Alzheimer’s disease (AD) is the most common cause of dementia and represents an enormous and growing global public health challenge. It is a uniformly fatal neurodegenerative disorder with no cure or substantially effective treatment. Alzheimer’s Disease International estimated that as of 2013, 44 million people had dementia worldwide, a figure which is expected to increase to 76 million people in 2030 and 136 million in 2050 because of the aging of societies globally (Alzheimer’s Disease International 2013). In the United States, the prevalence of AD in 2015 is estimated at 5 million people, a number which is anticipated to increase to 7 million in 2025 and to 14 million by 2050 (Alzheimer’s Association 2015). AD is strongly age-associated; for the great majority of patients the onset is 65 years of age or later, and half those over 85 may have AD.
The estimated worldwide cost of dementia was a staggering $604 billion in 2010, with about 70% of the costs being incurred in Western Europe and North America (Alzheimer’s Disease International 2013). Considering epidemiologic trends, massive increases in costs due to AD are anticipated globally in coming decades if no medical breakthroughs to prevent or cure the disease are developed.
Clinically, AD mainly manifests as progressive cognitive impairment, typically beginning as short-term memory impairment. Over time, it affects activities of daily living (ADL) and later the ability to perform even basic ADLs are lost. The time course is lengthy, with the dementia stage alone often spanning more than a decade. Not only does AD have a devastating impact on the quality of life for subjects and cause tremendous expense for society, but the protracted course of functional incapacity causes a terrible burden to caregivers, who are also typically elderly, and to other family members and loved ones.
Neuropathologically, AD is characterized by classic findings of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss/brain atrophy. Amyloid plaques contain substantial amounts of the amyloid beta (Aβ) peptide. Neurofibrillary tangles are intracellular structures composed of abnormally and extensively phosphorylated tau protein (p-tau); both plaques and tangles are believed to induce neuronal injury and neuronal death over time, but the correlation between Aβ deposition and the severity of cognitive impairment is relatively weak. While Aβ is widely thought to initiate AD, tau pathology is much more strongly associated with cognitive decline in AD. Interaction between Aβ and tau may also be important for disease progression. An important finding connecting Aβ and tau was the observation that tau is proteolytically cleaved at an aspartate residue (Asp421) in neurons exposed to Aβ. This cleavage produces the C-terminally truncated tau fragment tauC3.
A substantial body of research has demonstrated the importance of tauC3 in AD.