Dietary and Environmental Risk Factors in Parkinson's Disease and Alzheimer's Disease: Beware of Your Food Plate and Your Surroundings!

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by classical motor signs including bradykinesia, rigidity, rest tremor, and postural instability. Several non-motor symptoms including anosmia, constipation, rapid eye movement, sleep behavior disorder, and depression may predate motor features.[1] Degeneration of striatonigral dopaminergic neurons along with the accumulation of alpha-synuclein-laden Lewy bodies appear as the major pathology in PD. Although several genetic and environmental factors have been implicated in its causation, the pathophysiology is still evolving.[1] Environmental neurotoxins may enter the human body via food particles and influence the cerebral oxidative state, thereby increasing the risk of neurodegeneration.[2] Several studies have linked dietary factors to the causation of neurodegenerative disorders including PD and Alzheimer’s disease (AD), highlighting its importance as a modifiable risk factor for PD and AD.[3–6] Moreover, adherence to dietary modifications may delay the onset of both PD and AD.[7,8] Premorbid dietary factors may increase oxidative stress, precipitate neuroinflammation, modulate alpha-synuclein collection, and damage the dopaminergic neurons.[5] Consumed food particles may influence the brain pathways through the gut-brain axis.[5] Several mechanisms have been proposed to favor this association. Firstly, alteration of the gut microbiome, known as gut dysbiosis, may lead to low-grade inflammation, increased oxidative stress, cellular degeneration, and disturbance in the blood-brain barrier integrity.[9] The intestinal microbiota may also alter short-chain fatty acid metabolism, microglial activation, and modulate alpha-synuclein aggregation.[10,11] Secondly, it has been suggested that the alpha-synuclein from the enteric nervous system can reach the brain via the vagus nerve and dorsal motor nucleus of the vagus within the medulla oblongata.[12] Heterogeneity is a common feature of dietary patterns across the world because of the unequal geographical distribution of resources, along with environmental and cultural differences. Although few dietary factors may be reduced, others may increase the risk of neurodegenerative disorders, including PD and AD. An antioxidant-rich and vitamin-rich diet including fruits, vegetables, and fish have been found to lower the risk of PD and AD.[8] Although supplementation of vitamin B6 could be associated with a decreased risk of PD, studies have reported reduced vitamin B12 levels in PD as compared to health controls.[13] A polyphenols-rich diet including tea has been found to be neuroprotective in pre-clinical models of PD.[14] A diet rich in carbohydrates with a high glycemic index may reduce the risk of PD by causing an insulin-induced increase in brain dopamine levels.[15] On the other hand, a diet rich in animal fat and milk may increase the risk of PD.[3,4] Saturated fatty acids present in meat may increase oxidative stress and result in neuro-inflammation, thereby precipitating neurodegeneration.[16] Moreover, exogenous alpha-synuclein in dietary meat may reach the brain via the gut-brain axis.[17] Pesticide particles contaminating milk along with the urate-reducing effect of milk appear to be possible factors linking increased pre-morbid milk consumption to PD.[4] While polyunsaturated fatty acid reduces the risk of PD, arachidonic acid, and cholesterol may increase PD risk.[18] In addition to the above discussed impact of dietary factors on PD risk, a diet rich in carbohydrates, high-fat dairy products, and fatty acids (both trans and saturated) has been reported to increase the risk of AD.[6] Environmental risk factors, including pesticides such as rotenone and paraquat,[19] industrial exposures,[20] and heavy metals such as manganese, lead, and copper[21] have been reported to enhance the risk of PD. Pesticides like rotenone and paraquat act like mitochondrial toxins and may damage dopaminergic neurons in the nigrostriatal system.[19] Although rural living, farming and consumption of well water have been linked to PD, the literature shows conflicting results.[22–25] Well water can act as a medium for carrying pesticides and can be the reason behind its association with neurodegeneration. However, contrary to this, no significant correlation was found between well-water consumption and PD risk in the meta-analysis of 15 observational studies.[25] Interestingly, a recent study reported that the risk of PD was not linked to rurality, but to the residence in pulse-producing areas. Pulses belonging to the Fabaceae family secrete rotenone as a natural pesticide, which may precipitate neurodegeneration.[26] In addition to these environmental risk factors for PD, AD has been linked to exposure to metals (iron, zinc, aluminum, copper, and lead), air pollution and pesticides.[27] Although a couple of studies reported a lower prevalence of AD and related dementias in rural areas,[28,29] one study reported a higher prevalence of unadjusted dementia in rural populations as compared to urban ones.[30] In this issue of the journal, Roy et al.[31] have performed a single-center, hospital-based, case-control study to evaluate the environmental and dietary risk factors of PD and AD. They interviewed 105 PD and 53 AD patients along with 81 age-matched controls, using a validated Food-Frequency Questionnaire and Environmental Hazard Questionnaire, to assess the dietary and environmental risk factors during the pre-morbid periods in patients and pre-interview periods in controls. They used a retrospective model where patients were asked to report their dietary habits one year before the disease diagnosis and controls did the same for the year before the interview. Premorbid consumption of carbohydrates, fat, meat and milk was significantly higher (P < 0.001), whereas intake of fruits and dietary fibers was significantly lower (P < 0.001) in PD as compared to AD and controls. The authors failed to find any significant association between pre-morbid dietary habits and AD. Among the assessed environmental factors, the presence of waterbody within 500 m of residence [odds ratio (OR) =7.52, 95% CI: 3.43 – 12.48, P trend = 0.001], drinking well-water (OR = 4.67, 95% CI: 1.43–6.95, P trend = 0.001), and residence in rural areas (OR = 4.18, 95% CI: 2.20–5.96, P trend = 0.001) were factors significantly associated with PD. Rural residence (OR = 0.318, 95% CI: 0.15–0.67, P trend = 0.002) was significantly associated with AD. The authors suspected that dietary and environmental risk factors increase oxidative stress and neuroinflammation, thereby triggering neurodegeneration. Other contributory pathways included a central accumulation of dietary alpha-synuclein through the gut-brain axis and biomagnification of b-N-methylamino-L-alanine, a neurotoxin secreted by aquatic fauna including cyanobacteria.[32] Considering the modifiable nature of dietary risk factors, studies have reported that adherence to a Mediterranean diet may reduce the risk of AD and PD.[6,7,33] Mediterranean diet consists of a high portion of fruits, vegetables, bread, cereals, poultry products, fish, potatoes, beans, nuts, and olive oils. It includes a moderate intake of alcohol and a very low amount of red meat and dairy products.[6,7] This diet is very rich in fiber, the main source of energy for gut microbiota. Thus, by modulating the gut microbiota, the Mediterranean diet reduces the risk of neurodegeneration.[8] In a recent systematic review, adherence to a Mediterranean diet has been shown to reduce the risk of both AD and PD.[8] In conclusion, dietary and environmental factors are of prime concern in neurodegenerative disorders including PD and AD. Since these are modifiable risk factors, their identification and management are of utmost importance.