Caleb E. Finch

Caleb E. Finch

Leonard Davis School of Gerontology and Dornsife College, University of Southern California, Los Angeles CA



Environmental influences on Alzheimer’s disease (AD) are under appreciated. The 25-year search for AD genes has clearly shown that dominant familial genes for early AD account for a small minority of cases less than 5% (Tanzi 2013). The largest common risk factor is the APOE4 allele which may account for another 15-20% of cases, mainly in women (Finch and Shams 2016). Human E4 carriers and mouse AD models show increased levels of the amyloid deposits, with female excess (Barnes 2005; Cacciottolo et al. 2016a). Major efforts continue to find new gene risk factors, which are generally rarer and of lower risk than ApoE4 (Tanzi 2013).

Tobacco smoking is also recognized as an environmental risk factor for AD by epidemiological studies: a meta-analysis of 23 prospective studies attributed 11% of later onset AD to smoking (Barnes and Yaffee 2011). Correspondingly, an AD mouse showed increased brain amyloid from short term tobacco smoke (Moreno-Gonzalez et al. 2013).

A new, but familar smoke may also be relevant. Automotive traffic derived air pollution (TRAP) is associated with increased dementia risk (Oudin et al 2016; Jung et al 2015). We extended these findings with the WHIMS cohort, in which older women residing in zones with PM2.5 from TRAP above the EPA standard of 12 ug/m3 had a 70% higher risk of dementia. Moreover, apoE4 carriers had up to 4-fold higher risk. At a population level, about 20% of dementia may be attributable to excess TRAP exposure. Correspondingly in an experimental model for exposure to TRAP, mice carrying human FAD genes in combination with human ApoE4 had higher brain amyloid than E3FAD mice (Cacciottolo et al. 2016b). Thus chronic inhalation of carbonaceous air particulates from fossil fuels or leaf tobacco show a similar magnitude of risk for AD (10-20%), and similar amyloidogenic responses of mouse models.

I suggest that these findings may guide the selection of AD patients or those at risk in future clinical trial. While the apoE genotype is under consideration in AD drug trials, there has been no mention of tobacco smoking or exposure to air pollution. The Alzheimer field recognizes the huge complexity of processes in AF that begin decades before clinical symptoms. We may need to expand thinking further with gene-environmental interactions. Lastly, I note that global human exposure to toxic carbonaceous particles from tobacco or fossil fuels is very recent, within 5-10 generations. Given the apparent absence of severe AD-like neurodegeneration in great apes (Finch and Austad 2015), one may ask: is AD a modern disease in association with these evolutionarily novel toxins?

Acknowledgements: I am grateful for support by the Cure Alzheimer’s Fund and the NIH (R01 AG051521; R21-AG040683). As a founder of Acumen Pharmaceuticals, I have received no support for these studies or any input in writing this essay.


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