Early-life events may trigger biochemical pathways for Alzheimer's disease: the "LEARn" model

Abstract

Alzheimer's disease (AD), the most common form of dementia among the elderly, manifests mostly late in adult life. However, it is presently unclear when the disease process starts and how long the pathobiochemical processes take to develop. Our goal is to address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we have recently proposed a "Latent Early-life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. This model integrates both the neuropathological features (e.g., amyloid-loaded plaques and tau-laden tangles) and environmental factors (e.g., diet, metal exposure, and hormones) associated with the disease. Environmental agents perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene and by affecting the methylation status within the promoter of specific genes.

Fig. 1

The LEARn Model. The LEARn model proposes a mechanism for interaction between genes and environment in early developmental etiology for AD. Promoter regions of genes, such as SP1, APP, and possibly BACE, provide the substrate for LEARn activity. Environmental factors such as exposure to Pb, nutritional deficiencies (e.g., folate or B12), or oxidative stress alter DNA epigenetically, by reducing the activity of enzymes such as DnMT, which would result in hypomethylation and reprogram gene expression. In some cases, this results in immediate alteration in gene expression levels. In LEARn systems, alterations are latent and effects are primarily notable later in life. In both immediate and LEARn systems, epigenetic changes in gene regulation result in disorder.