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Original Investigation
October 2016

Heterogeneity in Suspected Non–Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals

Author Affiliations
  • 1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown
  • 2Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown
  • 4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 5Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Neurol. 2016;73(10):1185-1191. doi:10.1001/jamaneurol.2016.2237
Key Points

Question  Do cognitively normal older individuals with suspected non–Alzheimer disease pathophysiology (SNAP) show evidence of early Alzheimer disease processes?

Findings  In this longitudinal study, the SNAP group did not show elevated levels of tau or cognitive decline. A small subset of the SNAP group with subthreshold Pittsburgh Compound B values and small hippocampus showed rapid cognitive decline.

Meaning  Those with SNAP are heterogeneous, and further biomarker refinement will be necessary to characterize this group.


Importance  A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non–Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ−) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear.

Objective  To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline).

Design, Setting, and Participants  This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]–labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ−/ND−), 1 (Aβ+/ND−), and 2 (Aβ+/ND+) and SNAP (Aβ−/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016.

Main Outcomes and Measures  Evidence of amyloid-independent tau deposition and/or cognitive decline.

Results  Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ− range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = −0.005 [SE, 0.036]; parahippocampal gyrus, β = −0.001 [SE, 0.027]; and inferior temporal lobe, β = −0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = −0.125 [SE, 0.041]; parahippocampal gyrus, β = −0.074 [SE, 0.030]; and inferior temporal lobe, β = −0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = −0.239 [SE, 0.042]; stage 1, β = −0.242 [SE, 0.051]; and SNAP, β = −0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = −0.082 [SE, 0.037]; P = .03).

Conclusions and Relevance  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. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ− CN individuals.