Pesticides and Development of Alzheimer’s Disease — New Evidence
Abstract & Commentary
By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
Dr. Isaacson reports that he is a scientific advisor/consultant for Novartis and Accera.
Synopsis: A new case-control study finds that increased levels of dichlorodiphenyldichloroethylene (DDE), which is the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), are associated with an increased risk for Alzheimer's disease. In addition, carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE.
Source: Richardson JR, et al. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol 2014;71:284-290.
The search for any of the myriad of potential "causes" of Alzheimer’s disease (AD) has continued in the right direction with the recent article by Richardson and colleagues from Emory University's Alzheimer’s Disease Research Center and the University of Texas Southwestern Medical School’s Alzheimer’s Disease Center. While the etiology of AD is yet unknown, it is highly likely that a combination of genetic, environmental, and lifestyle factors influence a person’s risk. Richardson et al have expanded on their past pilot work to find the most definitive proof of an association between pesticide exposure and the development of AD.
Over the last decade, great progress has been made in determining modifiable and non-modifiable risk factors involved in the development of AD, as well as pharmacogenomics and nutrigenomic considerations for AD management.1 While APOE4 is the most commonly known and most well-understood gene associated with late-onset AD, and Presenilin-1, Presenilin-2, and amyloid precursor protein gene mutation are the most common for early-onset cases (comprising ~6% of total AD cases), more than 10 genes now have been found to be involved in the development of AD. In addition, a variety of epigenetic mechanisms play a role, including changes in the expression of thousands of genes and upregulation of several pathologic pathways (e.g., beta-amyloid deposition, tau hyperphosphorylation, inflammation, oxidative stress, and energy metabolism).2
The objective of the Richardson study was to further investigate the potential role of serum pesticide levels and to determine whether the apolipoprotein E (APOE) genotype modifies an association. Past epidemiological research has suggested that exposure to pesticides is associated with AD, and a prior pilot study (n = 20) found that serum levels of DDE were elevated in AD patients.
In this two-site, case-control study consisting of 86 AD cases and 79 controls, serum levels of DDE were measured and degree of cognitive impairment was assessed via Mini-Mental State Examination (MMSE) scores. While DDE was detected in 70% of controls and 80% of AD cases, mean DDE levels were 3.8-fold higher in the AD cases. MMSE scores were significantly lower in the highest DDE-tertile. A significant interaction between serum DDE levels and APOE status was also found, compared with those without an ε4 allele. Since serum DDE levels did not differ by genotype, this suggested a functional
interaction.
Commentary
Although further research is warranted, the mechanistic explanation of why pesticide exposure (DDT/DDE) would increase AD risk is rooted in their propensity to increase amyloid precursor protein. From a practical clinical perspective, it is unclear at this time whether to suggest to patients at risk for AD to avoid potential exposure to DDT. It is important to note that in the United States, the Environmental Protection Agency banned the use of DDT in 1972 due to safety concerns; however, many other countries throughout the world continue to allow DDT. The impact of DDT on AD risk is still a consideration due to an exceptionally long half-life (8-10 years) and additional exposure from food imports from abroad where DDT is still used, or from legacy contamination of soil and waterways in the United States. While it is unclear whether recommending that patients at risk for AD preferentially select organic foods, this recommendation may deserve consideration in certain circumstances (balanced by a generally increased cost of organic food). Additionally, from a diagnostic perspective, elevated levels of DDE and APOE ε4 allele positivity may in the future lead to earlier identification of some cases of AD.
References
- Oboudiyat C, et al. Alzheimer’s disease: Pathophysiology and targeted therapeutic approaches. Sem Neurol 2013;33:313-329.
- Mastroeni D, et al. Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 2011;32:1161-1180.
