University of Kentucky Background
Alzheimer’s disease (AD) is one form of dementia that affects memory, thinking and behavior, and gradually worsens over time. About 4 million Americans are diagnosed with Alzheimer’s disease resulting in an economic burden of over $100 billion annually. These numbers are expected to rise as the population continues to quickly age at an unprecedented rate. It is predicted that the prevalence of the AD population will reach 14 million by 2040 unless successful preventative strategies are developed. Most clinical trial failures targeted the Beta Amyloid pathway and so there is a need for identification of new targets and development of drugs targeting other pathways/mechanisms. Recent studies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD.
There is a need to develop novel drugs targeting the immune system of the brain to combat 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. CD33 (a sialic acid binding transmembrane receptor important for phagocytosis and Aβ clearance, found in microglia) is one of the top-ranked AD risk genes identified by genome-wide association studies. Alzheimer’s disease (AD) is a large and increasing unmet medical need with no disease-modifying treatment currently available. Genetic evidence from genome-wide association studies (GWASs) and gene network analysis has clearly revealed a key role of the innate immune system in the brain, of which microglia are the most important element.
Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer’s disease (AD). UK researchers have discovered a novel genetic polymorphism in CD33 that protects from AD by decreasing full length CD33. Full length CD33 impairs phagocytic clearance of microglia to clear Aβ particles. The newly discovered polymorphism increases the proportion of CD33 expressed as a truncated CD33 receptor that lacks the sialic acid ligand-binding domain, reducing the AD risk. This is an important discovery suggesting that blocking functional CD33 and its associated immune suppression will be protective from Alzheimer’s disease. The patent proposes the use of monoclonal antibodies to inhibit CD33 to reduce AD pathogenicity and risk.
M. Malik et al, CD33 Alzheimer’s risk-altering polymorphism, CD33 expression and exon 2 splicing. J. Neurosci. Vol 33: pp. 13320-05, 2013. PMC3742922
M. Malik et al., “Genetics of CD33 in Alzheimer’s disease and acute myeloid leukemia,” Hum. Mol. Genet., vol. 24, no. 12, pp. 3557–3570, 2015.
S. Estus et al, Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol. Vol. 138: pp. 187-199.PMID: 30949760
Blocking the receptor (CD33) is more feasible than altering protein structure or enzymatic activity as a treatment option for Alzheimer’s disease.
CD33 antibodies (lintuzumab and gemtuzamab) have been tested in extensive human clinical trials for cancer and found to be safe. Gemtuzumab ozogamicin is FDA approved for cancer therapy. They could be repurposed for Alzheimer’s Disease.
Treatment of Alzheimer’s disease.