Genetic polymorphism is the term used to define a gene that has multiple (poly) forms (morphism) which result from substitutions of alleles at single points in the genetic code. These genetic polymorphisms give rise to different structural forms of proteins including enzymes that participate in metabolism and detoxification of neurotoxicants. Proteins with different structures may also possess different functional attributes which render these proteins incapable of performing their intended normal role in various biological processes.
Studies looking at genetic polymorphisms implicated in the toxicokinetic and toxicodynamic interactions between neurotoxicants and neurodegenerative disease have begun to shed light on the complex relationship between chemical exposure and disease onset. A recent study by Carmona and colleagues (2019) employing cryogenic nanoimaging technology revealed how a mutation in the SLC30A10 gene, which codes for a protein that transports manganese across cell membranes, leads to the bioaccumulation of manganese within nanovesicles of the Golgi apparatus in patients with this mutation who also present with childhood onset parkinsonism. While the stunning relationships between this particular genetic mutation, exposure to the neurotoxic trace element manganese, and very early onset of parkinsonism is profound (Quadri et al., 2015), it is important to recognize that the emergence of symptoms of most age-related neurodegenerative diseases is unlikely to be modified as remarkably by a single enzymatic point mutation that influences chemical metabolism. On the contrary, while it would not be surprising to see a 15% decrease in age at onset due to genetic polymorphisms that modify chemical metabolism, a 75-90% decrease is less likely in the absence of a severe exposure circumstance. Thus, "in most cases" the major factor influencing age at onset of any age-related neurodegenerative disease remains age per se with neurotoxicant exposures and genetic polymorphisms acting in concert as disease modifying factors or "promoters".
Despite the aforementioned expectation that the effect size of exposure to neurotoxicants may not be very large, the development of motor and cognitive deficits during the most productive years of an individual's life (e.g. between the ages 50 or 55) can have profound personal and public health implications especially as the population ages.
That said, is also important to recognize that in addition to genetics, the magnitude and duration of the exposure play an important role in the extent to which chemicals damage peripheral nerves and brain cells and, thereby potentially modify neurodegenerative disease progression. High level exposures can easily overwhelm the ability of the body to detoxify and eliminate neurotoxicants while chronic lower level exposures are more likely to produce insidious cumulative effects on nervous system function which emerge more slowing in stark contrast to abrupt onset of changes in function associated with higher level acute exposures to toxic concentrations of the same chemical substances. A dose-response relationship is expected, with higher concentration and longer duration exposures having a greater effect on age at onset. This dose-response relationship is further modified by genetic polymorphisms that influence the detoxification process. With these thoughts in mind, the following paragraphs serve to summarize the literature and provide examples of genetic factors previously shown to influence neurotoxicity and neurodegenerative disease progression. Specific enzymes involved in the metabolism, detoxification and elimination of neurotoxicants are discussed (for additional information see Ratner, 2016).
Note: The recently reported FDA approval of direct-to-consumer genetic testing is expected to provide clinicians, scientists and medical-legal experts with a new tool that will undoubtedly lead to a better understanding of the genetic factors that contribute to individual differences in risk for and age at onset of neurodegenerative diseases. It is important to recognize that genetic testing alone cannot determine a person’s overall risk of developing a neurodegenerative disease; this is because there are other factors that contribute to the development and age onset of neurodegenerative disease including environmental and occupational exposures to toxic chemicals. Combining exposure history data with genetic data is likely to yield important information that can be used to minimize risk for neurodegenerative disease among susceptible populations.
Parkinson's Disease
Wilk and colleagues (2006) found a younger age at onset of Parkinson's disease among subjects exposed to herbicides who also had a single nucleotide polymorphism in a gene that codes for the enzyme glutathione-S-transferase (GST). This enzyme plays an important role in the second phase of chemical metabolism commonly associated with detoxification of active metabolites formed in the first phase. Based on the reports published thus far in peer reviewed journals additional studies looking at the relationship between younger age at onset of Parkinson's disease, GST polymorphisms and neurotoxicant exposure appear warranted (Menegon et al., 1998; Golbe et al. 2007; Goldman et al., 2012; Pinhel et al., 2013).
An interaction between genetic factors that increase the risk for developing PD and exposure to chemicals has also been reported. Parkin polymorphisms and residential/occupational risk factors (pesticides, organic solvents, rural living) were found to be associated with a younger age at onset (Ghione et al., 2007).
An association between genetic variations encoding for the enzyme aldehyde dehydrogenase-2 (ALDH-2), pesticide exposure and Parkinson's disease susceptibility has also been reported (Fitzmaurice et al. 2014; Zhang et al., 2015).
A mutation in the gene encoding for solute carrier family 30 member 10 (SLC30A10), a protein which is highly expressed in the liver and inducible by manganese and has been implicated in a familial form of early onset parkinsonism associated with severe hypermanganesemia and bioaccumulation of manganese within nanovesicles of the Golgi apparatus (Quadri et al., 2015; Carmona et al., 2019). The role of this enzyme in idiopathic PD has yet to be fully elucidated.
Alzheimer's Disease and Age-Related Dementias
How genetic factors implicated in dementia interact with chemical exposures to influence the response of the nervous system and progression of subclinical or prodromal age-related amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is of particular importance to the pharmaceutical industry and those involved in setting public health policy (Ratner et al., 2021). Exposure to chemicals that promote or repress expression of genes implicated in aMCI and AD may therefore slow or hasten the progression of memory impairments (Pereira et al., 2016).
Alzheimer's disease occurs in three forms: familial, early onset and late onset. Late-onset AD is the most common type of AD and it is characterized by symptom onset in persons over the age of 65. Age at onset of late onset AD is influenced by multiple genetic factors. A study that did not stratify subject by type of AD found a decrease in GST activity in the amygdala, hippocampus, parahippocampal gyrus, inferior parietal lobe, and nucleus basalis of Meynert in the brains of AD patients at autopsy (Lovell et al., 1998). Although the cause of late-onset AD has not been fully elucidated interactions between environmental, genetic and lifestyle factors appear to be involved (Fratiglioni et al., 1993). Polymorphisms of the GST enzyme have been investigated in the age at onset of Alzheimer's disease (AD). Although studies looking at age at onset AD and history of neurotoxicant exposure and GST polymorphisms are lacking, a positive association between the GSTM1 null genotype and late onset AD has been reported suggesting that an interaction between environmental and genetic factors may play a role in this form of the disease (Piacentini et al., 2012).
The APOE ε4 allele modifies the association between lead (Pb) exposure (as quantified by tibia Pb levels measured by K-shell-x-ray fluorescence) and age-related cognitive decline in those individuals carrying both ε4 alleles (Prada et al., 2016). Bone Pb is a cumulative measure of lifetime exposure to this neurotoxic heavy metal. Mobilization of bone Pb continues for decades after cessation of exposures and bone lead mobilization is increased with osteoporosis (Silbergeld et al., 1988; Wilker et al., 2011).
The association between late in life environmental exposures to toxicants was recently assessed by Cacciottolo and colleagues in a US-wide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS) and in an experimental mouse model. These authors found that exposure to airborne particulate matter from traffic emissions increased dementia risk in older women and, that this outcome may involve a gene-environment interactions with APOE ε4 (Cacciottolo et al., 2017).
Huntington's Disease
Age at onset of Huntington's disease is influenced by an increase in the number of repetitions of three nucleic acids (C, A, and G). Variations in age at onset that cannot be attributed to trinucleotide repeat size, are attributable to modifier genes and environmental factors (Djoussé et al., 2003; Friedman et al., 2005). Sensitivity to environmental factors may play a greater role in those patients with with borderline numbers of CAG repeats (e.g., 39 repeats) (Friedman et al., 2005).
References:
Cacciottolo M, Wang X, Driscoll I, Woodward N, Saffari A, Reyes J, Serre ML, Vizuete W, Sioutas C, Morgan TE, Gatz M, Chui HC, Shumaker SA, Resnick SM, Espeland MA, Finch CE, Chen JC. (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry. 7(1):e1022.
Carmona A, Zogzas CE, Roudeau S, Porcaro F, Garrevoet J, Spiers KM, Salomé M, Cloetens P, Mukhopadhyay S, Ortega R. SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus. ACS Chem Neurosci. 2018 Oct 15. doi: 10.1021/acschemneuro.8b00451.
Djoussé L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, Ross C et al. (2003) Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. Am J Med Genet 119a: 279–282.
Fitzmaurice AG, Rhodes SL, Cockburn M, Ritz B, Bronstein JM. (2014) Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology. 82(5):419-26.
Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. (1993) Risk factors for late-onset Alzheimer's disease: a population-based, case-control study. Ann Neurol. 33(3):258-66.
Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. (2005) Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol. 62(6):995-997.
Ghione I, Di Fonzo A, Saladino F, Del Bo R, Bresolin N, Comi GP, Rango M. (2007) Parkin polymorphisms and environmental exposure: decrease in age at onset of Parkinson's disease. Neurotoxicology. 28(3):698-701.
Golbe LI, Di Iorio G, Markopoulou K, Athanassiadou A, Papapetropoulos S, Watts RL, Vance JM, Bonifati V, Williams TA, Spychala JR, Stenroos ES, Johnson WG. (2007) Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet. 144B(2):254-258.
Goldman SM, Kamel F, Ross GW, Bhudhikanok GS, Hoppin JA, Korell M, Marras C, Meng C, Umbach DM, Kasten M, Chade AR, Comyns K, Richards MB, Sandler DP, Blair A, Langston JW, Tanner CM. (2012) Genetic modification of the association of paraquat and Parkinson's disease. Mov Disord. 27(13):1652-1658.
Helou R, Jaecker P.(2014) Occupational exposure to mineral turpentine and heavy fuels: a possible risk factor for Alzheimer's disease. Dement Geriatr Cogn Dis Extra. 4(2):160-71.
Lovell MA, Xie C, Markesbery WR. (1998) Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease. Neurology. 51(6):1562-6.
Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG. (1998) Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet. 352(9137):1344-1346.
Pereira AC, Gray JD, Kogan JF, Davidson RL, Rubin TG, Okamoto M, Morrison JH, McEwen BS. (2016) Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry. (Epub ahead of print).
Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, Amorim GS, Florim GM, Mazeti CM, Martins DP, Oliveira Fde N, Nakazone MA, Tognola WA, Souza DR. (2013) Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease. Arq Neuropsiquiatr. 71(8):527-532.
Piacentini S, Polimanti R, Squitti R, Ventriglia M, Cassetta E, Vernieri F, Rossini PM, Manfellotto D, Fuciarelli M. (2012) GSTM1 null genotype as risk factor for late-onset Alzheimer's disease in Italian patients. J Neurol Sci. 317(1-2):137-40.
Prada D, Colicino E, Power MC , Weisskopf MG, Zhong J, Hou L, Spiro A, Vokonas P, Brenan K, Herrera LA, Schwartz J, Baccarelli AA (2106) APOE ε4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals. Environmental Research 151:101–105.
Quadri M, Kamate M, Sharma S, Olgiati S, Graafland J, Breedveld GJ, Kori I, Hattiholi V, Jain P, Aneja S, Kumar A, Gulati P, Goel M, Talukdar B, Bonifati V. Manganese transport disorder: novel SLC30A10 mutations and early phenotypes. Mov Disord. 2015 Jun;30(7):996-1001.
Ratner MH. A critical review of the interrelationships between genetics, neurotoxicant exposure, and age at onset of neurodegenerative diseases. Current Topics in Toxicology. 2016; (12):1-10.
Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, Robitsek RJ, Xia W, Farb DH. Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer’s disease. Heliyon, September 2021, 7(9): e07895.
Silbergeld EK, Schwartz J, Mahaffey K. (1988) Lead and osteoporosis: mobilization of lead from bone in postmenopausal women. Environ Res. 47(1):79-94.
Wilk JB, Tobin JE, Suchowersky O, Shill HA, Klein C, Wooten GF, Lew MF, Mark MH, Guttman M, Watts RL, Singer C, Growdon JH, Latourelle JC, Saint-Hilaire MH, DeStefano AL, Prakash R, Williamson S, Berg CJ, Sun M, Goldwurm S, Pezzoli G, Racette BA, Perlmutter JS, Parsian A, Baker KB, Giroux ML, Litvan I, Pramstaller PP, Nicholson G, Burn DJ, Chinnery PF, Vieregge P, Slevin JT, Cambi F, MacDonald ME, Gusella JF, Myers RH, Golbe LI. (2006) Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study. Neurology. 67(12):2206-2210.
Wilker E, Korrick S, Nie LH, Sparrow D, Vokonas P, Coull B, Wright RO, Schwartz J, Hu H: (2011) Longitudinal Changes in Bone Lead Levels: The VA Normative Aging Study. Journal of Occupational and Environmental Medicine 53(8):850–855.
Zhang X, Ye YL, Wang YN, Liu FF, Liu XX, Hu BL, Zou M, Zhu JH. (2015) Aldehyde dehydrogenase 2 genetic variations may increase susceptibility to Parkinson's disease in Han Chinese population. Neurobiol Aging. ;36(9):2660.e9-13.
Last update: January 2, 2023.
Studies looking at genetic polymorphisms implicated in the toxicokinetic and toxicodynamic interactions between neurotoxicants and neurodegenerative disease have begun to shed light on the complex relationship between chemical exposure and disease onset. A recent study by Carmona and colleagues (2019) employing cryogenic nanoimaging technology revealed how a mutation in the SLC30A10 gene, which codes for a protein that transports manganese across cell membranes, leads to the bioaccumulation of manganese within nanovesicles of the Golgi apparatus in patients with this mutation who also present with childhood onset parkinsonism. While the stunning relationships between this particular genetic mutation, exposure to the neurotoxic trace element manganese, and very early onset of parkinsonism is profound (Quadri et al., 2015), it is important to recognize that the emergence of symptoms of most age-related neurodegenerative diseases is unlikely to be modified as remarkably by a single enzymatic point mutation that influences chemical metabolism. On the contrary, while it would not be surprising to see a 15% decrease in age at onset due to genetic polymorphisms that modify chemical metabolism, a 75-90% decrease is less likely in the absence of a severe exposure circumstance. Thus, "in most cases" the major factor influencing age at onset of any age-related neurodegenerative disease remains age per se with neurotoxicant exposures and genetic polymorphisms acting in concert as disease modifying factors or "promoters".
Despite the aforementioned expectation that the effect size of exposure to neurotoxicants may not be very large, the development of motor and cognitive deficits during the most productive years of an individual's life (e.g. between the ages 50 or 55) can have profound personal and public health implications especially as the population ages.
That said, is also important to recognize that in addition to genetics, the magnitude and duration of the exposure play an important role in the extent to which chemicals damage peripheral nerves and brain cells and, thereby potentially modify neurodegenerative disease progression. High level exposures can easily overwhelm the ability of the body to detoxify and eliminate neurotoxicants while chronic lower level exposures are more likely to produce insidious cumulative effects on nervous system function which emerge more slowing in stark contrast to abrupt onset of changes in function associated with higher level acute exposures to toxic concentrations of the same chemical substances. A dose-response relationship is expected, with higher concentration and longer duration exposures having a greater effect on age at onset. This dose-response relationship is further modified by genetic polymorphisms that influence the detoxification process. With these thoughts in mind, the following paragraphs serve to summarize the literature and provide examples of genetic factors previously shown to influence neurotoxicity and neurodegenerative disease progression. Specific enzymes involved in the metabolism, detoxification and elimination of neurotoxicants are discussed (for additional information see Ratner, 2016).
Note: The recently reported FDA approval of direct-to-consumer genetic testing is expected to provide clinicians, scientists and medical-legal experts with a new tool that will undoubtedly lead to a better understanding of the genetic factors that contribute to individual differences in risk for and age at onset of neurodegenerative diseases. It is important to recognize that genetic testing alone cannot determine a person’s overall risk of developing a neurodegenerative disease; this is because there are other factors that contribute to the development and age onset of neurodegenerative disease including environmental and occupational exposures to toxic chemicals. Combining exposure history data with genetic data is likely to yield important information that can be used to minimize risk for neurodegenerative disease among susceptible populations.
Parkinson's Disease
Wilk and colleagues (2006) found a younger age at onset of Parkinson's disease among subjects exposed to herbicides who also had a single nucleotide polymorphism in a gene that codes for the enzyme glutathione-S-transferase (GST). This enzyme plays an important role in the second phase of chemical metabolism commonly associated with detoxification of active metabolites formed in the first phase. Based on the reports published thus far in peer reviewed journals additional studies looking at the relationship between younger age at onset of Parkinson's disease, GST polymorphisms and neurotoxicant exposure appear warranted (Menegon et al., 1998; Golbe et al. 2007; Goldman et al., 2012; Pinhel et al., 2013).
An interaction between genetic factors that increase the risk for developing PD and exposure to chemicals has also been reported. Parkin polymorphisms and residential/occupational risk factors (pesticides, organic solvents, rural living) were found to be associated with a younger age at onset (Ghione et al., 2007).
An association between genetic variations encoding for the enzyme aldehyde dehydrogenase-2 (ALDH-2), pesticide exposure and Parkinson's disease susceptibility has also been reported (Fitzmaurice et al. 2014; Zhang et al., 2015).
A mutation in the gene encoding for solute carrier family 30 member 10 (SLC30A10), a protein which is highly expressed in the liver and inducible by manganese and has been implicated in a familial form of early onset parkinsonism associated with severe hypermanganesemia and bioaccumulation of manganese within nanovesicles of the Golgi apparatus (Quadri et al., 2015; Carmona et al., 2019). The role of this enzyme in idiopathic PD has yet to be fully elucidated.
Alzheimer's Disease and Age-Related Dementias
How genetic factors implicated in dementia interact with chemical exposures to influence the response of the nervous system and progression of subclinical or prodromal age-related amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is of particular importance to the pharmaceutical industry and those involved in setting public health policy (Ratner et al., 2021). Exposure to chemicals that promote or repress expression of genes implicated in aMCI and AD may therefore slow or hasten the progression of memory impairments (Pereira et al., 2016).
Alzheimer's disease occurs in three forms: familial, early onset and late onset. Late-onset AD is the most common type of AD and it is characterized by symptom onset in persons over the age of 65. Age at onset of late onset AD is influenced by multiple genetic factors. A study that did not stratify subject by type of AD found a decrease in GST activity in the amygdala, hippocampus, parahippocampal gyrus, inferior parietal lobe, and nucleus basalis of Meynert in the brains of AD patients at autopsy (Lovell et al., 1998). Although the cause of late-onset AD has not been fully elucidated interactions between environmental, genetic and lifestyle factors appear to be involved (Fratiglioni et al., 1993). Polymorphisms of the GST enzyme have been investigated in the age at onset of Alzheimer's disease (AD). Although studies looking at age at onset AD and history of neurotoxicant exposure and GST polymorphisms are lacking, a positive association between the GSTM1 null genotype and late onset AD has been reported suggesting that an interaction between environmental and genetic factors may play a role in this form of the disease (Piacentini et al., 2012).
The APOE ε4 allele modifies the association between lead (Pb) exposure (as quantified by tibia Pb levels measured by K-shell-x-ray fluorescence) and age-related cognitive decline in those individuals carrying both ε4 alleles (Prada et al., 2016). Bone Pb is a cumulative measure of lifetime exposure to this neurotoxic heavy metal. Mobilization of bone Pb continues for decades after cessation of exposures and bone lead mobilization is increased with osteoporosis (Silbergeld et al., 1988; Wilker et al., 2011).
The association between late in life environmental exposures to toxicants was recently assessed by Cacciottolo and colleagues in a US-wide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS) and in an experimental mouse model. These authors found that exposure to airborne particulate matter from traffic emissions increased dementia risk in older women and, that this outcome may involve a gene-environment interactions with APOE ε4 (Cacciottolo et al., 2017).
Huntington's Disease
Age at onset of Huntington's disease is influenced by an increase in the number of repetitions of three nucleic acids (C, A, and G). Variations in age at onset that cannot be attributed to trinucleotide repeat size, are attributable to modifier genes and environmental factors (Djoussé et al., 2003; Friedman et al., 2005). Sensitivity to environmental factors may play a greater role in those patients with with borderline numbers of CAG repeats (e.g., 39 repeats) (Friedman et al., 2005).
References:
Cacciottolo M, Wang X, Driscoll I, Woodward N, Saffari A, Reyes J, Serre ML, Vizuete W, Sioutas C, Morgan TE, Gatz M, Chui HC, Shumaker SA, Resnick SM, Espeland MA, Finch CE, Chen JC. (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry. 7(1):e1022.
Carmona A, Zogzas CE, Roudeau S, Porcaro F, Garrevoet J, Spiers KM, Salomé M, Cloetens P, Mukhopadhyay S, Ortega R. SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus. ACS Chem Neurosci. 2018 Oct 15. doi: 10.1021/acschemneuro.8b00451.
Djoussé L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, Ross C et al. (2003) Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. Am J Med Genet 119a: 279–282.
Fitzmaurice AG, Rhodes SL, Cockburn M, Ritz B, Bronstein JM. (2014) Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology. 82(5):419-26.
Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. (1993) Risk factors for late-onset Alzheimer's disease: a population-based, case-control study. Ann Neurol. 33(3):258-66.
Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. (2005) Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol. 62(6):995-997.
Ghione I, Di Fonzo A, Saladino F, Del Bo R, Bresolin N, Comi GP, Rango M. (2007) Parkin polymorphisms and environmental exposure: decrease in age at onset of Parkinson's disease. Neurotoxicology. 28(3):698-701.
Golbe LI, Di Iorio G, Markopoulou K, Athanassiadou A, Papapetropoulos S, Watts RL, Vance JM, Bonifati V, Williams TA, Spychala JR, Stenroos ES, Johnson WG. (2007) Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet. 144B(2):254-258.
Goldman SM, Kamel F, Ross GW, Bhudhikanok GS, Hoppin JA, Korell M, Marras C, Meng C, Umbach DM, Kasten M, Chade AR, Comyns K, Richards MB, Sandler DP, Blair A, Langston JW, Tanner CM. (2012) Genetic modification of the association of paraquat and Parkinson's disease. Mov Disord. 27(13):1652-1658.
Helou R, Jaecker P.(2014) Occupational exposure to mineral turpentine and heavy fuels: a possible risk factor for Alzheimer's disease. Dement Geriatr Cogn Dis Extra. 4(2):160-71.
Lovell MA, Xie C, Markesbery WR. (1998) Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease. Neurology. 51(6):1562-6.
Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG. (1998) Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet. 352(9137):1344-1346.
Pereira AC, Gray JD, Kogan JF, Davidson RL, Rubin TG, Okamoto M, Morrison JH, McEwen BS. (2016) Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry. (Epub ahead of print).
Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, Amorim GS, Florim GM, Mazeti CM, Martins DP, Oliveira Fde N, Nakazone MA, Tognola WA, Souza DR. (2013) Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease. Arq Neuropsiquiatr. 71(8):527-532.
Piacentini S, Polimanti R, Squitti R, Ventriglia M, Cassetta E, Vernieri F, Rossini PM, Manfellotto D, Fuciarelli M. (2012) GSTM1 null genotype as risk factor for late-onset Alzheimer's disease in Italian patients. J Neurol Sci. 317(1-2):137-40.
Prada D, Colicino E, Power MC , Weisskopf MG, Zhong J, Hou L, Spiro A, Vokonas P, Brenan K, Herrera LA, Schwartz J, Baccarelli AA (2106) APOE ε4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals. Environmental Research 151:101–105.
Quadri M, Kamate M, Sharma S, Olgiati S, Graafland J, Breedveld GJ, Kori I, Hattiholi V, Jain P, Aneja S, Kumar A, Gulati P, Goel M, Talukdar B, Bonifati V. Manganese transport disorder: novel SLC30A10 mutations and early phenotypes. Mov Disord. 2015 Jun;30(7):996-1001.
Ratner MH. A critical review of the interrelationships between genetics, neurotoxicant exposure, and age at onset of neurodegenerative diseases. Current Topics in Toxicology. 2016; (12):1-10.
Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, Robitsek RJ, Xia W, Farb DH. Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer’s disease. Heliyon, September 2021, 7(9): e07895.
Silbergeld EK, Schwartz J, Mahaffey K. (1988) Lead and osteoporosis: mobilization of lead from bone in postmenopausal women. Environ Res. 47(1):79-94.
Wilk JB, Tobin JE, Suchowersky O, Shill HA, Klein C, Wooten GF, Lew MF, Mark MH, Guttman M, Watts RL, Singer C, Growdon JH, Latourelle JC, Saint-Hilaire MH, DeStefano AL, Prakash R, Williamson S, Berg CJ, Sun M, Goldwurm S, Pezzoli G, Racette BA, Perlmutter JS, Parsian A, Baker KB, Giroux ML, Litvan I, Pramstaller PP, Nicholson G, Burn DJ, Chinnery PF, Vieregge P, Slevin JT, Cambi F, MacDonald ME, Gusella JF, Myers RH, Golbe LI. (2006) Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study. Neurology. 67(12):2206-2210.
Wilker E, Korrick S, Nie LH, Sparrow D, Vokonas P, Coull B, Wright RO, Schwartz J, Hu H: (2011) Longitudinal Changes in Bone Lead Levels: The VA Normative Aging Study. Journal of Occupational and Environmental Medicine 53(8):850–855.
Zhang X, Ye YL, Wang YN, Liu FF, Liu XX, Hu BL, Zou M, Zhu JH. (2015) Aldehyde dehydrogenase 2 genetic variations may increase susceptibility to Parkinson's disease in Han Chinese population. Neurobiol Aging. ;36(9):2660.e9-13.
Last update: January 2, 2023.
