Although the statistical power is limited due to the low number of Ab+Ptau�C MCI participants, and bearing in mind that CSF measures are global and so do not fully inform on pathology within particular subregions, a possible interpretation of these findings is that elevation of the hippocampal Chlorhexidine hydrochloride atrophy rate is an early event occurring during the progression from the initial Ab�CPtau�C stage to the Ab+Ptau�C stage, with more widespread atrophy occurring at a later stage, when ptau pathology becomes evident. This interpretation is not obviously at variance with the Gomisin-D neuropathological evidence, which shows that the entorhinal cortex and hippocampus are both affected by NFT lesions in pre-clinical Braak stage II, additionally with scattered neuritic plaques appearing in the CA1 region, while substantial neuron loss for both regions appears to begin in later Braak stages when clinical symptoms manifest: 35% in the entorhinal cortex and 46% in CA1. It is possible, perhaps likely, that the Ab�CPtau�C MCI participants 
do not have prodromal AD, but that their cognitive impairment is due to some other condition, such as vascular dementia or hippocampal sclerosis. It is also interesting to note that annual atrophy rates for the 48 MCI Ab+MRI�C participants are relatively high, almost 2% per year for the entorhinal, amygdala, and hippocampus, even though these participants do not exhibit a baseline atrophy pattern indicative of AD. However, 39 of these 48 participants are also Ptau +, indicating that neuronal injury is likely taking place. Thus, although these participants have not yet lost substantial amounts of cortical tissues in AD-vulnerable areas, they are experiencing a rapid rate of degeneration in these areas. Due to the failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD, there is growing interest in conducting secondary and tertiary prevention trials and treatment trials for AD, targeting cognitively healthy individuals exhibiting biomarker evidence of the disease and those with mild cognitive impairment. In addition to arresting or slowing clinical decline, establishing disease-modifying properties of therapies will require demonstrating an effect on disease biomarkers. Structural MRI measures of change have emerged as the most promising biomarkers for detecting effects of therapy. The dominant component to structural atrophy is neuron loss, prior to which there will be synapse loss and reduction in neuropil complexity. In the preclinical stage of AD, cognition remains intact, reflecting the preservation of neurons, and structural atrophy on MRI is minimally different from that in older individuals who are not in the preclinical stage. In contrast, cellular biomarkers for AD, indicating advancing amyloid and tau pathologies, become manifest during this stage. Based on the observed atrophy rates in the HCs most likely to have preclinical AD, sample size estimates for preclinical trials are prohibitively large. Longer natural history studies of HCs likely to progress to AD are needed to inform on potential strategies for evaluating treatment effects in this group. It will also be important to take cohort age into account, as larger disease-related effects would be expected with younger cohorts. In contrast to the preclinical stage, effect sizes are large enough in MCI cohorts to render clinical trials quite feasible at this disease stage. However, given the heterogeneity in etiology and in rates of change in outcome measures across individuals categorized as MCI, enrichment in this disease stage offers important benefits. MCI participants testing positive for the AD atrophy pattern at baseline are likely to be more advanced along the disease trajectory than those testing negative.