Between 20% and 25% of patients diagnosed with Alzheimer's disease (AD) do not have amyloid burden as assessed by positron emission tomography imaging. Thus, there is a need for nonamyloid-directed therapies for AD, especially for those patients with non-amyloid AD. The family of phosphodiesterase-4 (PDE4) enzymes are underexploited therapeutic targets for central nervous system indications. While the PDE4A, B, and D subtypes are expressed in brain, the strict amino acid sequence conservation of the active site across the four subtypes of PDE4 has made it difficult to discover subtype inhibitors. The recent elucidation of the structure of the PDE4 N- and C-terminal regulatory domains now makes it possible to design subtype-selective, negative allosteric modulators (PDE4-NAMs). These act through closing the N-terminal UCR2 or C-terminal CR3 regulatory domains, and thereby inhibit the enzyme by blocking access of cyclic adenosine monophosphate (cAMP) to the active site. PDE4B-NAMs have the potential to reduce neuroinflammation by dampening microglia cytokine production triggered by brain amyloid, while PDE4D-NAMs have potent cognitive benefit by augmenting signaling through the cAMP/protein kinase A/cAMP response element-binding protein (CREB) pathway for memory consolidation. The importance of PDE4D for human cognition is underscored by the recent discovery of PDE4D mutations in acrodysostosis (ACRDY2: MIM 600129), an ultra rare disorder associated with intellectual disability. Thus, the family of PDE4 enzymes provides rich opportunities for the development of mechanistically novel drugs to treat neuroinflammation or the cognitive deficits in AD.