Invited Perspective: Long-Lasting Legacy of Banned Contaminants in Alzheimer's Disease Etiology-Convergence of Epidemiological and Toxicological Findings.

Alzheimer’s disease and related dementias (ADRD) are among the most dreaded diseases because of their devastating effects on cognitive function and the limitations of treatments in significantly modifying the disease course. The genetics of ADRD have been intensely investigated, especially with respect to Alzheimer’s disease (AD), with both mutations and risk-modifying polymorphisms identified.[1] Although highly penetrant mutations responsible for familial AD have been identified, the vast majority of cases are deemed sporadic, arising from unknown causes.[2,3] The identification of significant modifiable risk factors could have a major impact on the public health crisis of ADRD, which impacts patients, families/loved ones, and the economy. The avoidance of such risk factors could potentially lessen the number of future cases. Moreover, with an increased understanding of gene–environment interactions (alongside the rise of genetic testing), individuals with specific susceptibilities could be cautioned to avoid certain exposures. Such an impact is the scientific hope of many epidemiologists and toxicologists.

In this issue of Environmental Health Perspectives, Richardson et al.[4] report a significant translational advance in understanding the possible role of pesticides in AD. They focus on dichlorodiphenyltrichloroethane (DDT), which was widely used as a pesticide in the United States from the 1940s to the 1970s; although banned in 1972, occasional emergency use has occurred since.[5] Current and emergent exposures rightfully garner much attention. However, DDT is known to have long environmental and biological half-lives, exemplifying that legacy exposures also deserve continued attention.[6,7] Collectively, Richardson’s and others’ work undeniably shows that even when a toxic chemical is banned, the risk (possibly specific to neurological disease) it poses may (and often likely does) extend for decades, if not far longer.[4,8,9]

When considering the association between an environmental exposure and an adverse outcome, the strength of that association depends on both epidemiological and toxicological findings, which generally have complementary strengths and weaknesses.[10] For example, with an epidemiological study, it can be difficult to discern if unknown/unmeasured exposures contributed to an observed adverse outcome or if the disease state itself modulated the absorption, distribution, metabolism, and excretion (ADME) of the agent under study, producing higher blood levels of a biomarker.

In a case–control study published in 2014, Richardson’s group showed that DDT metabolite levels were higher in AD patients and that there was an interaction with a genetic risk factor ().[8] In their current paper, Richardson et al.[4] complement human studies through detailed animal exposure experiments, which together have high translational value for understanding how DDT may influence AD etiopathogenesis. This study was conducted in three overarching systems: cell culture (lines and primary mouse neurons), Drosophila melanogaster fly strains, and transgenic mice. Given that each animal model system has both known and unknown strengths and weaknesses, testing across model systems likely increases translational value.

Moreover, the in vivo dosing strategy achieved brain DDT levels similar to those that occurred in human adipose tissue in the 1960s,[11,12] an effort that was laudable for achieving dose relevance. For reference, people who were infants, children, or teenagers in 1960 would now be 62–80 years of age, a period when the risk for AD exponentially increases.[13] Exposures at these relevant doses produced alterations in multiple AD genes in wild-type mice and increased AD pathology (amyloid beta) in AD transgenic mice, findings that were confirmed in fly and cell culture models.

These findings further support the likelihood that DDT exposure may play a role in the etiopathogenesis of AD. It will be fascinating to learn whether other critical AD pathways, such as the tau protein pathway, are affected and whether there are critical windows of sensitivity (specific developmental origins of adult adverse neurological outcomes). These are especially important questions given that the highest exposures may have occurred many decades prior to clinical outcomes and subsequent diagnosis.

A key mechanistic finding is the role of voltage-gated sodium channels in mediating DDT-induced AD-relevant neurotoxicity, where blockage of tetrodotoxin-sensitive channels was protective.[3] The identification of sodium channels as a key target of DDT neurotoxicity[14-16] and the emergence of a potential role of sodium channels in modulating AD-relevant enzymes and amyloid beta release (possibly through prolonged opening, leading to hyperexcitability and network dysfunction)[17-21] both raise significant questions for future research. Could specific aspects of sodium channel signaling be a pharmacological target for those with high blood DDT concentrations that may be at risk for AD? Do the DDT study results apply more broadly to other environmental exposures and AD, or to AD pathogenesis in general?

Although blockage of sodium channels (as with tetrodotoxin) is not a viable clinical approach, the results, taken together with previously published literature, identify a possible physiological therapeutic pathway. For example, one recent study showed that knockdown of the tetrodotoxin-sensitive -subunit Nav1.6 was protective of the AD phenotype in transgenic mice, where protection was found to be through modulation of the -site amyloid precursor protein-cleaving enzyme 1 (BACE1).[22]

In summary, the use of human data to inform laboratory studies on AD etiopathogenesis, along with studies in multiple complementary models, has achieved a key mechanistic advance with potential high translational value. These findings also remind us that even after an agent is banned, our work as epidemiologists and toxicologists is far from over, especially as it relates to chemicals with long environmental and biological half-lives linked to diseases thought to develop over many decades.