Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation.
Level 3 - non-randomized controlled study
Non-randomized prospective cohort follow-up study
PubMed 29476033 · doi:10.1212/WNL.0000000000005214
What was done
This observational study examined whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation 15 years later and whether APOE ε4 modifies this risk. Investigators recruited 60 non-demented participants (mean age 55.4 years at baseline, 70.9 years at follow-up; 55.5% women) from the nationwide Finnish Health2000 study. Participants were selected based on baseline homeostatic model assessment of insulin resistance (HOMA-IR) tertiles: an insulin-resistant group (IR+, HOMA-IR >2.17, n = 30) and a control group (IR-, HOMA-IR <1.25, n = 30), enriched to include 50% APOE ε4 carriers (n = 15 per group). Follow-up brain amyloid was measured using [11C]Pittsburgh compound B-PET imaging (2014–2016) and analyzed with multivariate logistic and linear regression.
What was found
An amyloid-positive PET scan was present in 60.0% of the IR+ group compared to 33.3% of the IR- group (odds ratio 3.0, 95% confidence interval 1.1–8.9, p = 0.04). This increased risk was observed in both APOE ε4 carriers and noncarriers. Higher midlife continuous HOMA-IR was associated with greater follow-up brain amyloid burden after multivariate adjustment for cognitive and metabolic risk factors (β = 0.11, 95% confidence interval 0.002–0.22, p = 0.04), whereas late-life continuous HOMA-IR was not associated.
Why it matters
The findings demonstrate that midlife metabolic dysfunction predicts late-life brain amyloid deposition independently of APOE ε4 status over a 15-year timeframe.
Limits
The sample size was small (n = 60), yielding wide confidence intervals. The extreme-tertile recruitment strategy excluded the intermediate tertile of HOMA-IR, and the observational cohort design cannot establish causality.
Cited by
- context Carriers of the APOE4 allele have a significantly greater accumulation of beta-amyloid in the brain if they are insulin resistant.