The molecular mechanisms underlying the onset and progression of Alzheimer?s disease (AD) are not well understood. Microarray technology was utilized to isolate disease-specific changes in gene expression by sampling across inferior parietal lobes of patients suffering from AD or non-AD-associated dementia and non-demented controls, with a primary focus on understanding how inflammation might play a role in AD pathogenesis. Data was subsequently validated on an expanded set of samples. Gene ontology analysis revealed that the most differentially expressed genes related to nervous system development and function and neurological disease, followed closely by genes involved in inflammation and immunological signaling. Pathway analysis also implicated a role for chemokines and their receptors, more specifically CXCR4 and CCR3, in AD pathogenesis. Immunohistological analysis revealed that these chemokine receptors are significantly upregulated in AD patients. Western blot analysis demonstrated an increased activation of PKC, a downstream mediator of chemokine receptor signaling, in the majority of AD patients compared to control subjects. Moreover, a very specific cohort of genes related to amyloid beta accumulation and clearance were found to be significantly altered in AD versus control subjects. The most significantly down regulated gene in this neuronal gene data set was the endothelin converting enzyme 2 (ECE2), an enzyme implicated in beta-amyloid clearance although loss of ECE expression has yet to be demonstrated in human AD tissues. ECE2 expression was significantly down-regulated in the microarray dataset of AD samples and these data were subsequently confirmed by real time PCR and Western blot analysis. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and amyloid clearance in AD patients.