Abstract
Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets for discovering disease-modifying treatments. Past studies of AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent studies have provided an increasingly rich harvest of genetic, molecular and cellular data that are creating unprecedented opportunities to both understand and treat AD. Among the most significant are those documenting the presence within the AD brain of toxic oligomeric species of Aβ and tau. Existing data support the view that such species can propagate and spread within neural circuits. To place these findings in context we first review the genetics and neuropathology of AD, including AD in Down syndrome (AD-DS). We detail studies that support the existence of toxic oligomeric species while noting the significant unanswered questions concerning their precise structures, the means by which they spread and undergo amplification and how they induce neuronal dysfunction and degeneration. We conclude by offering a speculative synthesis for how oligomers of Aβ and tau initiate and drive pathogenesis. While 100 years after Alzheimer’s first report there is much still to learn about pathogenesis and the discovery of disease-modifying treatments, the application of new concepts and sophisticated new tools are poised to deliver important advances for combatting AD.
Highlights
It is increasingly apparent that Alzheimer disease (AD) pathogenesis is more tightly linked to toxic assemblies of the proteins that contribute to amyloid plaques and neurofibrillary tangles (NFTs) than to these structures themselves
More than 100 years after Alois Alzheimer report of a patient whose disorder bears his name, and in spite of detailed neuropathological studies and 40 years of robust research investments in AD, there is much to learn about pathogenesis and the need for disease-modifying treatments continues
The use of a variety of cell types, ability to generate cells in very large numbers, robust differentiation paradigms and gene editing tools to create isogenic lines have greatly enhanced the value of induced pluripotent stem cells (iPSC) for modeling childhood and monogenetic diseases
Summary
AD is the most common cause of dementia, accounting for up to 70% of cases (Plassman et al, 2007). Distinct from FAD cases are those of early onset (i.e., age less than 65) in which there may be no family history and in which no definite genetic risk factor can be defined. Such cases are referred to as young onset AD (YOAD). In addition to mutations that cause AD – i.e., those in PSEN1, PSEN2, and APP, a number of genetic factors have been discovered that confer increased risk of AD. Increased risk of AD is correlated with age, head injury in males, diabetes, smoking, and lower social engagement (Hersi et al, 2017)
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