Beyond Lipidation: CSF APOE4 Protein Burden, Not HDL Subclass, Drives Tau Associations in APOE4 Alzheimer’s Disease

Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet whether its pathogenic effects are driven by HDL lipidation state or by elevated APOE4 levels in the CNS remains unclear. Using ADNI data, we analyzed cerebrospinal fluid (CSF) and plasma small and large HDL particle concentrations, total APOE levels, and isoform-specific APOE3 and APOE4 protein levels in 144 participants with APOE ε3/ε3, ε3/ε4, or ε4/ε4 genotypes, grouped by cognitive state and memory progression over 4 years. Memory loss was defined as ≥ 10% decline on the Rey Auditory Verbal Learning Test (RAVLT) delayed recall between baseline and 48-month follow-up. Cross-sectional associations with CSF Aβ1–42, total tau, and p-tau181 were evaluated using covariate-adjusted linear regression, and longitudinal trajectories were examined using linear mixed-effects models over 6 years. CSF small and large HDL levels were higher in cognitively normal individuals and non-progressors, while APOE4 carriers exhibited reduced CSF small HDL relative to ε3 homozygotes. Importantly, APOE4 status moderated HDL–biomarker associations in opposing directions: in carriers, higher CSF small HDL was associated with lower tau and Aβ1–42, whereas in non-carriers, higher CSF small HDL was associated with higher CSF tau levels. Higher CSF APOE4 protein levels were associated with elevated tau and p-tau181, while plasma APOE measures showed minimal and often opposing associations with CSF biomarkers. Longitudinally, higher baseline CSF APOE4 proportion was associated with greater memory decline over 6 years but did not predict biomarker change. These findings argue against a protective role of APOE4 lipidation in AD and instead support a CNS-compartment model in which APOE4 protein burden aligns more closely with tau pathology and cognitive decline than peripheral APOE or HDL measures.