Alzheimer’s disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.

Keywords:
CD33, Alzheimer’s disease, Amyloid beta peptide, Neuroinflammation, Drug discovery
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