Alzheimer’s disease (AD) is a neurodegenerative age-related progressive disease and the most common cause of dementia in the elderly.¹ Current estimates hold that there are upwards of 5 million people with AD in the US.² This number is expected to almost triple over the next few decades, and the worldwide incidence of AD will reach even more staggering proportions.² As the prevalence of AD grows, the accompanying economic and psychosocial costs related to acute hospitalizations, nursing home care, and care-giver stress will also escalate. Therefore, it is not surprising that efforts to understand the pathophysiology of AD and thereby derive effective treatments for this devastating disease have never been greater.

Over the last few decades a great deal of information has been learned about the underlying cellular and molecular pathology of AD. Since the early 1900s it has been recognized that the major pathologic hallmarks of AD are senile or neuritic plaques and neurofibrillary tangles, composed primarily of amyloid-beta (Aβ) peptide and hyperphosphorylated tau protein, respectively.³ The pathologic consequences of these lesions are synaptic dysfunction, neuronal loss, and gross cerebral atrophy.⁴

Several other AD-related pathologies have been identified, includinginflammation and microvascular deposition of Aβ (also known as amyloid angiopathy).⁴ These pathologic features are the targets of substantial drug development efforts that are aimed primarily at preventing the deposition of Aβ and/or abnormally phosphorylated tau, as described below.

Aβ Pathology
For at least two decades the primary focus of AD pathophysiology has been on the extracellular plaques containing a core of Aβ peptide that is 40–42 amino acids in length. Over the years a series of elegant studies have shown that the Aβ peptide is cleaved from a larger precursor molecule, the amyloid precursor protein (APP) (see Figure 1).⁵

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