Current symptomatic and future disease-modifying treatments for Alzheimer's disease (AD) should be applied when the least neuropathological damage has yet occurred. The goal of this study is to evaluate the time point in the preclinical phase at which newly established cognitive biomarkers, magnetic resonance imaging (MRI), and/or functional MRI (fMRI) show first signs of impending AD.
Neurofibrillary tangles of pathological tau protein are one of the main characteristics of AD (Braak & Braak, 1991), interrupting neuronal functioning that is substantial for cognition (Kimura et al., 2007). The first cortical structure affected by neurofibrillary tangles in typical AD is the medial perirhinal cortex (mPRC; Braak & Braak, 1991; Taylor & Probst, 2008). While there is significant mPRC atrophy in patients with very early AD, the lateral aspect of the perirhinal cortex (lPRC) is only affected at a later stage (Krumm et al., 2016). Thus, we think that earliest diagnosis should focus on the mPRC, which is not yet the case in clinical routine. In previous studies we established several new neuropsychological tests, which are able to measure mPRC functionality. Further, the process of neural disintegration in AD is accompanied by neurobiological processes that partly compensate a macroscopic decrease in volume over a short time (e.g., gliosis; de Calignon et al., 2012). We think that MRI sequences that monitoring such processes (e.g. magnetization transfer ratio [MTR] imaging) might detect AD related alterations to brain structure earlier than e.g., routinely used volumetric or thickness measures (i.e. 3D T1-weighted scans). Alternatively, our fMRI paradigm, for which we use one of our newly established mPRC tests, might turn out to be the best option to detect impending AD as early as possible. 
In our baseline study, we assessed 406 cognitively healthy elderly
participants with neuropsychological tests, MRI, and some with fMRI. In the follow-up study we will asses roughly 360 of our baseline participants with the same multimodal panel of biomarkers to answer our main research questions: Are earliest signs of impending AD detected first by a) our new mPRC tests or by the commonly used neuropsychological instruments, b) MTR or by the commonly used T1, c) cognitive markers, MRI, or fMRI?
Literature on the mPRC is very scarce and no longitudinal study has yet focused on this region. Further, it is unknown to what extent (e.g. mean thickness) the mPRC atrophies within normal aging. Finally, we apply a new and highly innovative automatic segmentation protocol and we will apply multivariate markers to enhance predictive power for healthy aging vs. disease related cognitive decline. We believe that no matter the outcome, our study will not only provide lasting and significant benefits to research but will also advance our understanding of longitudinal trajectories in healthy aging and neurodegeneration and provide directions to improve the diagnostic process of AD.