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