**6. Future directions**

The potential benefits for complete definition of microglial phenotypes by immunohistochemistry in human brains could be significant. The development of effective inflammationfocused therapies for AD requires the identification of therapeutic targets that are relevant to the human disease, not to models of disease in a transgenic animal or cell culture. AD is a uniquely human disease of the elderly, with pathology having developed for years before dementia becomes observable. In transgenic models, disease pathology can develop over weeks. There have been many agents that can reverse plaque development and inflammation in AD mice models that have failed to be effective in humans. There are many challenges involved in human focused studies, but the benefits of having human disease targets validated in human tissue could involve significant saving in time and resources from pursuing the wrong approaches. Immunohistochemistry is not considered a state of art technique in the twenty-first century as the technologies have not much changed in 30 years, but ultimately it is required to show that gene discovery findings are valid. The need for large numbers of high quality human tissue samples has been one limitation, but this can be addressed by collaborative studies. Brain tissue that has been consistently prepared with appropriate clinical and pathological records allow studies involving progressive changes in pathology from negligible to severe rather than the less useful classification of control or AD. There is also a need for improved expectations on the performance of antibodies. The performance and reproducibility of antibodies in all biological experiments has been a growing concern [70], but ultimately it is the responsibility of the experimenter/pathologist to determine the suitability of antibodies used to make a unique observation. The field of neuroinflammation in AD has been reinvigorated with discoveries about TREM-2 having a direct link to AD risk. To be able to reliably identify TREM-2 positive microglia in brain is needed to fully understand its role in sporadic AD, and validate the large numbers of model studies that have proposed therapeutic strategies for AD focused on TREM-2.
