Let’s explore the most ubiquitous of lifestyle-related problems – obesity and metabolic dysfunction – and their relationship to the pervasive and increasingly common neurodegenerative disease, Alzheimer’s Disease (AD).[1]
The most recent research to emphasise the link between morbidity, metabolic disruption and brain matter changes further qualified the intrinsic connection between blood sugar abnormalities and the sensitivity of certain neuronal tissues to neurodegeneration.[2]
Metabolic dysfunction and AD
Notably, the researcher’s work reinforces data previously generated in preclinical animal models and demonstrates the importance of dysregulated metabolism centred on insulin resistance as a mediator of neurodegeneration. AD should therefore be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions occurring in diabetes mellitus, non-alcoholic fatty liver disease, metabolic syndrome and obesity.[3]
The key takeaway is that brain glucose metabolism and systemic glucose metabolism work in concert, and both brain and systemic metabolic disorders can contribute to the development of neurological disease.[4]
There is plenty of data supporting this mechanistic connection in AD. The public health alarm should be sounded even louder, the level of obesity in the United Kingdom is increasing annually. In 2022 it reached 63.9%, a 0.3 percentage point increase on the previous year and combines overweight and obese numbers. Britain now has one of the highest levels of obesity in Europe. In the USA more than two-thirds of adults are overweight or have obesity. (2022), and rising rates among children, who in many cases are then programmed to remain metabolically dysfunctional.
But neither the experimental, nor human data, indicate that obesity alone is sufficient to actually cause AD.
Obesity is not the only factor
Instead, the findings suggest that obesity is a co-factor contributing to neurodegeneration, a concept that fits with independent data showing that exercise and weight loss as well as spending time in nature can improve cognition and reduce the related risks.[5],[6] A study of nearly 62 million Medicare beneficiaries suggests that nature may help protect against the risk of developing certain neurodegenerative disorders.[7] Another paper from the journal Nature indicated that just 2 hours a week was enough to have a beneficial impact.[8]
To delve deeper into the weight and brain function matter, the experimental data in the introduction paper showed that obesity associated with AD pathology was linked to dysregulated insulin metabolism and inflammatory states and that the obesity was largely visceral. Previous studies in humans have linked diabetes and other insulin-resistant states to cognitive impairment. No doubt, obesity is a contributing factor, but attention must be paid to the associated pathologies that are linked to insulin resistance, inflammation, and oxidative stress, rather than simply body weight or BMI. Plenty of normal or underweight individuals develop AD.
Nutrition
In animal models, a diet high in refined carbohydrates increases the risk of dementia and AD. A human study in France replicated this effect and confirmed that older participants who ate a daily snack high in refined carbohydrates were more likely to develop dementia.[9]
Another study linked processed meat products, such as sausages, salami, and bacon, with dementia. Regular consumption of processed meat increased the relative risk (a measure of the risk of a certain event happening in one group compared to the risk of the same event happening in another group) of all dementias by 44% and Alzheimer’s disease by 52%.[10]
The mechanistic links between diet, inflammation, oxidation and disordered metabolism are extensive and many flow through the microbiome in the gut. Evidence is growing that a varied diet rich in plants will support a varied gut microbiome. And a varied gut microbiome helps to reduce the inflammation implicated in dementia.
The gut microbiome
Detrimental changes in the gut microbiome composition can result in an increase of intestinal permeability and systemic inflammation, which negatively affects the blood-brain barrier integrity.[11] Further, bacterial lipopolysaccharides (LPS) and proinflammatory cytokines may activate microglia and accelerate neuroinflammation which contributes to neuronal loss.[12]
Activation of many intestinal NLRP3 (Nucleotide-Binding Domain, Leucine-Rich–Containing Family, Pyrin Domain–Containing-3) inflammasomes by triggering gut flora were also shown to be involved in AD pathogenesis. In animal model upregulation of NLRP3 inflammasomes after faecal microbiota transplantation (FMT) from AD patients leads to activation of systemic inflammation and neuroinflammation in the hippocampus.[13] The most discussed potential mechanisms of gut microbiota impact on AD risk are associated with active metabolites and signalling molecules such as; trimethylamine N-oxide (TMAO), bile acids, dysregulated P-glycoprotein, kynurenine, and nuclear factor-κB-sensitive microRNA-146a.[14]
There is sufficient evidence from epidemiological and observational studies and randomised controlled trials (RCTs) that suggest a neuroprotective role of the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and the KetoFLEX 12/3 diet in reducing cognitive decline.[15]
Supplements
Food selection and supplemental intakes are both able to mitigate or exacerbate these disruptions and contribute to reduced risk of metabolic dysfunction and neurodegeneration. Whilst lifestyle changes can be hard to make, taking a supplement can seem an easy insurance. But there is only modest evidence for direct benefit from isolated supplemental intake, chiefly Omega 3 EFAS and B vitamins.[16]
Prof. Dale Bredesen has been investigating the role of utilising a multifactorial approach to metabolic dysfunction, genetic variations and neurodegeneration for a number of years. His paper out in the International Journal of Molecular Science in Jan 2023 qualifies why lifestyle-led neurodegeneration is a process that no single intervention will mitigate. A multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may prove to be more effective than a mono-therapeutic approach.
Comment
This multifactorial approach resonates with practitioners trained in functional medicine, who seek to work upstream from the symptoms to trace back to the multiple triggers, mediators and antecedents that need to be addressed for best outcomes, less so with single therapeutic-orientated clinicians.
References
[1] Engin A. The Definition and Prevalence of Obesity and Metabolic Syndrome. Adv Exp Med Biol. 2017;960:1-17.
[2] Filip Morys, Olivier Potvin, Yashar Zeighami, Jacob Vogel, Rémi Lamontagne-Caron, Simon Duchesne, Alain Dagher. Obesity-Associated Neurodegeneration Pattern Mimics Alzheimer’s Disease in an Observational Cohort Study. Journal of Alzheimer’s Disease, 2022
[3] de la Monte SM. Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease. Drugs. 2017 Jan;77(1):47-65.
[4] Zhang S, Lachance BB, Mattson MP, Jia X. Glucose metabolic crosstalk and regulation in brain function and diseases. Prog Neurobiol. 2021 Sep;204:102089.
[5] Kronschnabl JM, Kneip T, Weiss LM, Bergmann M (2021) Bodyweight change and cognitive performance in the older population. PLOS ONE 16(4)
[6] Nicola Napoli, Krupa Shah, Debra L Waters, David R Sinacore, Clifford Qualls, Dennis T Villareal, Effect of weight loss, exercise, or both on cognition and quality of life in obese older adults, The American Journal of Clinical Nutrition, Volume 100, Issue 1, July 2014, Pages 189–1
[7] Klompmaker JO, Laden F, Browning MHEM, et al. Associations of Greenness, Parks, and Blue Space With Neurodegenerative Disease Hospitalizations Among Older US Adults. JAMA Netw Open. 2022;5(12):e2247664.
[8] White, M.P., Alcock, I., Grellier, J. et al. Spending at least 120 minutes a week in nature is associated with good health and wellbeing. Sci Rep 9, 7730 (2019).
[9] Gentreau, M, Chuy, V, Féart, C, et al. Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer’s disease in apolipoprotein E ε4 allele carriers. Alzheimer’s Dement. 2020; 16: 1043– 1053.
[10] Huifeng Zhang, Darren C Greenwood, Harvey A Risch, David Bunce, Laura J Hardie, Janet E Cade, Meat consumption and risk of incident dementia: cohort study of 493,888 UK Biobank participants, The American Journal of Clinical Nutrition, Volume 114, Issue 1, July 2021, Pages 175–184
[11] Askarova S, Umbayev B, Masoud AR, Kaiyrlykyzy A, Safarova Y, Tsoy A, et al. The links between the gut microbiome, aging, modern lifestyle and Alzheimer’s disease. Front Cell Infect Microbiol. (2020)
[12] Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil. (2019) 25:48–60
[13] Shen H, Guan Q, Zhang X, Yuan C, Tan Z, Zhai L, et al. New mechanism of neuroinflammation in Alzheimer’s disease: the activation of NLRP3 inflammasome mediated by gut microbiota. Prog Neuropsychopharmacol Biol Psychiatry. (2020) 100:109884
[14] Romanenko M, Kholin V, Koliada A and Vaiserman A (2021) Nutrition, Gut Microbiota, and Alzheimer’s Disease. Front. Psychiatry 12:712673.
[15] Toups K, Hathaway A, Gordon D, Chung H, Raji C, Boyd A, Hill BD, Hausman-Cohen S, Attarha M, Chwa WJ, Jarrett M, Bredesen DE. Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project. J Alzheimers Dis. 2022;88(4):1411-1421
[16] Arellanes IC, Choe N, Solomon V, He X, Kavin B, Martinez AE, Kono N, Buennagel DP, Hazra N, Kim G, D’Orazio LM, McCleary C, Sagare A, Zlokovic BV, Hodis HN, Mack WJ, Chui HC, Harrington MG, Braskie MN, Schneider LS, Yassine HN. Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial. EBioMedicine. 2020 Sep;59:102883.
