, Corcoran C, Mielke MM, Norton M, Breitner J, Green R, Leoutsakos J, Welsh-Bohmer K, Lyketsos C, Tschanz J. Vascular risk factors and neuropsychiatric symptoms in Alzheimer’s disease: the Cache County Study. Int J Geriatr Psychiatry. 2014 Feb;29(2):153-9.

26. Vergnaud AC, Bertrais S, Oppert JM, Maillard-Teyssier L, Galan P, Hercberg S, et al. Weight fluctuations and risk for metabolic syndrome in an adult cohort. Int J Obes. (2008) 32:315–21.

27. Lissner L, Odell PM, D’Agostino RB, Stokes J, III, Kreger BE, Belanger AJ, et al. Variability of body weight and health outcomes in the Framingham population. N Engl J Med. (1991) 324:1839–44. 

28. Blair SN, Shaten J, Brownell K, Collins G, Lissner L. Body weight change, all-cause mortality, and cause-specific mortality in the multiple risk factor intervention trial. Ann Intern Med. (1993) 119:749–57. 

29. Bangalore S, Fayyad R, Laskey R, DeMicco DA, Messerli FH, Waters DD. Body-weight fluctuations and outcomes in coronary disease. N Engl J Med. (2017) 376:1332–40. 

30. Anderson EK, Gutierrez DA, Kennedy A, Hasty AH. Weight cycling increases T-cell accumulation in adipose tissue and impairs systemic glucose tolerance. Diabetes. (2013) 62:3180–8. 

31. Roh E, Hwang SY, Kim JA, Lee Y-B, Hong S-H, Kim NH, Seo JA, Kim SG, KimNH,  Choi KM, Baik SH, Yoo HJ. Body Weight Variability Increases Dementia Risk Among Older Adults: A Nationwide Population-Based Cohort Study.Front Endocrinol (Lausanne). 2020 May 12;11:291.

32. Yang Y, Zhang Z.Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease. Front Aging Neurosci. 2020 May 14;12:110.

33. Braak H, Braak E, Bohl J. Staging of Alzheimer-related cortical destruction.Eur Neurol. 1993; 33(6):403-8.

34. Lazarov O, Marr RA. Neurogenesis and Alzheimer’s disease: at the crossroads. Exp Neurol. 2010 Jun; 223(2):267-81.

35. Mu Y, Gage FH.  Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener. 2011; 6: 85.

36. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN, Uranga RM, Bruce-Keller AJ, Keller JN. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem. 2010 Sep; 114(6):1581-9.

37. Jacka FN, Cherbuin N, Anstey KJ, Sachdev P, Butterworth P. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med. 2015 Sep 8;13:215.

38. Akbaraly T, Sexton C, Zsoldos E, Mahmood A, Filippini N, Kerleau C, Verdier JM, Virtanen M, Gabelle A, Ebmeier KP, Kivimaki M. Association of Long-Term Diet Quality with Hippocampal Volume: Longitudinal Cohort Study.Am J Med. 2018 Nov;131(11):1372-1381.e4.

39. Town T, Nikolic V, Tan J. The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation. 2005 Oct 31;2:24.

40. Olson JK, Miller SD. Microglia Initiate Central Nervous System Innate and Adaptive Immune Responses Through Multiple TLRs. J Immunol. 2004 Sep 15;173(6):3916-24.

41. Baldwin KT, Carbajal KS, Segal BM, Giger RJ. Neuroinflammation Triggered by β-glucan/dectin-1 Signaling Enables CNS Axon Regeneration. Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2581-6. 

42. Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, Sun Y, Zhu B, Piña-Crespo JC, Zhang M, Zhang N, Chen X, Bu G, An Z, Huang TY, Xu H. TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron. 2018 Mar 7;97(5):1023-1031.e7.

43. Correale C, Genua M, Vetrano S, Mazzini E, Martinoli C, Spinelli A, Arena V, Peyrin-Biroulet L, Caprioli F, Passini N, Panina-Bordignon P, Repici A, Malesci A, Rutella S, Rescigno M, Danese S. Bacterial sensor triggering receptor expressed on myeloid cells-2 regulates the mucosal inflammatory response.Gastroenterology. 2013 Feb;144(2):346-356.e3.

44. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol. 2003 Jul 15;171(2):594-9.

45. Zhang B, Wang HE, Bai YM, Tsai SJ, Su TP, Chen TJ, Wang YP, Chen MH. Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study. Gut. 2020 Jun 23:gutjnl-2020-320789.

46. Leo EEM, Campos MRS.Effect of Ultra-Processed Diet on Gut Microbiota and Thus Its Role in Neurodegenerative Diseases.  Nutrition. 2020 Mar;71:110609.

47. Shi H, Wang Q, Zheng M, Hao S, Lum JS, Chen X, Huang XF, Yu Y, Zheng K.J. Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice. Neuroinflammation. 2020 Mar 4;17(1):77. 

48. Gubert C, Kong G, Renoir T, Hannan AJ. Exercise, diet and stress as modulators of gut microbiota: Implications for neurodegenerative diseases.Neurobiol Dis. 2020 Feb;134:104621. Review.

This text was originally published here on Friday, July 3, 2020.
This is a guest post. Any opinions expressed are the writer’s own.

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