Amyloid Accumulation Below Clinical Threshold Still Contributes to Cognitive Decline, Neurodegeneration


Findings suggest that a subgroup of patients categorized as amyloid beta-negative may continue to accumulate the destructive protein and experience cognitive changes.

Susan M. Landau, PhD

Susan M. Landau, PhD

Subthreshold accumulations of amyloid beta are associated with subtle but detectable Alzheimer dementia (AD)-like changes in cognitively normal individuals, according to research presented at the 2019 Alzheimer’s Association International Conference, July 14-18, in Los Angeles, California.

Typically, people who are cognitively normal and amyloid-beta negative are defined as not being on the AD pathway; however, some people may continue to accumulate amyloid and other markers of AD and experience cognitive changes. This presents an opportunity for early therapeutic intervention.

In order to better explore this subset of patients and the cognitive changes they experience, researchers led by Susan M. Landau, PhD, of the University of California, Berkeley, examined cognitively normal patients who were negative for amyloid beta from the Alzheimer Disease Neuroimaging Initiative with serial amyloid beta PET, as well a subset of these patients who were cognitively normal but had abnormal neurodegeneration according to intracranial hippocampal volume. These patients, whose characteristics have been termed “SNAP” (suspected non-AD pathophysiology) account for approximately 20% of the cognitively normal population.

Landau and colleagues specifically assessed associations between baseline amyloid beta, amyloid beta accumulation, cognitive decline, and progression to abnormal diagnoses across the cohort.

Among cognitively normal patients who were negative for amyloid beta, accumulations of amyloid beta in the subthreshold range were associated with declines in memory function. Among patients in the SNAP subgroup, elevated baseline amyloid beta PET within a negative range was linked to longitudinal memory decline as well as longitudinal increased in amyloid beta accumulation similar to what is observed in patients who are positive for both amyloid beta and neurodegeneration. Alternately, patients in the SNAP subgroup who had amyloid beta PET significantly below the threshold showed less memory decline than those who were positive for amyloid beta and neurodegeneration, and also showed minimal increases in longitudinal PET.

Overall, the findings suggest that even slight elevation within the negative range of amyloid beta is suggestive of early changes in memory and is associated with continued amyloid beta accumulation.

“This decline, though subtle, is detectable even among cognitively normal individuals (in the presence and absence of abnormal neurodegeneration), and occurs prior to conversion to Aβ+ status or to clinically-relevant impairment, raising the possibility of a window for therapeutic early intervention,” Landau and colleagues concluded.

For more coverage of AAIC 2019, click here.


Landau M, et al. Subthreshold amyloid accumulation: Does it predict memory decline? Presented at: 2019 Alzheimer’s Association International Conference. July 14-18, 2019; Los Angeles, CA. Abstract 28980.

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