Yang, Yisu; Lorenz, Anna; Sathe, Aditi; Schilling, Kurt G.; Gaynor, Leslie S.; Choi, Seo-Eun; Lee, Michael L.; Scollard, Phoebe; Trittschuh, Emily H.; Mukherjee, Shubhabrata; Mez, Jesse; Dumitrescu, Logan C.; Landman, Bennett A.; Crane, Paul K.; Cuccaro, Michael L.; Hohman, Timothy J.; Archer, Derek B. (2026).听.听Alzheimer’s & Dementia, 22(7), e71663.听
Memory decline is one of the hallmark features of聽Alzheimer’s disease (AD), but measurable changes in memory often occur only after significant changes have already taken place in the brain. This study investigated whether brain characteristics seen in聽midlife聽share genetic links with memory performance later in life, with the goal of identifying earlier markers of Alzheimer’s-related cognitive decline. The researchers analyzed genetic data from more than 24,000 older adults alongside brain imaging and genetic data from over 33,000 middle-aged participants in the UK Biobank. They found that brain features related to the structure and microscopic organization of the聽medial temporal lobe鈥攁 region critical for memory鈥攁nd the聽frontal lobe聽showed the strongest shared genetic links with memory performance. They also identified shared genetic patterns involving the聽default mode network, a network of brain regions that is important for memory and is known to be affected early in Alzheimer’s disease. These findings suggest that changes in specific brain regions during midlife may reflect genetic pathways that contribute to later-life memory decline and Alzheimer’s disease, potentially helping researchers identify earlier biomarkers and new targets for treatment.
FIGURE 1
Genetic covariance between imaging-derived phenotypes (IDPs) and memory performance. Volcano plots show strength of genetic covariance of diffusion (top panel), structural (middle panel), and functional (bottom panel) IDPs with cross-sectional memory performance (MEM) for all, impaired, and unimpaired individuals, including the聽APOEregion in the analyses. Colors highlight significant genetic covariance with memory (FDR-corrected聽p聽<聽0.05), with green indicating positive covariance and red indicating negative covariance. Data point shape for structural IDPs indicates the atlas used to generate the cortical measure, with circles representing the Desikan-Killiany atlas, squares representing the Destrieux atlas, diamonds representing the Desikan-Killiany-Tourville (DKT) atlas, and triangles representing other smaller atlases (e.g., thalamic nuclei, hippocampal subfields). Data point shape for functional IDPs indicates the dimensionality of group ICA, with diamonds representing 100-dimensional ICA and circles representing 25-dimensional ICA. Top IDPs for each modality and analysis that survived FDR correction are labeled. Diffusion measures highlight regions such as the fornix and corona radiata; structural measures highlight regions such as the lingual gyrus, anterior cingulate gyrus and sulcus, fusiform gyrus, and superior temporal gyrus and sulcus. Table聽聽provides the mapping between original UKB IDP names and our intuitive names. Ant., anterior; L, left hemisphere; Lat., lateral; Post., posterior; R, right hemisphere; Sup., superior.