APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations

Abstract

Objective Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer’s disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus, need to be further clarified. Methods We reviewed National Alzheimer’s Coordinating Center (NACC) clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology. Results Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer’s disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in the water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation and oxidative stress compared to apoE3- or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, in spite of higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. Interpretation APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect.

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…Our recent study using apoE-TR mice could recapitulate the observations in a large human cohort from the National Alzheimer’s Coordinating Center (NACC) showing age-related cognitive decline in an APOE genotype-dependent manner [20]. Therefore, apoE-TR mice may serve as an appropriate model for apoE-targeted therapy when cognitive function is used as an important outcome.…”

“…When compared to individuals carrying APOE ε3/ε3, carrying an APOE ε2 allele reduces the risk of developing AD (OR, 0.621; 95% CI, 0.456–0.85) (http://www.alzgene.org/meta.asp?geneID=83). While the allelic number-dependent protective effect of APOE ε2 in AD morbidity has not been determined likely due to the relatively small population of APOE ε2/ε2, the risk of cognitive decline during aging tends to be lower in people carrying APOE ε2/ε2 compared to those carrying APOE ε2/ε3 [20]. …”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Elder APOE ε2 carriers were found to have reduced accumulation of amyloid pathology via multimodal neuroimaging (Grothe et al, 2017). Mice carrying human apoE2‐targeted replacement (apoE2‐TR) exhibited preserved memory function as compared to apoE3‐TR or apoE4‐TR mice, but this is independent with age‐related synaptic loss or neuroinflammation, and higher level of apoE and lower level of cholesterol in the cortex might contribute to this protective effect (Shinohara et al, 2016). …”

Apolipoprotein E particle size is increased in Alzheimer's disease

“…In patients with ε4/ε4, 91% eventually suffer from AD, whereas little AD is seen in ε2/ε2 subjects. ApoE2 is also associated with less cognitive decline during aging [3]. In addition, two ε4 alleles reduce the age of disease onset by 15 years.…”