Why is it that some people exhibit only a minimal loss of cognitive function in later life? Here researchers suggest that mechanisms relating to APOE variant are relevant. Largely researched in the context of Alzheimer’s disease, but more broadly applicable to other manifestations of age-related neurodegeneration, the APOE-ε4 variant may increase disease risk by promoting greater inflammation and dysfunction in microglia, among other mechanisms. In comparison people with the APOE-ε2 exhibit a lower risk of disease. The degree to which APOE variants contribute to later life inflammation and dysfunction seems likely to impact cognitive function, but is only one of a number of influences. Lifestyle choices, such as those that impact weight and fitness, affect the burden of inflammation and are thus also likely important in determining whether cognitive function is sustained in later life.
“SuperAgers” is a term used to describe oldest-old (ages 80+) adults with episodic memory performance most closely resembling adults in their 50s to mid-60s. Apolipoprotein E (APOE)-ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), while APOE-ε2 is in comparison the protective APOE allele.
The present study aims to explore APOE-ε4 and -ε2 allele frequency in SuperAgers compared to AD dementia cases and controls in a large, harmonized multicohort dataset from the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). Using harmonized clinical diagnoses and cognitive domain scores (e.g., memory, executive function, language), we classified non-Hispanic Black (NHB) and non-Hispanic White (NHW) middle-aged, old, and oldest-old adults as cases, controls, or SuperAgers, and compared APOE-ε4 and -ε2 allele frequency of SuperAgers to cases and controls.
NHW SuperAgers had significantly lower frequency of APOE-ε4 alleles and higher frequency of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. Thus we demonstrated strong evidence that APOE allele frequency relates to SuperAger status.
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