Pesticide-Induced Diseases: Alzheimer’s Disease

According to the Alzheimer’s Association, Alzheimer’s disease (AD), the most common form of dementia, is a progressive and fatal brain disease. As many as 5.3 million Americans are living with Alzheimer’s disease. Alzheimer’s destroys brain cells, causing memory loss and problems with thinking and behavior severe enough to affect work, lifelong hobbies or social life. Alzheimer’s gets worse over time, it is fatal, and has no current cure.

  • 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. ]
  • 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]
  • 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.
    This study examined the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. A total of 17,429 hospital records were collected 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. This study supports and extends previous findings 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., et al. 2011. Toxicol Appl Pharmacol. Epub ahead of print]
  • Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2.
    This study investigated the effects of paraquat pesticide exposure on wild-type mice and β-amyloid precursor protein (APP) transgenic mice. Results show 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. Results demonstrate that mitochondrial damage is a key mechanism underlying cognitive impairment and elevated amyloidogenesis induced by paraquat.
    [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]