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J Alzheimers Dis. 2017;58(3):747-762. doi: 10.3233/JAD-170201.

Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer's Disease Pathology.

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Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.
Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada.
Department of Psychiatry, University of Toronto, Toronto, Canada.
Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada.
The Jikei University School of Medicine, Tokyo, Japan.
Cerebral Imaging Centre, Douglas Mental Health Institute, McGill University, Montreal, QC, Canada.
Department of Psychiatry and Biomedical Engineering, McGill University, Montreal, QC, Canada.


Suspected non-Alzheimer's disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer's Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND-), neither amyloid nor hypometabolism (Aβ-ND-), and SNAP (Aβ-ND+). Aβ+ND+(n = 33), Aβ+ND-(n = 32), and Aβ-ND-(n = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n = 40) were also matched to SNAP for age, gender, and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ-ND-and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ-ND-and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ-ND-and controls, 2) no differences with Aβ+ND-, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades.


Functional decline; hippocampus; mild cognitive impairment; suspected non-Alzheimer’s pathology

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