This open access paper is illustrative of a dogmatic mainstream of Alzheimer's disease research in which treatments must be immunotherapy approaches to clearance of amyloid-β or tau, or lifestyle changes and other means of management of risk factors such as blood pressure. Little else is acceptable. Yet many other lines of investigation do exist, such as drainage or filtration of cerebrospinal fluid, or tageting viral causes of amyloid-β accumulation, and some have progressed as far as development in biotech startups. They are nowhere to be found in this review paper.
Alzheimer's disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease.
While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as neurofibrillary tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development.
Here we focus on current AD therapeutic strategies which comprise of mechanism-based approaches including amyloid-beta (Aβ) clearance, tau protein deposits, apolipoprotein-E (ApoE) function, neuroprotection and neuroinflammation, as well as non-mechanism based approaches including symptomatic cognitive stimulation, AD prevention, lifestyle modifications, and risk factor management including non-pharmacological interventions.