Association of circulating proteasome activity with Alzheimer’s pathology and cognitive functions in APOE ε4 carriers

Background: Proteasome is a major intracellular protease complex, but the significance of circulating proteasome activity in Alzheimer’s disease (AD) is not well established. Because APOE ε4 is the strongest genetic risk factor for AD, we examined whether plasma proteasome activity is associated with AD-related pathology, neurodegeneration, and cognitive decline, focusing on APOE ε4 carriers. Methods: In this observational study, participants were classified as cognitively normal (CN), mild cognitive impairment (MCI), and dementia. All underwent 3.0-T MRI, [ ¹⁸ F]flutemetamol PET for amyloid, [ ¹⁸ F]MK-6240 PET for tau, APOE genotyping, and neuropsychological testing. Circulating proteasome activity was measured using fluorogenic substrates. Associations between proteasome activity and imaging or clinical features were assessed after stratifying by APOE ε4 status. Mediation analyses evaluated whether amyloid or tau burden indirectly linked proteasome activity with hippocampal volume or cognition. Results: A total of 148 individuals were included (58 CN, 39 MCI, 38 AD dementia, and 13 other dementia). Significant associations appeared only in APOE ε4 carriers (n = 55). Higher proteasome activity was associated with lower amyloid burden (β = − 0.142, p  = 0.009), lower global tau burden (β = − 0.447, p  = 0.047), and reduced tau in Braak I/II (β = − 0.460, p  = 0.033) and Braak III/IV regions (β = − 0.454, p  = 0.033). Proteasome activity was positively associated with hippocampal volume (β = 0.294, p  = 0.001) and with cognitive performance, including MMSE (β = 2.375, p  = 0.026), CDR-SOB (β = − 1.604, p  = 0.005), and memory function. No significant associations were found in noncarriers. Mediation analyses showed that amyloid burden explained ~ 29% and Braak I/II tau ~ 23% of the proteasome–hippocampal volume relationship, while tau in Braak I/II and III/IV regions mediated 24–41% of the associations between proteasome activity and global cognition. Conclusions: Downregulated proteasome activity is strongly associated with amyloid burden, early tau accumulation, hippocampal atrophy, and cognitive impairment only in APOE ε4 carriers. These findings suggest that plasma proteasome activity may serve as a noninvasive marker of AD-related vulnerability in genetically at-risk individuals. Further studies are needed to clarify whether proteasome activity contributes to or results from amyloid and tau aggregation. Trial registration ■ Trial registration number: KCT0005428. Registered September 24, 2020. ■ Study subjects included in this analysis were those recruited from November 2018 onwards. (retrospectively registered)