Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline

The associations of 4 proteins-AK4, ITPK1, HSPB2, and IGFBP5-with cognitive function in older adults were largely unexplained by known brain pathologies. We examined the extent to which individual protein associations with cognitive decline were attributable to microstructural changes in the brain. This study included 521 participants (mean age 90.3, 65.9-108.3) with the postmortem reciprocal of transverse relaxation time (R₂) magnetic resonance image. All participants came from one of the 2 ongoing longitudinal cohorts of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project. Higher abundance of AK4, HSPB2, and IGFBP5 was associated with faster cognitive decline and mediated through lower postmortem R₂ in the frontal and temporal white matter regions. In contrast, higher abundance of ITPK1 was associated with slower cognitive decline and mediated through higher postmortem R₂ in the frontal and temporal white matter regions. The associations of 4 proteins-AK4, ITPK1, IGFBP5, and HSPB2-with cognition in late life were explained via microstructural changes in the brain.