Increased vulnerability to low-density lipoprotein cholesterol in apolipoprotein E4-positive females: Longitudinal effects on neurodegeneration and cognition

BackgroundAlzheimer's disease (AD) is the most common form of dementia, marked by progressive cognitive decline. Low-density lipoprotein cholesterol (LDL-C) has been implicated in AD pathology, but findings remain inconsistent. Apolipoprotein E4 (APOE4) status and sex may contribute to this variability.ObjectiveTo examine how LDL-C association with neurodegeneration in AD patients, differ according to APOE4 status and gender.MethodsWe stratified 106 AD patients by APOE4 status and sex into four subgroups: male APOE4+, female APOE4+, male APOE4-, and female APOE4-. Longitudinal cortical thickness changes were assessed using magnetic resonance imaging (MRI). We examined the association between LDL-C levels and cortical thinning within each subgroup.ResultsIn APOE4-positive females, higher LDL-C levels were significantly associated with accelerated cortical thinning in several regions, including the parahippocampal (β = -0.0075, p = 0.017), medial orbitofrontal (β = -0.0025, p = 0.028), fusiform (β = -0.0047, p = 0.034), posterior cingulate (β = -0.0097, p = 0.006), and inferior temporal cortices (β = -0.0085, p = 0.019). This subgroup also showed a significant association between LDL-C and MMSE decline (β = -1.409, p = 0.014) as well as longitudinal increases in cerebrospinal fluid phosphorylated tau181 (β = 0.014, p = 0.039). These effects were not observed in other subgroups.ConclusionsElevated LDL-C is associated with increased neurodegeneration and cognitive decline in female AD patients carrying the APOE4 allele. These exploratory findings highlight a subgroup-specific vulnerability to lipid-related neurodegeneration in AD and underscore the importance of considering both sex and genetic background in future studies.