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Inverse correlation between Alzheimer’s disease and cancer: implication for a strong impact of regenerative propensity on neurodegeneration?

Jian-Ming Li, Chao Liu, Xia Hu, Yan Cai1, Chao Ma, Xue-Gang Luo and Xiao-Xin Yan
Source : BMC Neurology 2014, © 2014 Li et al.; licensee BioMed Central Ltd.
http://www.biomedcentral.com/1471-2377/14/211

Abstract

Background
Recent studies have revealed an inverse epidemiological correlation between Alzheimer¿s disease (AD) and cancer?patients with AD show a reduced risk of cancer, while cancer survivors are less likely to develop AD. These late discoveries in human subjects call for explorative studies to unlock the underlying biological mechanism, but also may shed new light on conceptual interrogation of the principal pathogenic players in AD etiology.

Discussion

Here we hypothesize that this negative correlation reflects a rebalance of biosynthetic propensity between body systems under the two disease statuses. In normal condition the body cellular systems are maintained homeostatically under a balanced cell degenerative vs. surviving/regenerative propensities, determined by biosynthetic resources for anabolic processing. AD pathogenesis involves neurodegeneration but also aberrant regenerative, or reactive anabolic, burden, while cancer development is driving by uncontrolled proliferation inherent with excessive anabolic activity. The aberrant neural regenerative propensity in AD pathogenesis and the uncontrolled cellular proliferative propensity in cancer pathogeneses can manifest as competitive processes, which could result in the inverse epidemiological correlation seen among the elderly.

Summary

The reduced prevalence of AD in cancer survivors may implicate a strong impact of aberrant neural regenerative burden in neurodegeneration. Further explorative studies into the inverse correlation between AD and cancer should include examinations of the proliferative propensity of tumor cells in AD models, and the development of AD-like neuropathology in cancer models as well as following anti-proliferative drug treatment.
Keywords: Aberrant neuroplasticity; Cell cycle activation; Neurodegeneration; Tumorogenesis

Background

Alzheimer's disease (AD) and cancer are major risk factors threatening human health and life especially in the elderly. AD is an age-dependent neurodegenerative disease, while the incidence of cancer is also dramatically increased with age. With the global population aging, AD and cancer become the leading causes of death in most societies across the globe [1],[2]. A number of recent studies have revealed a novel inverse correlation in the prevalence of AD vs. cancer in multiple ethnic groups [3]¿[11]. Such a phenomenon points to a certain biological/pathogenic interaction, likely some type of competitive cellular process, between the two disease conditions. Decoding this phenomenon may allow a better understanding of the governing pathogenic factors for AD and/or cancer, and could be also informative for the development of new therapeutical strategies for these diseases. Accordingly, it is of medical relevance to formulate hypothetical model(s) to facilitate mechanistic investigation into the AD/cancer relationship. AD and cancer are both complex conditions with numerous molecular and signaling anomalies occurring in multiple body systems. At the present, little information about the molecular links between the two conditions can be drawn from the human studies. Nonetheless, to understand the inverse correlation it can be benefited from an analysis of the major pathogenic features of the two disease conditions in reference to some basic cell biology principle(s). In this article we first review recent literature documenting the negative association between AD and cancer in human population-based studies. Next we elaborate some major pathological features of AD, with an emphasis on the coexistence of neurodegenerative and aberrant regenerative propensities in the brain...

Discussion

Reduced comorbidity between Alzheimer¿s disease and cancer in the elderly
The reduced comorbidity of AD vs. cancer in the elderly is recognized fairly lately, for less than ten years. In 2005, Roe et al. reported prospective longitudinal data showing a reduced risk of developing cancer among participants with dementia of the Alzheimer-type (DAT), and a reduced risk of developing DAT among individuals with a history of cancer [3]. A follow-up study by this group confirmed the inverse correlation of cancer with sporadic AD, but not with vascular dementia, among white older adults [4], attracting much attention in the field (see the September issue of Neurology, 2010). In 2012, similar findings are established in a community-based prospective cohort study (1278 participants in total) in the United States [5], and in a case¿control study (enrolled 126 AD patients and 252 matched controls) in Italy [6]. In 2013, a population-based longitudinal study (enrolled 1,102 adults with a mean age of 79 years) further shows that individuals with non-melanoma skin cancer have a reduced risk of developing AD [10]. In a large Italy-based cohort study (on more than 1 million Northern Italy residents), the risk of cancer in patients with AD dementia is found to be halved, while the risk of AD dementia in patients with cancer reduced one-third [8]. More recently, a population-based prospective study of 2,627 people without dementia aged 65 years and older shows that individuals with faster cognitive decline have a decreased risk of cancer mortality [11]. Besides western communities, a decreased incidence of overall cancers is observed among Chinese (with 6,960 patients enrolled) with sporadic AD [9]. Thus, the inverse correlation of AD with cancer in the elderly presents among different ethnic groups, and is likely irrelevant to environmental factors.

Summary

AD has become a global healthcare crisis due to population aging, while no promising preventive and therapeutic strategies are currently available for this disease. The inverse association between AD and cancer discovered in human population-based studies deserves a great attention in disease biology and translational research. Additional epidemiological studies should be carried out to further confirm this relationship, with stratified analyses applied to determine whether this phenomenon links to different cancer types and the use of cancer drugs. Experimental studies should start to explore how AD conditions may influence tumorogenesis, and the cellular and molecular mechanism thereof. Vice versa, additional studies should be conducted to determine whether, and if so, how, condition of cancer or anti-cancer drugs modulate AD-type neuropathology. The concept raised in this work may be informative for additional clinical and explorative studies to unlock the biological basis underlying the novel inverse correlation between AD and cancer seen in humans. Our hypothesis has put together multiple pieces of information (e.g., the major neuropathological events and some genetic/molecular modulations in AD, the Warburg-type energy metabolism in physiological and pathological cell replication and regeneration, and the potential effect of anti-proliferative chemotherapy) that appear to be coherent in regard to the mutual-competitive nature of AD vs. cancer development. Obviously, much additional effort is needed to develop other conceptual models in order to fully unlock the mystery behind the AD/cancer inverse association.
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