Amyloid-β deposition in basal frontotemporal cortex is associated with selective disruption of temporal mnemonic discrimination.

Abstract

Cerebral amyloid-beta (Aβ) accumulation, a hallmark pathology of Alzheimer's disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aβ contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of Aβ deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aβ deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aβ-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aβ pathology would be selectively associated with temporal discrimination performance due to Aβ's propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aβ-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher Aβ-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aβ accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and future work is needed to determine whether assessing temporal mnemonic discrimination can aid in predicting emerging AD progression.Significance Statement Identifying subtle cognitive changes that reflect emerging Aβ accumulation could lead to the development of cognitive tasks to detect individuals at risk of AD and sensitively assess clinical intervention outcomes for Aβ-lowering therapeutics. Temporal mnemonic discrimination, the ability to distinguish between events occurring at different times, is supported by basal frontotemporal regions which are among the earliest impacted by Aβ. We demonstrate that Aβ-positivity, as well as increased Aβ deposition in basal frontotemporal regions, is selectively associated with deficits in temporal mnemonic discrimination, but not other domains of mnemonic discrimination such as object identity or spatial relationships. These results suggest that Aβ disrupts cortical circuits supporting temporal processing and highlights inclusion of temporal mnemonic discrimination tasks in future clinical assessments.