Current Alzheimer Research - Volume 4, Issue 2, 2007

Obesity and its related diseases are the leading cause of death in western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and breast, prostate and colon cancer. Recent epidemiologic data indicate an increased risk of Alzheimer's disease in association with adult obesity. There is now convincing evidence that, in both human and animal models, the in utero environment may impact on fetal developmental processes, altering offspring homeostatic regulatory mechanisms. “Gestational programming” may result in altered cell number, organ structure, hormonal set points or gene expression, with effects being permanent or expressed only at select offspring ages (e.g., newborn, adult). Our laboratory and others have demonstrated that low birth weight rats, induced by maternal food restriction or uterine artery ligation, paradoxically develop adult obesity with glucose intolerance and hypertension. Recent studies indicate alterations in peripheral (hepatic) and central (hippocampus) IGF-1 gene expression and epigenetic regulation among these offspring. These findings suggest that potential risk factors for the development of Alzheimer's disease may be present as early as newborn life.

Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are “protein-only”, they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur “late in the game”. Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a “Latent Early-Life Associated Regulation” (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

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This is with reference to the article entitled, “Quetiapine to Treat Agitation in Dementia: A Randomized, Double-Blind, Placebo-Controlled Study”, by Kate X. Zhong, Pierre N. Tariot, Jacobo Mintzer, Margaret C. Minkwitz and Nancy A. Devine, published in Current Alzheimer Research, February 2007, Vol. 4, No. 1, pp. 81-93. The authors unintentionally omitted to include the “Disclosure Information” in the article: DISCLOSURE INFORMATION Pierre N Tariot has received consulting fees and research support from Abbott Laboratories, Bristol-Myers Squibb, Janssen Pharmaceuticals and Eli Lilly & Company. He has also received consulting fees, research support and educational fees from AstraZeneca and Pfizer Inc and research support from the NIA, NIMH, Alzheimer's Association, Arizona Department of Health Services and the Institute for Mental Health Research. Jacobo E Mintzer is a paid consultant and speaker for Abbott Laboratories Inc., AstraZeneca Pharmaceuticals Co., Ltd, Bristol-Myers Squibb, Johnson & Johnson and Pfizer Inc.