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In Alzheimer's disease, the earliest stages of cortical β-amyloid (Aβ) deposition, before Aβ is widespread throughout the cortex, are not well understood. But cognitively normal people who test negative for positron emission tomography (PET) amyloid may hold biologically valuable clues about who might convert to Aβ status, a recent analysis suggests.

Writing online in , Susan Landau, PhD, of the University of California at Berkeley, and co-authors proposed that subclinical amyloid levels may represent the earliest detectable indication of pathology with cognitive consequences. In 142 cognitively normal people from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an increase in florbetapir PET Aβ signal over about 4 years was associated with elevated subclinical baseline Aβ levels. Aβ accumulation was associated with memory decline, but not a decrease in executive function.

These findings are relevant to research studies and clinical trials that want to target patients before they are Aβ positive, the team wrote.

So are amyloid "accumulators" the next candidates for Alzheimer's clinical trials?

In an accompanying the study, Corey McMillan, PhD, of the University of Pennsylvania in Philadelphia, and Gael Chetelat, PhD, of the University of Caen in France, raise the question of whether PET Aβ should be a categorical biomarker (Aβ or not) or quantitative biomarker along a continuum of Aβ accumulation.

"PET amyloid has historically largely been considered a positive or negative diagnostic test," McMillan told MedPage Today. "But this study suggests that quantitative measurements of PET amyloid in pre-symptomatic individuals can be informative."

"There is an increasing emphasis on earlier-stage amyloid-targeted clinical trials and, ideally, on pre-symptomatic trials. However, it is difficult to identify pre-symptomatic individuals other than those with inherited forms of Alzheimer's disease, which constitute only about 1% of individuals affected by Alzheimer's."

Landau and colleagues are not the first to suggest that PET-Aβ values below but near threshold levels could help predict who might convert to amyloid-positive status, McMillan and Chetelat noted. There's evidence that florbetapir binding at subthreshold levels in patients 20 to 60 years old. And 80% of patients who might be considered in the first amyloid stage when looking at certain brain regions in routine binary visual assessment.

While Aβ accumulators may be optimal candidates for early-stage clinical trials, several hurdles still need to be addressed, McMillan and Chetelat observed. In both medicine and research, there's a strong preference for visual or categorical reads of PET imaging. And synergistic risk factors for Aβ accumulation have not been identified: in the Landau et al study, for instance, the slope of PET Aβ signal was not related to age, APOE4, or hippocampal volume.

Still, the research "suggests that quantitative measurements of PET amyloid in pre-symptomatic individuals can be informative," McMillan noted, and may increase the feasibility of earlier amyloid-targeted trials.