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As world populations grow older and fertility rates decline,^1,2 leading to a simultaneously shrinking and aging society, neurodegenerative disease is projected to become even more pervasive than it is today.^3,4 In the US alone, the incidence of Alzheimer’s disease could more than double by 2050 to more than 13 million, from 6.9 million today.⁴ These diseases are complex and multifactorial, encompassing a variety of conditions, each with different pathological patterns, clinical presentations, and root causes. Researchers suggest that environmental risk factors play a key role in accelerating neurodegenerative disease onset and progression.⁵ With regard to the most common, Alzheimer’s disease (AD) and Parkinson’s disease (PD), the most rigorously studied environmental exposures have been on heavy metals and pesticides.⁶

Alzheimer’s Disease, Dementia, & Heavy Metals

Across the globe, over 50 million people suffer from dementia, and this number is expected to reach 152 million by the year 2050.⁷ AD development, which is clinically manifested by progressive impairment in cognition, learning ability, memory function, and executive reasoning,⁸ is partially attributable to environmental factors.⁷ Heavy metals like lead, cadmium, and manganese are widely used and may contribute to AD pathologies by increasing neuronal oxidative stress, inflammation, and apoptosis.^7,9

Lead

Lead is a known neurotoxicant that rapidly crosses the blood-brain barrier,⁵ leading to neuroinflammation, oxidative stress, endoplasmic reticulum stress, and apoptosis.⁷ It has been associated with neurodegeneration in cross-sectional human epidemiology studies,^7,10,11 and numerous studies have reported that either developmental or acute lead exposure contributes to the hallmark signatures of AD, including Aβ accumulation, tau pathology, and inflammation.⁵ Despite US legislative efforts to minimize lead exposure, this heavy metal is still used in industrial applications. Lead exposure sources tend to vary by geographic location; however, in general, globally high lead levels are associated with electronic waste recycling, lead mining, and smelting, with the primary routes of exposure being inhalation or ingestion.

Cadmium

Cadmium has recently emerged as a neurotoxicant, although evidence in humans remains limited.⁷ Diet is the primary exposure source, along with cigarette smoking. Like lead, cadmium is known to cross the blood-brain barrier; once in the body, this metal may induce oxidative stress, neuroinflammation, and apoptosis in neuronal cells.^5,7 A 2023 systematic review of observational studies found that among older adults, cognitive ability scores decreased as measured levels of blood, urine, and dietary cadmium increased.¹² A meta-analysis including eight studies covering 405 AD patients and 424 control subjects found that circulating concentrations (either whole blood, serum, or plasma) of cadmium were significantly higher in AD versus controls.^7,13 

Manganese

Despite the importance of manganese in human health (it is a cofactor for normal cell function enzymes), excessive manganese is neurotoxic, as high levels may cause accumulation in the brain.⁷ A 2022 systematic review of observational studies reported negative associations between manganese levels and neurodevelopment domains in children, including attention, memory, learning, and executive function.¹⁴ Those with occupational exposure have reported deficits in processing speed, attention, memory, reaction time, cognitive control, and other cognitive functions.¹⁵ Beyond occupational exposure, diet is the primary source of manganese in the general population, and toxicity can also result from elevated levels in drinking water or air; it is widely used in industrial processes and commercial products.¹⁶ Underlying mechanisms include induction of oxidative stress, mitochondrial dysfunction, autophagy dysregulation, accumulation of intracellular toxic metabolites, and apoptosis.^5,7

Parkinson’s Disease & Pesticides

Parkinson’s disease (PD) is a progressive neurological disease, with a global prevalence that has doubled in the past few decades.¹⁷ PD is characterized by motor symptoms, including bradykinesia plus rigidity and resting tremor, as well as postural instability at a more advanced stage.¹⁷ It may also be coupled with non-motor features such as dementia, depression, and autonomic dysfunction.⁸ A 2019 systematic review and meta-analysis suggests that exposure to pesticides increases the risk of developing a neurodegenerative disease, including PD, by 50%.⁶ The group of pesticides known as organochlorines have most frequently been associated with the risk of PD, as they have consistently been shown to be neurotoxic and to promote oxidative stress.¹⁸ Rural living and occupational exposure to pollutants are additional exacerbating factors.¹⁸ Many epidemiological and observational studies suggest a link between insecticide exposure through ingestion or skin contact and incidence of PD.^19,20

Clinical Applications: The Functional Medicine Approach

Understanding toxicity and taking practical steps to improve biotransformation and the elimination of toxicants are essential and critical pieces in the functional medicine approach to health and well-being. Functional medicine educates clinicians about the biochemistry and genetics of biotransformation pathways, the connection between organ system dysfunction and potential toxic exposures, the laboratory evaluations necessary in working up a toxin-exposed patient, and various personalized treatment approaches. Treatments for patients concerned about toxic exposures may include support of mitochondrial health and concurrent consideration of multiple lifestyle factors, including nutrition and exercise.

Specific nutrients and dietary patterns have been investigated for their neuroprotective properties. Research studies suggest that increased dietary quality and adherence to dietary guidelines that emphasize consumption of fiber, fruits, vegetables, and fish were related to better cognition.^21,22 More recent research also supports the role of vitamin D and specific diets such as the Mediterranean diet in neuroprotection and in reducing the risk of dementia.^23,24

Nutrition is an essential part of a patient’s personalized clinical intervention for neurodegenerative diseases. A functional medicine strategy for prevention and treatment of neurodegeneration may include a therapeutic food plan, which benefits patients by helping them eat more of the foods that support pathways in the liver for healthy elimination. In functional medicine, practitioners often utilize phytonutrient-dense therapeutic food plans to support intestinal and liver function during the metabolic detoxification process.

Certainly, avoiding toxic exposures is key to optimal wellness, but in today’s society, it has become increasingly challenging to do so. Given the presence of a vast array of chemicals that humans may be exposed to in their lifetime, how do we ensure human health? An individual’s ability to detoxify or biotransform and excrete toxic substances is of critical importance to overall health. Learn how to assess both exposures and total toxic load to appropriately assess and address each individual’s toxicological situation at IFM’s Environmental Health Advanced Practice Module (APM).

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References

1. World Health Organization. Ageing and health. WHO. Published October 1, 2022. Accessed July 9, 2024. https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
2. GBD 2021 Fertility and Forecasting Collaborators. Global fertility in 204 countries and territories, 1950-2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10440):2057-2099. doi:1016/S0140-6736(24)00550-6
3. Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The epidemiology of Alzheimer’s disease modifiable risk factors and prevention. J Prev Alzheimers Dis. 2021;8(3):313-321. doi:14283/jpad.2021.15
4. Alzheimer’s Association. 2024 Alzheimer’s disease facts and figures. Published 2024. Accessed July 9, 2024. https://www.alz.org/alzheimers-dementia/facts-figures
5. Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R. Metal toxicity links to Alzheimer’s disease and neuroinflammation. J Mol Biol. 2019;431(9):1843-1868. doi:1016/j.jmb.2019.01.018
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8. Cui L, Hou NN, Wu HM, et al. Prevalence of Alzheimer’s disease and Parkinson’s disease in China: an updated systematical analysis. Front Aging Neurosci. 2020;12:603854. doi:3389/fnagi.2020.603854
9. Cicero CE, Mostile G, Vasta R, et al. Metals and neurodegenerative diseases. A systematic review. Environ Res. 2017;159:82-94. doi:1016/j.envres.2017.07.048
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11.  Farace C, Fiorito G, Pisano A, et al. Human tissue lead (Pb) levels and amyotrophic lateral sclerosis: a systematic review and meta-analysis of case-control studies. Neurol Sci. 2022;43(10):5851-5859. doi:1007/s10072-022-06237-y
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13.  Xu L, Zhang W, Liu X, Zhang C, Wang P, Zhao X. Circulatory levels of toxic metals (aluminum, cadmium, mercury, lead) in patients with Alzheimer’s disease: a quantitative meta-analysis and systematic review. J Alzheimers Dis.2018;62(1):361-372. doi:3233/jad-170811
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15.  Vlasak T, Dujlovic T, Barth A. Manganese exposure and cognitive performance: a meta-analytical approach. Environ Pollut. 2023;332:121884. doi:1016/j.envpol.2023.121884
16.  Balachandran RC, Mukhopadhyay S, McBride D, et al. Brain manganese and the balance between essential roles and neurotoxicity. J Biol Chem. 2020;295(19):6312-6329. doi:1074/jbc.rev119.009453
17.  World Health Organization. Parkinson disease. WHO. Published August 9, 2023. Accessed July 9, 2024. https://www.who.int/news-room/fact-sheets/detail/parkinson-disease
18.  Dardiotis E, Aloizou AM, Sakalakis E, et al. Organochlorine pesticide levels in Greek patients with Parkinson’s disease. Toxicol Rep. 2020;7:596-601. doi:1016/j.toxrep.2020.03.011
19.  Shrestha S, Parks CG, Umbach DM, et al. Pesticide use and incident Parkinson’s disease in a cohort of farmers and their spouses. Environ Res. 2020;191:110186. doi:1016/j.envres.2020.110186
20.  Yan D, Zhang Y, Liu L, Shi N, Yan H. Pesticide exposure and risk of Parkinson’s disease: dose-response meta-analysis of observational studies. Regul Toxicol Pharmacol. 2018;96:57-63. doi:1016/j.yrtph.2018.05.005
21.  Wesselman LMP, Doorduijn AS, de Leeuw FA, et al. Dietary patterns are related to clinical characteristics in memory clinic patients with subjective cognitive decline: the SCIENCe project. Nutrients. 2019;11(5):1057. doi:3390/nu11051057
22.  Fieldhouse JLP, Doorduijn AS, de Leeuw FA, et al. A suboptimal diet is associated with poorer cognition: the NUDAD project. Nutrients. 2020;12(3):703. doi:3390/nu12030703
23.  Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol. 2019;19(1):284. doi:1186/s12883-019-1500-6
24.  Nucci D, Sommariva A, Degoni LM, et al. Association between Mediterranean diet and dementia and Alzheimer disease: a systematic review with meta-analysis. Aging Clin Exp Res. 2024;36(1):77. doi:1007/s40520-024-02718-6