Diagnostic Images for Mild Cognitive Impairment Are Sensitive to Alzheimer's Disease Biomarkers and Reveal Abnormal Scene Processing

Abstract Research on visual episodic memory impairment in Alzheimer's disease often focuses on memory processes rather than the specific content of the images being remembered. We previously showed that patients with mild cognitive impairment (MCI), a transitional stage that may precede Alzheimer's disease, can memorize certain images well, indicating that episodic memory is not uniformly impaired. Conversely, other specific images could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for these diagnostic images relates to impaired neural processing in specific brain regions and Alzheimer's biomarker pathology. We assessed 64 healthy controls and 48 MCI participants from the DZNE Longitudinal Cognitive Impairment and Dementia Study. Participants performed a visual scene memory task during fMRI and provided cerebrospinal fluid biomarker data for amyloid and tau. Diagnostic images demonstrated significantly larger behavior–biomarker correlations (total tau, phospho-tau, Aβ42/Aβ40, and Aβ42/phospho-tau) compared with nondiagnostic images. This suggests memory for these specific diagnostic images is more affected by Alzheimer's disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control/MCI) and image diagnosticity (diagnostic/nondiagnostic). MCI participants exhibited higher activation in scene-processing regions (parahippocampal place area, retrosplenial cortex, and occipital place area) for diagnostic compared with nondiagnostic images. Healthy controls, however, showed no processing differences between diagnostic and nondiagnostic images. These findings suggest MCI individuals may engage in inefficiently heightened encoding activation for diagnostic images. Our results show that special “diagnostic” images exist that can reliably reveal underlying amyloid and tau pathology alongside altered neural activity in scene regions.