Alzheimer’s disease syndrome – Recognizing the complexity of dementia

Abstract

Therapies designed to disrupt amyloid plaque deposits or prevent their formation have yielded disappointing results against cognitive failure, suggesting that both our mechanistic models of dementia and interventions must become more nuanced. These treatments targeted Aβ40/42, but the amyloid accumulated in Alzheimer's disease patients is modified extensively and far more structurally diverse. Despite intensive work, the structure and physical state of the most toxic amyloid species remains mysterious. In addition, multiple lines of evidence suggest the genesis and progression of dementia is more complicated than the accumulation of senile plaques beyond a tolerable threshold. If amyloid plays key, but non-exclusive, roles in dementia pathogenesis this hypothesis must be addressed through investigations that are more holistic in scope. New imaging methods provide investigators unprecedented capabilities to detect and classify neuropathology in living subjects. Interpreting future clinical trial outcomes will hinge on correlating effects against dementia in subject cohorts that are precisely differentiated with respect to neuropathology and neurochemistry. Improving understanding of the comorbidities and the environmental/lifestyle factors foreshadowing cognitive failure will aid in the interpretation of clinical trials. Most important, as we seek an elusive cure for AD, these findings may be rapidly translatable into concrete and achievable public health improvements.