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The environmental causes of Alzheimer's disease

Morbus Alzheimer has a complex aetiology determined by congenital and acquired factors. Until a few years ago, the molecular mechanisms underlying Alzheimer's-associated gene-environment interactions were largely unknown. In today's blog post, I would like to introduce the exogenous effects on the development of Alzheimer's disease, based on a recent article by Lucia Migliore and Fabio Coppedè published in Nature Reviews. In particular, these are pollutants that alter gene expression without damaging our DNA; in other words, they have an 'epigenetic' effect.

Epigenetics plays an important role in the theory proposed by David Barker on the origins of diseases. It states that exogenous factors can already take effect in the unborn child or infant and increase the risk of chronic diseases that occur later, such as obesity, diabetes or cardiovascular disorders. This also includes psychosocial stress, which can significantly impair brain development, especially in the first three years of life (see my blog post from June 16, 2022).

Epigenetic changes include enzymes attacking DNA and histones (DNA-associated proteins), e.g. methyltransferases and histone acetylases, which regulate gene expression. In addition, nucleic acids (non-coding RNAs) are also among the epigenetic factors that take effect outside the cellular nucleus. Life experiences and environmental influences thus leave epigenetic traces via changes in DNA and non-coding RNAs, which are passed on over several generations and, in combination with genetic data, can help to identify individuals with an increased risk of neurodegenerative diseases. However, it should not be forgotten in this context that the epigenetically active RNAs and enzymes themselves are in turn based on the genetically fixed DNA. How exactly we react to stress and environmental influences is therefore also determined in our innate blueprint.

Mutations in Alzheimer's-associated genes that code for the amyloid precursor protein APP or for the presenilins PSEN1 and PSEN2 lead to increased formation and deposition of Aβ-peptides, which play an important role in the pathogenesis of Alzheimer's (see chapter 2.3.2 in my book on Neurodegeneration). However, they occur only rarely. Carriers of the so-called APOE ε4 gene are found more frequently and have a threefold increased risk of developing the disease (in the presence of two copies of the APOE ε4 gene even a 15-fold increased risk). Genome-wide association studies (GWAS) have led to the further identification of over 40 DNA segments that are considered Alzheimer's risk areas. These include protein-coding genes (clusterin, PICALM, ABCA7, BIN1, ADAM10 and others).

It is known that many of these proteins are involved in inflammatory processes, Aβ degradation, tau aggregation, cholesterol metabolism, endocytosis or protein ubiquitination. However, with the exception of APOE ε4, most of the risk variants identified by GWAS make only a small contribution to the individual risk of Alzheimer's disease. In the majority of cases, the disease appears to be multifactorial, i.e. the result of interactions between various genetic and epigenetic changes that can be influenced by environmental factors.

Today, individual, so-called polygenic risk scores (PRS) can be determined and thus Alzheimer's risk profiles can be created. In addition, attempts are being made to carry out subject-specific environmental factor analyses, which also influence the risk of Alzheimer's disease. However, this mostly requires the use of data that are not based on objective measurements, but on questionnaires or interviews that do not provide reliable information on the dose and duration of an environmental trigger.

In general, the exogenous causes of neuronal degeneration discussed include metals and metalloids, which are known to inhibit the activity of DNA methyltransferases (DNMTs) and thus cause epigenetic changes. The heavy metals lead, mercury and cadmium as well as aluminium and the metalloid arsenic are known to be neurotoxic in higher concentrations. So far, however, no clear link between exposure to these substances and an increased risk of Alzheimer's has been established.

Other environmental exposures, including solvents, paints or fuels, have also been considered as potential risk factors for dementia, but are negligible based on statistical analyses. In addition, exposure to low-frequency electromagnetic fields (EMF) has been associated with an increased risk of Alzheimer's disease. However, this does not exceed the significance threshold either. A causal relationship between exposure to neurotoxic pesticides and cognitive dysfunction seems most likely: according to a meta-analysis of 31 studies, occupational exposure to pesticides increases the risk of developing a neurodegenerative disease by at least 50% (pesticides had previously been associated with Parkinson's disease rather than cognitive impairment).

Of particular importance are also studies on the exposure of pregnant women to arsenic, mercury and lead; but also hormonally active substances such as bisphenol A or generally unhealthy lifestyle habits such as smoking or excessive alcohol consumption cause epigenetic changes in the offspring, which are then passed on to subsequent generations via the germ line and can thus lead to a familial predisposition to neurodegenerative diseases. In addition, paternal causes have been identified that induce permanent epigenetic defects in sperm. The epigenome of spermatozoa becomes more unstable with age and more susceptible to stress and nutritional factors that can alter specific microRNAs (so-called miRNAs and Piwi-interacting RNAs) in spermatozoa and testes.

The first comprehensive work on a possible link between environmental risk factors in the air and the occurrence of dementia appeared in the 2010s. Comparing nitrogen oxides, carbon monoxide, tobacco smoke, particulate matter and ozone, there is particular evidence for a link with nitrogen dioxide (NO2). A systematic review of air pollution exposure in relation to dementia, which included 13 longitudinal studies with a follow-up period of up to 15 years, found that, in addition, particulate matter of particle size PM2.5 and carbon monoxide (CO) are associated with an increased risk of dementia.

Furthermore, high alcohol consumption and typical Western diets, i.e. excessive intake of saturated fat and sugar, lead to systemic changes associated with blood-brain barrier impairment, neuroinflammation, amyloid formation and cognitive impairment. In general, people who eat a diet rich in fruits and vegetables and high in flavonols have a lower risk of Alzheimer's disease. Numerous studies have demonstrated the antioxidant properties of polyphenols, which are commonly found in vegetables, fruits, tea and red wine. Interestingly, some research suggests that caffeine also has positive effects on Alzheimer's risk. Moderate amounts (100-400 mg of caffeine per day - consumed through coffee or green tea) reduce the risk of dementia and cognitive decline, especially in women.

Finally, there is evidence of the importance of vitamins influencing Alzheimer's pathogenesis through epigenetic mechanisms. For example, severe vitamin D deficiency is associated with an increase in dementia risk. Likewise, a folate and vitamin B12 deficiency leads to an increase in presenilin and BACE1 via demethylation of the corresponding DNA promoters and thus to increased Aβ production.

In summary, it can be stated that, in addition to psychosocial stress factors, our diet and exposure to air pollutants also significantly increase the risk of neurodegenerative disease via epigenetic changes. A healthy lifestyle protects against dementia and cognitive decline independent of known Alzheimer's risk factors such as APOE genotype.


Migliore L, Coppedè F (2022) Gene-environment interactions in Alzheimer disease: the emerging role of epigenetics. Nature Reviews Neurology 18:643

Image credit: iStock/Aaltazar


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