Prospective associations of interleukin-6 and APOE allele with cognitive decline in biracial community-dwelling older adults: The Chicago Health and Aging Project (CHAP)

Introduction: It is unclear whether inflammation, that is, high interleukin-6 (IL-6) levels, and genetic risk, that is, apolipoprotein E (APOE) ε4 allele, have a compounding effect on cognitive decline (CD).

Methods: We analyzed a subset of participants from the longitudinal cohort study, Chicago Health and Aging Project, comprising 1120 biracial community-dwelling older adults (60% Black and 62% women), and mean follow-up = 6.4 years. We ran adjusted mixed-effects models on2 longitudinal CD.

Results: In APOE ε4 carriers, higher serum IL-6 was not associated with the rate of CD (β = -0.0091 [standard deviation (SD) = 0.0165, p = 0.5800]). Conversely, in non-ε4 carriers, compared to the lower tertile, those with the upper tertile of serum IL-6 levels experienced significantly accelerated CD (β = -0.0257 [SD = 0.0084, p = 0.0023]).

Discussion: Even without the largest genetic risk factor for late-onset Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), elevated serum IL-6 still accelerate the rate of CD in non-APOE ε4 carriers. Hence, interventions ameliorating inflammation may prevent AD/ADRD.

Highlights: Interleukin-6 (IL-6) and the apolipoprotein E (APOE) ε4 allele have been separately associated with an increased risk for cognitive decline, but their interaction remains unclear.In ε4 carriers, IL-6 was not associated with cognitive decline. However, even without the biggest genetic risk factor for Alzheimer's disease (AD), that is, APOE ε4, elevated serum IL-6 still could confer accelerated rate of cognitive decline, with a detrimental effect half of that imposed by APOE ε4 alone.We found no racial differences in these associations.These findings contribute complementary evidence on non-APOE ε4-dependent and non-AD biological pathways through which cognitive decline can still be accelerated in non-APOE ε4 carriers and highlight a specific subgroup of older adults who are at a higher risk of AD and thus may benefit from anti-inflammatory interventions.