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EV0402

APOE4 genotype, not peripheral insulin resistance, determines episodic memory impairment: a cross-sectional study in a memory clinic sample

RELATIONSHIP BETWEEN CEREBRAL INSULIN RESISTANCE AND APO E4 GENOTYPE IN ALZHEIMER'S DISEASE. CROSS-SECTIONAL STUDY.

APOE4 genotype is the independent and predominant determinant of episodic memory impairment in a memory clinic sample; peripheral insulin resistance neither differs by genotype nor mediates the relationship between APOE4 and memory.

The study aimed to examine whether peripheral insulin resistance (IR) mediates the relationship between APOE4 genotype and cognitive performance, thereby testing the chain linking genetic risk, metabolic dysfunction, and cognitive decline proposed by the type 3 diabetes hypothesis. The design was cross-sectional; 205 patients with cognitive complaints were assessed at the Alzheimer’s Center of Hospital de Clinicas, University of Buenos Aires, and APOE genotyping was performed in 109 patients (53.2%). Assessments included the dementia risk factors identified by the 2024 Lancet Commission, a comprehensive neuropsychological battery (RAVLT, Signoret, TMT-A/B, Boston Naming Test), a peripheral metabolic panel (fasting glucose, fasting insulin, HbA1c, LDL, HOMA-IR), and structural imaging; statistical methods included the Mann–Whitney U test, Fisher’s exact test, Spearman correlation, multiple OLS regression, and mediation analysis using the Baron–Kenny approach and bootstrapping (Hayes 2018; 5,000 BCa resamples). APOE4 was the most discriminating marker in the study, with carriers performing significantly worse on the RAVLT, which measures episodic memory (median 3.0 [IQR 2.0–3.0] versus 2.0 [IQR 1.0–3.0]; Mann–Whitney U p = 0.0003; rank-biserial r = 0.435, a medium-to-large effect size). In the adjusted regression (N = 58, R2 = 0.312), APOE4 positivity (B = 0.748; 95% CI 0.204–1.292; p = 0.009) and years of education (B = -0.087; 95% CI -0.163 to -0.012; p = 0.027) were significant predictors, whereas HOMA-IR and HbA1c remained nonsignificant; years of education correlated with RAVLT performance (Spearman rho = 0.308; p = 0.0002; n = 140). No peripheral marker of insulin resistance independently predicted cognitive performance, and the prevalence of insulin resistance was similar between APOE4 carriers and noncarriers across all clinical thresholds (all p values ≥ 0.68; comparisons of continuous measures: fasting insulin p = 0.79, HbA1c p = 0.77). In the mediation analysis, paths a and b were nonsignificant, and the 95% BCa confidence intervals for the indirect effect included zero. Although the four-group interaction comparison (APOE4 × HOMA-IR ≥ 2.5, n = 72) was significant overall (Kruskal–Wallis H = 12.347; p = 0.006), this difference was entirely attributable to APOE4 genotype, with identical median RAVLT scores in the APOE4-positive groups regardless of insulin resistance status (3.0 in both groups; post hoc p = 0.736; this finding is exploratory because the subgroup positive for both APOE4 and insulin resistance included only 7 participants). In conclusion, impairment was specific to memory, simple visuomotor speed (TMT-A) was preserved, and cognitive reserve was protective independently of genetic risk; the limitations noted included the availability of APOE genotype data for only 53% of the sample, the possibility that peripheral markers may not reflect central insulin resistance, and the inability to infer causality from the cross-sectional design.

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