Fig. (3) presents an overview of selected findings to date. The model highlights the important role of mixed pathology and neural reserve in the development of clinical AD. It illustrates that some risk factors such as APOE, CR1, and CEPT lead to clinical AD in part through an association with AD pathology. However, it also shows that some other factors associated with the development of clinical AD such as parkinsonian signs, grip strength, frailty, and odor identification, are not risk factors at all. Rather they are likely to be early signs of AD and other pathology that manifest prior to the onset of dementia and in some cases prior to the onset of MCI. It is conceivable that these non-cognitive manifestations could be the sole clinical manifestation of AD pathology in some persons. By contrast, we have not been able to directly relate psychological and experiential factors to any known type of neuropathology. It is interesting that we have only identified genetic risk factors associated with AD pathology, and an ongoing genome-wide association study is examining additional genomic variants associated
