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Alzheimer’s Disease

• Environmental pesticide exposure and Alzheimer's disease in southern Spain: A cross-sectional study
  The intensive cultivation under plastic in southern Spain has made the agricultural model highly productive. Although strict regulations on pesticide usage exist, exposure to pesticides in the environment has been associated with an increased appearance of neurodegenerative diseases including Alzheimer's disease (AD). A cross-sectional study was performed to examine the prevalence and risk of AD related to pesticide exposure in Andalusia (Spain). We utilized the Odds Ratio statistical test to compare the prevalence rate of AD in the exposed and unexposed areas. 40,044 cases were collected from computerized hospital records between 2000 and 2021. Districts with higher pesticide use showed significantly higher prevalence rates and increased risk of developing AD, compared to those with lower pesticide use. These findings provide further evidence supporting an increased risk of AD following environmental exposure to pesticides at the level of the general population.
  [Ruiz-González, C. et al. (2024) Environmental pesticide exposure and alzheimer’s disease in southern Spain: A cross-sectional study, Psychiatry Research. Available at: https://www.sciencedirect.com/science/article/pii/S0165178124002178?via%3Dihub. ]
• Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells
  Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment. The disruption of autophagosome-lysosome function has been linked to the pathogenesis of Alzheimer's disease. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant that has the potential to cause neuronal damage. We found that TDCIPP significantly increased the expression of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), presenilin-1 (PS1) and Aβ42. Proteomic studies with TMT labeling revealed changes in the profiles of N2a-APPswe cells after exposure to TDCIPP. Proteomic and bioinformatics analyses revealed that lysosomal proteins were dysregulated in N2a-APPswe cells after treatment with TDCIPP. The LC3, P62, CTSD, and LAMP1 levels were increased after TDCIPP exposure, and dysregulated protein expression was validated by Western blotting. The exposure to TDCIPP led to the accumulation of autophagosomes, and this phenomenon was enhanced in the presence of chloroquine (CQ). Our results revealed for the first time that TDCIPP could be a potential environmental risk factor for AD development. The inhibition of autophagosome-lysosome fusion may have a significant impact on the generation of Aβ1-42 in response to TDCIPP.
  [Zou, C. et al. (2024) Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells, Heliyon. Available at: https://www.cell.com/heliyon/fulltext/S2405-8440(24)02863-9. ]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
  Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
  [Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ]
• Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease
  Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
  [Tang, B.L., 2020. Toxics, 8(2), p.21.]
• Pesticides, cognitive functions and dementia: A review
  Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person’s quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer’s disease.
  [Aloizou, A.M., Siokas, V., Vogiatzi, C., Peristeri, E., Docea, A., Petrakis, D., Provatas, A., Folia, V., Chalkia, C., Vinceti, M. and Wilks, M., 2020. Pesticides, cognitive functions and dementia: A review. Toxicology Letters.]
• Gut microbiota in neurodegenerative disorders
  Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.

   
  [Sarkar, S. R., & Banerjee, S. (2019). Gut microbiota in neurodegenerative disorders. Journal of neuroimmunology, 328, 98-104. https://www.sciencedirect.com/science/article/pii/S0165572818304545 ]

• Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
  Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
  [Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.]
• Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
  Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.
  [Pearson, B.L., Simon, J.M., McCoy, E.S., Salazar, G., Fragola, G. and Zylka, M.J., 2016. Nature communications, 7(1), pp.1-12.]
• Organophosphate pesticide exposure and neurodegeneration
  Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
  [Sánchez-Santed, F., Colomina, M.T. and Hernández, E.H., 2016. Cortex, 74, pp.417-426.]
• Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment.
  Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.Search was conducted in PubMed and Web of Science databases and articles were selected if the following inclusion criteria were met: being a SR, published until April 2015 and without language restrictions.The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.
  [Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M. 2016. Environ Int. 92-93:657-79. ]
• Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.
  Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.
  [Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. 2015. Front Cell Neurosci. 9:124]
• Elevated serum pesticide levels and risk for Alzheimer disease.
  The aim of this study was to evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association.A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases.Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status.Levels of DDE were 3.8-fold higher in the serum of those with AD when compared with control participants. The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD and lower Mini-Mental State Examination scores. The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele. Serum levels of DDE were highly correlated with brain levels of DDE. Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein.Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.
  [Richardson JR, Roy A, Shalat SL, et al. 2014. JAMA Neurol.71(3):284-90]
• Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
  The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
  [Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
• Linking pesticide exposure and dementia: what is the evidence?
  There has been a steep increase in the prevalence of dementia in recent decades, which has roughly followed an increase in pesticide use some decades earlier, a time when it is probable that current dementia patients could have been exposed to pesticides. This raises the question whether pesticides contribute to dementia pathogenesis. Indeed, many studies have found increased prevalence of cognitive, behavioral and psychomotor dysfunction in individuals chronically exposed to pesticides. Furthermore, evidence from recent studies shows a possible association between chronic pesticide exposure and an increased prevalence of dementia, including Alzheimer's disease (AD) dementia. At the cellular and molecular level, the mechanism of action of many classes of pesticides suggests that these compounds could be, at least partly, accountable for the neurodegeneration accompanying AD and other dementias. For example, organophosphates, which inhibit acetylcholinesterase as do the drugs used in treating AD symptoms, have also been shown to lead to microtubule derangements and tau hyperphosphorylation, a hallmark of AD. This emerging association is of considerable public health importance, given the increasing dementia prevalence and pesticide use. Here we review the epidemiological links between dementia and pesticide exposure and discuss the possible pathophysiological mechanisms and clinical implications of this association.
  [Zaganas I, Kapetanaki S, et al. 2013. Toxicology. 307:3-11]
• Neurotoxicity of pesticides: its relationship with neurodegenerative diseases
  Several epidemiological studies suggest that pesticides could lead to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Among pesticides, insecticides appear more neurotoxic than others but the neurotoxic mechanisms leading to adverse health effects remain unclear. The currently used pesticides such as rotenone and paraquat could disrupt mitochondrial bioenergetic function, reactive oxygen metabolism, redox function and promote α-synuclein aggregation. In addition, recent studies demonstrate that genetic susceptibility to Parkinson's disease could monitor pesticide susceptibility, as demonstrated for polymorphisms in pesticide metabolizing enzymes that are involved in organophosphorus sensitivity.
  [Thany SH, Reynier P, Lenaers G. 2013. Med Sci (Paris). 29(3):273-8]
• Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica.
  Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. Authors conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica. Initial screens were given: mini-mental states exam (MMSE) and a modified version of a 10-item united Parkinson's disease rating motor subscale (UPDRS). Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed. The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest, and finger-tapping. Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3-4 times the expected based on international data. Among subjects who took the UPDRS, the exposed had an increased risk of PD. No excess risk was found for a diagnosis of AD or mild cognitive impairment. Authors conclude that elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure.
  [Steenland K, Wesseling C, Román N, Quirós I, Juncos JL. 2013. Environ Res.120:96-101]
• Parkinson disease and Alzheimer disease: environmental risk factors.
  The purpose of this review is to update and summarise available evidence on environmental risk factors that have been associated with risk of Parkinson disease (PD) or Alzheimer disease (AD) and discuss their potential mechanisms.Evidence consistently suggests that a higher risk of PD is associated with pesticides and that a higher risk of AD is associated with pesticides, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, smoking, traumatic brain injury and depression. There is weak evidence suggesting that higher risk of PD is associated with high iron intake, chronic anaemia and traumatic brain injury. Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use, while a lower risk of AD is associated with moderate alcohol consumption, physical exercise, perimenopausal hormone replacement therapy and good cognitive reserve. Several environmental factors contribute significantly to risk of PD and AD. Some may already be active in the early stages of life, and some may interact with other genetic factors. Population-based strategies to modify such factors could potentially result in fewer cases of PD or AD.
  [Campdelacreu J.2012. Neurologia. Epub ahead of print]
• Association between environmental exposure to pesticides and neurodegenerative diseases
  Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
  [Parrón, T., Requena, M., Hernández, A.F. and Alarcón, R., 2011. Toxicology and applied pharmacology, 256(3), pp.379-385.]
• Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2.
  Pesticide exposure is a risk factor of Alzheimer's disease (AD). However, little is known about how pesticide exposure may promote AD pathogenesis. In this study, we investigated the effects of paraquat pesticide exposure on β-amyloid (Aβ) levels and cognition using wild-type (WT) mice and β-amyloid precursor protein (APP) transgenic mice. Our results showed that wild-type mice and APP transgenic mice after paraquat exposure had increased oxidative damage specifically in mitochondria of cerebral cortex and exhibited mitochondrial dysfunction. Moreover, the elevated mitochondrial damage was directly correlated with impaired associative learning and memory and increased Aβ levels in APP transgenic mice exposed to paraquat. Furthermore, overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme important for H2O2 removal, protected against paraquat-induced mitochondrial damage and concomitantly improved cognition and decreased Aβ levels in APP transgenic mice. Therefore, our results demonstrate that mitochondrial damage is a key mechanism underlying cognitive impairment and elevated amyloidogenesis induced by paraquat and that enhanced removal of mitochondrial H2O2 could be an effective strategy to ameliorate AD pathogenesis induced by pesticide exposure.
  [Chen, L., et al. 2011. Neurobiol Aging. [Epub ahead of print]
• Alzheimer disease: Risk of dementia and Alzheimer disease increases with occupational pesticide exposure
  Occupational exposure to pesticides increases the risk of developing dementia and Alzheimer disease (AD) in later life, according to this longitudinal population-based cohort study. The results of this study provide further evidence that certain environmental factors are risk factors for these debilitating conditions.
  [Jones N.2010. Nat Rev Neurol. 6(7):353]
• Occupational exposure to pesticides increases the risk of incident AD
  Study of individuals from an agricultural community in Utah shows increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09–1.76, and for Alzheimer’s Disease (AD) (HR 1.42, 95% CI 1.06–1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05–2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99–2.24)
  [Hayden KM, et al. 2010. Neurology, May 11;74(19):1524-30]
• Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies.
  Eleven studies explored the relationship of AD with solvents, seven with EMF, six with pesticides, six with lead and three with aluminium. For pesticides, studies of greater quality and prospective design found increased and statistically significant associations.
  [Santibáñez M, et al. 2007. Occup Environ Med. Nov;64(11):723-32. Epub 2007 May 24]
• Neurodegenerative Diseases and Exposure to Pesticides in the Elderly.
  Study of 1,507 French elderly (1992–1998) shows lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson’s disease and Alzheimer’s disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively.
  [Baldi, I, et al. Am J Epidemiol 2003; 157:409-414.]
• Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada.
  Study of a longitudinal, population-based study of dementia in Manitoba, Canada shows occupational exposure to fumigants and/or defoliants was a significant risk factor for Alzheimer's disease (relative risk [RR] = 4.35; 95% CI : 1.05--17.90).
  [Tyas SL, et al. Int J Epidemiol. 2001 Jun;30(3):598-9]