<i>APOE ε4</i>allele advances the age-dependent decline of amyloid β clearance in the human cortex

<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Our previous study indicated that the pericapillary clearance of amyloid β (Aβ) declines with age in<jats:italic>APOE 3/3</jats:italic>subjects. Here, we examine whether the<jats:italic>APOE</jats:italic>ε<jats:italic>4</jats:italic>allele has an impact on this age-related decline.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We examined 69 autopsy brains of<jats:italic>APOE</jats:italic>ε<jats:italic>3/</jats:italic>ε<jats:italic>4</jats:italic>or<jats:italic>APOE</jats:italic>ε<jats:italic>3/</jats:italic>ε<jats:italic>3</jats:italic>individuals (30-65 years) for the immunohistochemical localization of intracellular, extracellular, and pericapillary Aβ in the cerebral cortex.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In<jats:italic>APOE</jats:italic>ε<jats:italic>3/</jats:italic>ε<jats:italic>4</jats:italic>individuals, the percentage of Aβ positive pericapillary spaces began to decrease (p=0.030), and the number of extracellular Aβ particles increased in the early 30s (p=0.0008). Those average values were significantly lower (p<0.0001) and higher (p<0.0001), respectively, compared to<jats:italic>APOE</jats:italic>ε<jats:italic>3/</jats:italic>ε<jats:italic>3</jats:italic>individuals.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Our observations indicate that<jats:italic>APOE</jats:italic>ε<jats:italic>4</jats:italic>allele advances by one decade at the onset of age-related decline in Aβ glymphatic clearance. This finding supports early clinical intervention and stratification by APOE genotype to prevent Aβ deposition and AD progression.</jats:p></jats:sec>