Alzheimer's disease (AD) is the most common form of senile dementia that affects 5.4 million Americans, and at least $183 billion was spent in 2011 on management of AD and related dementia patients. The situation is worsening as our aging population is burgeoning. By 2050, the projected number of AD patients could range from 11 to 16 million people in the United States alone if neither effective cure nor preventive measure for AD is identified. As such, AD has quickly become a pandemic and exacted a huge socioeconomic toll [1]. The National Alzheimer's Project Act (NAPA) that has been passed by the Congress and signed by the President Obama is merely an urgent call for fighting these debilitating medical conditions. AD is manifested by a gradual onset of a progressive and irreversible cognitive decline. Memory impairment appears in the earliest stage of the disease followed by motor and sensory impairment in the later stages [2]. AD is a genetically complex disease. The majority of AD cases are sporadic while 5-10% of cases are early-onset familial AD (FAD) with an autosomal dominant inheritance pattern. The neuropathology of AD is characterized by the accumulation of insoluble Aβ amyloid peptides, neurofibrillary tangles (NFTs, the misfolded microtubuleassociated tau protein), neuropil threads, and neuronal losses in postmortem AD brains [3,4].As shown in the Figure 1 from one of our recent review paper [5], Aβ amyloid peptides (39-43 amino acid residues, ͌ 4 kDa), the main constituents of both senile plaques and cerebrovascular amyloid deposits [3,4], are generated from a much larger metalloproteinamyloid precursor protein (APP) [6][7][8]. APP cleavage by α-secretase generates neurotrophic APP(s), while its synergistic cleavage by β-and γ-secretases leads to production of a pool of Aβ peptides with carboxyl-terminal heterogeneity [9]: Aβ1-40 (40 amino acid residues) is the major soluble Aβ species, which is found in the CSF at low nanomolar concentrations [10]; Aβ1-42 (42 residues) is a minor Aβ species, but more neurotoxic than Aβ1-40, and is heavily enriched in interstitial plaque amyloid. However, the amyloid cascade hypothesis remains to be fully validated as AD is a polygenic and multifactorial complex disease [11]. Although exact AD etipathology remains to be fully elucidated, brain Aβ amyloidosis is still considered to be one of AD neuropathological hallmarks. A recent genetic study has identified a coding mutation (A673T) in APP gene. This mutation is close to β-secretase action site, and it can engender 40% reduction in Aβ amylodosis and protect against AD and cognitive decline in non-AD seniors. This provides further support for the essential role of Aβ amyloidosis in AD pathology [12]. However, environmental risk factors that directly interact with AD pathogenic pathways and contribute to AD pathophysiology are not well studied [11].Numerous experimental data indicate that abnormal brain metal metabolism is intimately involved in AD pathology [11,[13][14][15][16][17]. The gene expression profile of ...

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