The ALS Exposome in Nature Reviews Neurology

Just what is the exposome?

Eva Feldman, M.D., Ph.D., James W. Albers Distinguished University Professor and Russel N. DeJong Professor of Neurology, explains that it is the amalgamation of what comes into our body from the outside.

“It’s our environment, broadly defined, whether that’s climate, what you eat, what you're exposed to, and what you drink,” says Dr. Feldman. “The exposome really plays a major role, coupled with genetics, as to whether or not you're going to get the disease or not.”

That disease is ALS (Amyotrophic lateral sclerosis), a fatal condition of motor neuron degeneration.

Nature Reviews Neurology, one of the most prestigious academy journals, published “The amyotrophic lateral sclerosis exposome: recent advances and future directions,” in which Dr. Feldman and her team summarize the evidence for an ALS exposome, considering potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.

We have broken down the review into seven key points:

1.  Genetics cannot fully explain ALS, suggesting possible contributions from environmental factors to disease risk and progression.

2.  The gene-time-environment hypothesis of ALS: Genetic burden interacts or accumulates with environmental exposures over an individual’s lifetime to trigger disease.

1. 

   Nature Reviews Neurology, Figure 2: a,b, The gene–time–environment hypothesis of amyotrophic lateral sclerosis5 (ALS).

Nature Reviews Neurology, Figure 1: Studying the amyotrophic lateral sclerosis exposome.

3.  ALS multistep model of ALS: multiple ‘hits,’ possibly environmental in origin, conspire to trigger disease, notably in individuals who carry high-risk ALS mutations.

4.  Pesticides, metals, air pollution, occupational exposures, electromagnetic fields, trauma, gut microbiome, strenuous sports and physical activity, diet, and lifestyle factors point to influencing ALS risk (by population studies).

5.  How environmental factors trigger ALS isn’t completely understood, but research points to the involvement of neurotoxicity from specific environmental toxins, microbiome-mediated changes, inflammation, and excitotoxicity (i.e., excessive excitation of motor neurons).

Nature Reviews Neurology, Figure 3: Few studies have examined exposure-mediated pathophysiology in amyotrophic lateral sclerosis (ALS), although several possible mechanisms are emerging. a, Potential mechanisms of external exposures through metals, neurotoxins and air pollution.  b, Potential mechanisms of internal exposures in ALS through the microbiome and intensive physical activity. 

6.  Most environmental studies of ALS are retrospective, i.e., they use past data or questionnaires to ask ALS patients about past exposures, which may introduce uncertainty in the findings due to recall errors.

7.  Future environmental ALS studies will need to be prospective, i.e., query individuals at risk for ALS about their exposures in real-time until they develop ALS. This will capture data more accurately.

Nature Reviews Neurology, Figure 4: a, Advancement of amyotrophic lateral sclerosis (ALS) exposome science will require longitudinal studies of large, prospective, deeply phenotyped case–control cohorts of individuals at risk of developing ALS. b, Genetic profiles and ALS polygenic risk scores will also need to be generated to examine gene–environment interactions. 

“The exosome starts in utero,” says Dr. Feldman. “What you're exposed to from the day you're born will impact your disease risk for neurologic diseases like dementia, ALS, or Parkinson's disease.  By understanding the exposome, we can work to one day make them all preventable diseases.”