Early Detection of Alzheimer’s Risk Through APOE ε4-Linked Blood Protein Changes

Abstract: 

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that begins years before clinical symptoms start to appear. This study investigated whether carriers of the Apolipoprotein E4 (APOE ε4) allele exhibit early changes in plasma protein expression, independent of any amyloid deposition or any cognitive decline. A dataset comprising 560 plasma proteins was analyzed across three different stages: cognitively normal and amyloid PET-negative (pre-amyloid), cognitively normal but amyloid PET-positive (preclinical), and amyloid PET-positive individuals with mild cognitive impairment (MCI) or AD (symptomatic). Within each stage, Welch’s t-tests were used to compare protein levels between APOE ε4 carriers and APOE ε4 non-carriers. One specific protein, EFHC2, implicated in calcium signaling and immune regulation, was significantly associated with APOE ε4 status across all three groups, which suggests a consistent molecular signal preceding traditional AD biomarkers. Additional proteins, which include CDKL2, SYMPK, and LUZP2, appeared in multiple comparisons and are involved in neuronal function, RNA processing, and cytoskeletal regulation. While only one protein, CHD5, survived the strict correction thresholds from the Bonferroni and the Benjamini-Hochberg methods, the repeated detection of the other proteins with a standard p-value threshold highlights their potential relevance in APOE-driven disease pathways. These results suggest that APOE ε4 is associated with distinct, stage-independent changes in blood protein expression, even in the absence of any amyloid accumulation or any cognitive impairment. The identification of EFHC2 and other similarly related proteins supports many future investigations into blood-based biomarkers for early detection and risk assessment in AD, particularly among many genetically at-risk individuals.