Neuropsychological and neuroimaging characteristics of patients with mild cognitive impairment and negative-amyloid deposition

Objectives Accumulating studies have reported that some mild cognitive impairment (MCI) patients without significant β-amyloid (Aβ) deposition on amyloid positron emission tomography (PET) can later develop Alzheimer’s disease (AD). Therefore, this study profiled the cognitive and neural characteristics of MCI patients with negative Aβ deposition to better understand potential features associated with an increased risk of AD progression. Methods Thirty-seven MCI patients and 32 normal controls (NCs) underwent neuropsychological assessments, structural magnetic resonance imaging, and diffusion tensor imaging scans. MCI patients were stratified into amyloid-positive (Aβ pos ; n = 18) and amyloid-negative (Aβ neg ; n = 19) groups based on 18 F-florbetapir PET. We compared cognitive performance, white matter (WM) integrity, and gray matter volume (GMV) across the three groups and further examined the interplay among brain structural alterations and cognitive changes. Results Cognitively, relative to NCs, participants in Aβ neg MCI group showed significant deficits in multiple cognitive domains including episodic memory, attention, and executive function, as those in Aβ pos MCI group did. Both MCI subgroups exhibited extensive disruptions of WM integrity. Direct comparisons between the Aβ neg and Aβ pos groups revealed that Aβ-related structural changes were predominantly localized to the left hippocampus and adjacent regions. The increased Aβ deposition was closely associated with elevated mean diffusivity in the left hippocampal portion of the cingulum and reduced GMV of the left hippocampus. Moreover, the GMV of hippocampus could mediate the impact of WM disruption on episodic memory performance. Conclusion Aβ neg MCI patients who exhibit AD-like cognitive and structural abnormalities, particularly involving the hippocampus, may be associated with advanced cognitive decline or dementia progression. These results may help identify high-risk individuals within the heterogeneous Aβ neg MCI population.