Abstract

Background: The accumulation of proteins such as amyloid-beta and tau, which disrupt normal cellular processes, characterizes Alzheimer’s disease (AD). Cognitive decline is strongly linked to tau pathology, which initially manifests in the medial temporal lobe (MTL).

Aims: To investigated the association between cognitive performance and regional tau accumulation, as measured by positron emission tomography (PET) imaging, in cognitively normal older adults. Understanding this relationship is critical for early intervention before noticeable cognitive decline emerges.

Study Design: Retrospective study.

Methods: Tau PET scans were conducted on 440 participants enrolled in the anti-amyloid treatment in asymptomatic Alzheimer’s (A4) study. The participants, aged 65-85, were cognitively unimpaired and had complete demographic and genetic profiles. Tau levels in the MTL and temporal neocortex (NEO) was quantified using composite metrics. Cognitive function was evaluated using the preclinical Alzheimer’s cognitive composite (PACC) and its individual components. Multiple linear regression models were applied to determine the associations between tau burden and cognitive outcomes, including interaction terms to evaluate the moderating roles of sex and apolipoprotein E (APOE)-ε4 genotype.

Results: The average participant age was 71.8 years (standard deviation = 4.84), with females comprising 58% of the sample. Greater tau accumulation in both tau_MTL and tau_NEO regions was significantly associated with lower cognitive scores. Specifically, reduced PACC scores (p < 0.001) corresponded with higher tau levels in both regions, primarily influenced by declines in Delayed Logical Memory and Free and Cued Selective Reminding test scores. Additionally, tau_NEO levels were modestly linked to Mini-Mental State Examination scores. The effects of sex and APOE-ε4 status were minimal.

Conclusion: Elevated tau deposition in the MTL and NEO is associated with diminished cognitive function, particularly in memory and processing speed domains. Notably, tau accumulation in the MTL showed a strong association with poorer outcomes on memory-related cognitive measures. The limited influence of sex and APOE-ε4 genotype highlights tau pathology as a key contributor to early cognitive decline in preclinical AD.