Suspected non-Alzheimer disease pathophysiology--concept and controversy

Abstract

Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to clinically normal individuals (who do not meet criteria for either mild cognitive impairment or dementia) and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be reliably inferred from the clinical presentation. SNAP is present in ∼23% of clinically normal individuals aged >65 years and in ∼25% of mildly cognitively impaired individuals. APOE*ε4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article, we describe the available data on SNAP and address topical controversies in the field.

Figure 1. Signature patterns of AD

Individuals with AD dementia (n = 50) were age-matched and sex-matched with cognitively normal elderly individuals (n = 50). a | ¹⁸F-FDG–PET maps (FWE threshold set at P <0,001) illustrate decreased FDG uptake in the basal temporal, lateral temporal–parietal, lateral prefrontal, and posterior cingulate–precuneus areas in individuals with AD dementia compared with cognitively normal elderly individuals. This spatial pattern constitutes an “AD-signature” in FDG PET. b | Structural MRI maps (FWE threshold set at P <0.05) illustrate grey matter loss in the medial, basal and lateral temporal, lateral parietal, occipital, insula, and precuneus areas in individuals with AD dementia compared with cognitively normal elderly individuals. This spatial pattern constitutes an “AD-signature” in structural MRI. All voxel-based comparison images were generated with SPM5. 3D displays were generated by Brain Net Viewer. The colour bar scale indicates the t-test differences between the groups. Abbreviations: AD, Alzheimer disease; FEW, family-wise error; L, left; R, right; SPM5, statistical parametric mapping. From Jack et al. 2013 with permission.

Figure 2. Imaging differences between preclinical AD stage 1 and SNAP

Left-hand column, clinically normal 75 years old woman with abnormal amyloid-β levels as seen by PET and normal brain structure as seen by MRI, who was diagnosed as having preclinical AD stage 1. Right-hand column, clinically normal 77 years old woman with normal amyloid-β levels as seen by PET and visually obvious atrophic hippocampi as seen by MRI, who was diagnosed as having SNAP. Abbreviations: AD, Alzheimer disease; SNAP, suspected non-AD pathophysiology.

Figure 3. Comparisons of clinical outcomes of individuals with preclinical AD and SNAP across different cohorts

The percentages of individuals within each group who progressed clinically from being clinically normal to having mild cognitive impairment or dementia are shown for four different studies. Abbreviations: AD, Alzheimer disease; ADC, Amsterdam Dementia cohort; ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCSA, Mayo Clinic Study on Aging; SNAP, suspected non-AD pathophysiology; Wash U, Washington University.

Figure 4. Topographic atrophy patterns

Patterns of atrophy rates in individuals enrolled in the Alzheimer Disease Neuroimaging Initiative, diagnosed as clinically normal, or with MCI or AD dementia. Left column, maps of atrophy rates from serial MRI in clinically normal elderly individuals who were amyloid-β-negative (as assessed by measurement of amyloid-β₄₂ levels in the CSF) and APOE4 negative. Middle and right columns, similar maps from individuals with MCI and AD dementia, respectively. The top-row images are left lateral surface. The bottom-row images are left medial surface views. Atrophy rates are scaled within each group and changes are displayed relative to within-group means. A common topographic pattern of standardized rates of change is present in the lateral and medial temporal lobe across groups. The rates of loss of brain volume in AD-signature regions are not necessarily associated with amyloid-β, nor with APOE4 carrier status, and therefore cannot be ascribed solely to AD but rather seem to be a feature of normal ageing. Abbreviations: AD, Alzheimer disease; MCI, mild cognitive impairment. From Fjell et al. 2013 with permission.