Abstract
The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, characterized by an initial loss of short-term memory, followed by a progressive impairment in multiple cognitive domains
Several genetic risk factors have been linked with an increased risk of developing AD, such as mutations in the amyloid precursor protein (APP) and presenilin (PS) 1 and 2 for the familial cases of AD (FAD), as well as the APOE4 allele for the sporadic late-onset form of AD (LOAD)
These sections begin with a brief description of the epidemiological evidence in AD and continue with describing the findings from experimental animal studies in which the environmental factor was manipulated in AD transgenic mice and, when performed, in wild-type (WT) mice
Summary
Alzheimer’s disease (AD) is the most common form of dementia, characterized by an initial loss of short-term memory, followed by a progressive impairment in multiple cognitive domains. Various environmental exposures have been found to modify the risk of AD, such as diet and International Journal of Alzheimer’s Disease nutrition, physical exercise, exposure to metals, and brain trauma. Comorbidities, such as vascular disorders or depression, could be of considerable importance, since these have been suggested to contribute to the risk of AD. The main part of the paper describes the effects of several environmental exposures on AD-related phenotypes These sections begin with a brief description of the epidemiological evidence in AD (when available from meta-analyses) and continue with describing the findings from experimental animal studies in which the environmental factor was manipulated in AD transgenic mice and, when performed, in wild-type (WT) mice. Thereafter, we discuss the strengths and limitations of these studies, and we end with identifying future challenges and prospects
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