A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.

By 2050, more than 13 million Americans of all ages are estimated to be living with Alzheimer's disease (AD), and the aggregate costs of care will swell to approximately $1.2 trillion. The rapidly climbing number of those affected with AD includes a growing population of aging military veterans affected who may have an added risk for the disease as a consequence of traumatic brain injury, posttraumatic stress disorder, and/or service-related injuries. The increasing number of individuals, the long duration of disability, and the rising cost of care for AD and other dementia to our society are important public health challenges facing many older adults. These challenges are further compounded by a burgeoning military veteran population that is much younger, with an increased risk of AD and other dementia, and who may experience decades-long periods of disability and care. This outlook underscores the critical need for investments in research at the federal and international levels to accelerate the pace of progress in developing breakthrough discoveries that will change the trajectory of AD and related dementia.

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