Yu L, et al. - Through two community-based clinicopathologic cohort studies of elderly individuals without β-amyloid (a pathologic hallmark of Alzheimer disease [AD]) deposits, experts analyzed the correlations of cortical β-amyloid protein in the absence of insoluble deposits with cognitive decline, neurofibrillary tangles, other age-associated neuropathologic conditions, and APOE. No correlation of the β-amyloid protein with the drop in episodic memory was noted, however, accelerated rates of decline in processing speed and visuospatial abilities were correlated with the absence of β-amyloid deposits. No association of protein could be ascertained with paired helical filament tau tangle density; however, the protein was correlated with amyloid angiopathy but no other brain pathology. After controlling for amyloid angiopathy, the associations with cognitive decline were unaltered. The β-amyloid protein wasn’t linked to either APOE ε4 nor a polygenic Alzheimer risk score. In the absence of β-amyloid deposits, the cortical β-amyloid protein was linked to accelerated cognitive decline, supporting the role of cortical soluble β-amyloid as a neurotoxic agent in aging. Moreover, an underlying neuropathologic change that could vary from that of AD is implied by the lack of protein association with paired helical filament tau tangles, episodic memory decline, or strong genetic drivers of deposited β-amyloid.