Developing therapeutic vaccines against Alzheimer’s disease

ABSTRACT

Alzheimer’s disease (AD) is the most common form of dementia worldwide. It is characterized by an imbalance between the production and clearance of amyloid β (Aβ) and tau proteins. In AD these normal proteins accumulate, leading to aggregation and a conformational change forming oligomeric and fibrillary species with a high β-sheet content. Active and passive immunotherapeutic approaches result in dramatic reduction of Aβ pathology in AD animal models. However, there is much more limited evidence in human studies of significant clinical benefits from these strategies and it is becoming apparent that they may only be effective very early in AD. Vaccination targeting only tau pathology has shown benefits in some mouse studies but human studies are limited. Greater therapeutic efficacy for the next generation of vaccine approaches will likely benefit from specifically targeting the most toxic species of Aβ and tau, ideally simultaneously.

KEYWORDS:

• Amyloid-β
• tau
• immunotherapy
• neurodegenerative disease
• prion disease
• oligomers
• immunomodulation

Financial & competing interests disclosure

This manuscript is supported by NIH grants NS073502, AG20245 and AG08051. It is also supported by the Seix Dow Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Immunotherapy is an attractive therapeutic strategy for Alzheimer’s disease. Preclinical studies have shown that both active and passive approaches can remove amyloid and tau pathology and, in many cases, improve cognitive function.

• Numerous active and passive immunization strategies targeting Aβ have entered clinical trials. Aducanumab is the first monoclonal antibody to show clinical benefits on widely used measures such as mini-mental state examination and clinical dementia rating scale sum of boxes.

• A significant side effect of all passive immunization strategies targeting aggregated forms of Aβ is amyloid-related imaging abnormalities.

• Two active vaccines targeting either non-phosphorylated or phosphorylated tau have entered phase I testing.

• Alternative approaches of active or passive immunization targeting abnormal protein conformation are promising future therapeutic strategies, since these are capable of targeting amyloid and tau pathology simultaneously.

• Stimulation of the innate immune, which has been identified as a significant factor by genome-wide association studies in late-onset Alzheimer’s disease, is also showing promise as a therapeutic approach in preclinical studies.