Cerebral hypoperfusion, brain structural integrity, and cognitive impairment in older APOE4 carriers

• DOI: 10.1007/s11357-025-01642-5
• Publication Date: 2025-04-12T06:27:53Z
• Authors: Ioannis Pappas; Trevor Lohman; Shubir Dutt; Arunima Kapoor; Allison C. Engstrom; John Paul M. Alitin; Samuel Barnes; Ararat Chakhoyan; Lucas Saca; Raghav Gaggar; Elnaz Nourollahim...; Danny J. J. Wang; Mark H. C. Lai; Elizabeth B. Joe; John M. Ringman; Hussein N. Yassine; Lon S. Schneider; Helena C. Chui; Arthur W. Toga; Berislav V. Zlokovic; Daniel A. Nation
• Keywords: Cerebral Hypoperfusion; Structural integrity

Abstract Cerebral blood flow (CBF) deficits, cognitive decline, and brain structural changes have been reported in older adults with and without apolipoprotein E-e4 (APOE4)-related risk for dementia. However, it remains unclear whether brain structural changes mediate the effects of hypoperfusion on cognitive impairment in APOE4 carriers and non-carriers. We studied 166 (60–89 years) APOE4 carriers (ε3/ε4 or ε4/ε4) and APOE3 homozygotes (e3/e3) with and without cognitive impairment by clinical dementia rating (CDR) and neuropsychological testing. Pseudocontinuous arterial spin-labeling-MRI assessed regional CBF, and T1-anatomical and diffusion-MRI assessed structural integrity. Mediation analyses examined relationships among grey matter CBF, grey matter volume, and white matter integrity in regions underlying impairment in distinct cognitive ability domains. APOE4 carriers with global/memory impairment (CDR 0.5) exhibited decreased CBF in the posterior cingulate, decreased grey matter volume in the hippocampus, parahippocampal gyrus, and posterior cingulate, and decreased white matter integrity in the cingulum relative to APOE4 carriers with no impairment (CDR 0). Mediation analysis in APOE4 carriers indicated decreased posterior cingulate CBF effects on global/memory impairment were mediated by decreased cingulum integrity. In the combined APOE4 and APOE3 carriers sample, there were direct effects of frontal and inferior parietal CBF and superior longitudinal fasciculus integrity on attention/executive impairment. There were also direct effects of left inferior frontal CBF on language impairment. Findings suggest links between hypoperfusion and brain structural integrity underlying global/memory impairment in APOE4 carriers. Independent CBF relationships with structural integrity are also identified across genotypes and impairment domains.