Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration

Abstract

ObjectiveTo determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.MethodA total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN.ResultAmyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants.ConclusionRelative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.

Clinical Trials in Alzheimer’s Disease: A Hurdle in the Path of Remedy

“…Clinical efforts should also double down on pathological forms of tau particularly in light of two recent articles suggesting that tau far surpasses amyloid in predicting the location of future brain atrophy. In the first study, beta-amyloid plaques appear to be latecomers to the disease rather than an early trigger in that no statistical difference in plaque load was found during the earliest, subtle cognitive difficulties, suggesting that betaamyloid may not be the trigger for initial disease progression [115]. In the second study, using tau PET imaging (currently under review by the FDA), the authors eloquently demonstrated in early clinical stage AD patients, tau PET brain scans predict the location of brain atrophy measured by MRIs 1-2 years later, but amyloid PET imaging neither predicts the location of either tau nor future atrophy [116].…”

Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?

“…However, AChE inhibitors are expected to have the greatest anti-neurodegenerative impact at the earliest stages of the disease when there is still the maximum possible intact basal forebrain cholinergic system. AChE inhibitor therapy would best start at the earliest appearance of subtle cognitive impairment [15,16,81], a point at which signs of neurodegeneration are the earliest and most common biomarkers of AD and that often precede and predict the accumulation of amyloid [16][17][18]. By extension, it is tempting to speculate that AChE inhibitor therapy could be prophylactic in elderly persons at risk for AD [125,139].…”

An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of APP homeostasis

“…In a recent ADNI-based study patients with subtle cognitive decline had negative amyloid PET scans that subsequently became positive. 55 Early APP-derived products are the monomers/protofibrils and oligomers that precede fibrillization and aggregation into plaques that a PET scan could miss. Are these very early cognitive changes induced by these earlier Aβ species?…”

“…Subclinical memory decline is coincident or very nearly so with the onset of medial temporal tau pathology in the absence of locally aggregated Aβ. 23,55…”