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Do subtle cognitive deficits precede amyloid accumulation?

Over the last decade, a hypothesized model of dynamic sequential biomarker changes dominated the Alzheimer disease (AD) research field. The model, informed by the amyloid hypothesis,1 proposed a prototypical cascade, lasting up to decades, in which brain β-amyloid initiates acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. In this issue of Neurology®, Thomas et al.2 tested the specific hypothesis that if amyloid deposition occurs long before downstream detectable effects on cognition, the presence of cognitive deficits should not precede accumulating rates of amyloid deposition. They found, however, that they do: in a large cohort of older adults without dementia, a subgroup with objectively defined subtle cognitive difficulties identified on neuropsychological testing at baseline showed increasing brain amyloid deposition on PET imaging over 4 years, despite having baseline amyloid levels that were similar to those characterized as cognitively normal. This subgroup also showed faster entorhinal cortical thinning compared to those without subtle cognitive difficulties. By comparison, participants with frank, though mild, cognitive impairment did not show faster amyloid accumulation relative to cognitively normal individuals but did have faster entorhinal cortical thinning and hippocampal atrophy over 4 years, consistent with Braak-staged spreading of tau neuropathology.3