Insulin resistance and brain health in midlife: a potential dementia prevention target

BACKGROUND: Insulin resistance is recognised as a midlife risk factor for cognitive decline, yet the pathways linking metabolic dysfunction to early brain changes remain unclear. METHODS: We cross-sectionally analysed 355 cognitively normal adults from the PREVENT cohort to test associations between insulin sensitivity (Homoeostatic Model Assessment for Insulin Resistance; HOMA-IR), frontal white matter hyperintensities (WMH), cerebral blood flow (CBF), hippocampal volume, and cognition. FINDINGS: Multivariable regression showed higher log-transformed HOMA-IR was associated with greater frontal WMH burden (β = 0.118, p = 0.026) and lower global cognitive performance (β = -0.132, p = 0.012). Decreased insulin sensitivity was not associated with global CBF (β = -0.019, p = 0.74). Adjusting for WMH burden, hippocampal volume, and CBF, lower insulin sensitivity remained associated with lower global cognition (β = -0.123, p = 0.021). Structural equation modelling (n = 328) demonstrated a direct negative association between higher HOMA-IR and cognition (β = -0.055, p = 0.042) and trended toward higher vascular burden (p = 0.06). The indirect pathway through vascular burden was non-significant (p = 0.23), as vascular burden, hippocampal volume, and CBF did not associate with cognition. INTERPRETATION: Decreased insulin sensitivity was linked to early small vessel disease and measurable cognitive differences, suggesting the cognitive association was largely direct rather than explained by vascular injury, hippocampal atrophy, or global perfusion. These findings point toward partially parallel metabolic and vascular pathways rather than a sequential process. These cross-sectional associations suggest that insulin sensitivity warrants investigation as a modifiable midlife factor for cognitive health; interventional studies are needed to determine whether targeting it preserves cognition before neurodegenerative markers emerge. FUNDING: MRC Dementias Platform UK, NIHR, Alzheimer's Society, Alzheimer's Association, Race Against Dementia, and HRB.