SNAP Not Linked to Early Alzheimer’s Disease

Suspected non-Alzheimer disease pathophysiology (SNAP) does not appear to be linked to early Alzheimer disease processes.

Suspected non-Alzheimer disease pathophysiology (SNAP) is not associated with accelerated longitudinal β-amyloid (Aβ) accumulation or amyloid-independent tauopathy, according to 2 studies published in JAMA Neurology.

SNAP encompasses clinically normal individuals who have markers of neurodegeneration (ND) but no evidence of Aβ deposition in the brain. These people also do not fall into one of the 3 stages of preclinical Alzheimer’s disease (AD) as defined by the National Institute on Aging-Alzheimer’s Association (NIA-AA) research criteria.1 The etiology of SNAP and whether SNAP is a marker of early AD are unclear.1,2

To determine whether SNAP may eventually develop into AD, Brian A. Gordon, PhD, and colleagues of Washington University in St. Louis in St. Louis, MS compared longitudinal Aβ accumulation and hippocampal atrophy in cognitively normal adults with SNAP vs those with preclinical AD.1

A total of 174 cognitively-normal participants were followed for up to 7 years after obtaining baseline MRI scans, PET scans with carbon 11–labeled Pittsburgh Compound B (PiB), and tau and phosphorylated tau (ptau) levels in cerebrospinal fluid. Baseline ND was defined using tau and ptau levels and hippocampal volume. Longitudinal Aβ accumulation was measured using hippocampal volume on MRI and PiB PET.

Participants with SNAP (Aβ-/ND+) did not demonstrate any differences in rates of Aβ accumulation or loss of hippocampal volume compared with participants without pathologic features at baseline (NIA-AA stage 0; Aβ-/ND-). Individuals with stage 1 (Aβ+/ND-) or stage 2+ (Aβ+/ND+) had accelerated Aβ accumulation and hippocampal volume loss compared with individuals with SNAP.

“SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of tau or ptau in isolation may not accurately represent ongoing neurodegenerative processes,” the authors wrote.

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In a second study, Elizabeth C. Mormino, PhD, and colleagues of Massachusetts General Hospital in Boston sought to determine whether SNAP in cognitively normal individuals was associated with early AD as measured by tau levels and risk for cognitive decline.2

A total of 247 participants from the Harvard Aging Brain Study were followed for up to 5 years. The SNAP group had tau levels on PET scan in the medial and inferior temporal lobes similar to those of stage 0 participants (P ≥ .88) but lower than those of stage 2 participants (P ≤ .02).

Compared with the stage 0 group, the SNAP group had a diminished practice effect over time on cognitive performance testing, which was associated with higher subthreshold PiB values (P = .001) and lower hippocampal volume (P = .002). Cognitive decline in stage 2 participants was greater than in SNAP participants (P ≤ .001).

“In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy,” the authors concluded.

“SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline,” they added. “Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ− [cognitively normal] individuals.”


  1. Gordon BA, Blazey T, Su Y, et al. Longitudinal β-amyloid deposition and hippocampal volume in preclinical alzheimer disease and suspected non-alzheimer disease pathophysiology. JAMA Neurol. 2016 Aug 22.; doi: 10.1001/jamaneurol.2016.2642) [Epub ahead of print]
  1. Mormino EC, Papp KV, Rentz DM, et al. Heterogeneity in suspected non-alzheimer disease pathophysiology among clinically normal older individuals. JAMA Neurol. 2016 Aug 22; (doi: 10.1001/jamaneurol.2016.2237) [Epub ahead of print]