Elucidating the Risk Factors for Progression from Amyloid-Negative Amnestic Mild Cognitive Impairment to Dementia

Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer's disease from Alzheimer's disease-mimicking conditions. Around 15-20% of patients with clinically probable Alzheimer's disease have been found to have no significant Alzheimer's pathology on amyloid PET. However, a limited number of studies had been conducted on this subpopulation in terms of clinical progression.

We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI).

This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET.

During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer's diseaselike pattern despite the lack of evidence for significant Alzheimer's disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices.

Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer's disease-mimicking dementia are warranted.