CDK5 and Alzheimer disease: However, the lack of specificity, recognition of potential postmortem confounds in human AD studies, and possibility that chronic inhibition of Cdk5 might lead to neuronal hyperexcitability and epileptiform seizures, as found in aged Cdk5 conditional knockout mice, all contributed to impedance in the pursuit of anti-Cdk5 therapeutics, leaving first- and second-generation compounds, which had poor brain permeable systemic properties, unsuitable for in vivo study (Yoo and Lubec, 2001; Hawasli et al., 2009).