# Whole blood gene expression moderates associations between AD biomarkers and cognitive decline in cognitively unimpaired older adults **Authors:** Hannah M. Klinger, Mabel Seto, Vaibhav A. Janve, Jane A. Brown, Michelle Clifton, Colin Birkenbihl, Gillian T. Coughlan, Diana L. Townsend, Michael Properzi, Jane Zyski, Ting‐Chen Wang, Rebecca E. Amariglio, Kathryn V. Papp, Dorene M. Rentz, Hyun‐Sik Yang, Jasmeer Chhatwal, Michael C. Donohue, Rema Raman, Robert A. Rissman, Paul Aisen, Keith A. Johnson, Reisa A. Sperling, Logan Dumitrescu, Timothy Hohman, Rachel F. Buckley PMC · DOI: 10.1002/alz.71225 · Alzheimer's & Dementia · 2026-02-22 ## TL;DR This study shows that gene expression in blood can influence how Alzheimer's biomarkers relate to cognitive decline in older adults, with sex-specific patterns. ## Contribution The study identifies sex-specific gene expression signatures that moderate the relationship between AD biomarkers and cognitive decline. ## Key findings - Six genes interacted with Aβ-PET and 103 with tau-PET to influence cognitive decline. - Over 3000 gene-by-sex interactions reveal sex-specific transcriptomic vulnerability. - Pathways related to immunity, ribosomal biology, and vesicle trafficking were implicated. ## Abstract Early biological pathways explaining the risk for Alzheimer's disease (AD)–related cognitive decline remain poorly understood. Using linear mixed‐effects models, we investigated whether whole blood gene expression (RNA sequencing) moderates the relationship between AD biomarkers measured by amyloid beta (Aβ) and tau‐PET (positron emission tomography) imaging and longitudinal cognition in 770 cognitively unimpaired older adults (Agemean = 71.3, 62% female) from Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (A4/LEARN). We identified protective and AD risk–related gene expression signatures on the autosome and X chromosome. Six genes (ngenes(%); 2(33%) X‐linked) interacted with Aβ‐PET, whereas 103 genes (3(3%) X‐linked) interacted with neocortical tau‐PET, to influence cognitive decline. A total of 110 genes (17(15%) X‐linked) and 3156 genes (121(4%) X‐linked) were moderated by both sex and Aβ‐ or tau‐PET, respectively. Pathway enrichment analyses reflected immunity, protein synthesis, and lipid metabolism. These findings underscore the importance of peripheral transcriptomic markers in identifying sex‐differentiated pathways related to risk of and protection from cognitive decline in preclinical AD. Whole blood gene expression moderates biomarker–cognition associations in preclinical ADSix genes interacted with amyloid beta positron emission tomography (Aβ‐PET) and 103 with tau‐PET to influence cognitive declineOver 3000 gene‐by‐sex interactions reveal sex‐specific transcriptomic vulnerabilityPathways implicate immunity, ribosomal biology, and vesicle trafficking processesFindings support blood‐based, sex‐aware biomarkers for precision AD risk stratification Whole blood gene expression moderates biomarker–cognition associations in preclinical AD Six genes interacted with amyloid beta positron emission tomography (Aβ‐PET) and 103 with tau‐PET to influence cognitive decline Over 3000 gene‐by‐sex interactions reveal sex‐specific transcriptomic vulnerability Pathways implicate immunity, ribosomal biology, and vesicle trafficking processes Findings support blood‐based, sex‐aware biomarkers for precision AD risk stratification ## Linked entities - **Genes:** ab (abrupt) [NCBI Gene 34560], MAPT (microtubule associated protein tau) [NCBI Gene 4137] - **Diseases:** Alzheimer's disease (MONDO:0004975) ## Full-text entities - **Genes:** MMGT1 (membrane magnesium transporter 1) [NCBI Gene 93380] {aka EMC5, TMEM32}, ZBTB44 (zinc finger and BTB domain containing 44) [NCBI Gene 29068] {aka BTBD15, HSPC063, ZNF851}, ORC2 (origin recognition complex subunit 2) [NCBI Gene 4999] {aka ORC2L}, MTM1 (myotubularin 1) [NCBI Gene 4534] {aka CNM, CNMX, MTMX, XLMTM}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, ZBTB7B (zinc finger and BTB domain containing 7B) [NCBI Gene 51043] {aka CKROX, THPOK, ZBTB15, ZFP-67, ZFP67, ZNF857B}, BTBD3 (BTB domain containing 3) [NCBI Gene 22903] {aka dJ742J24.1}, GDPD2 (glycerophosphodiester phosphodiesterase domain containing 2) [NCBI Gene 54857] {aka GDE3, OBDPF}, MIRLET7F2 (microRNA let-7f-2) [NCBI Gene 406889] {aka LET7F2, MIRNLET7F2, let-7f-2}, PPP4C (protein phosphatase 4 catalytic subunit) [NCBI Gene 5531] {aka PP-X, PP4, PP4C, PPH3, PPP4, PPX}, PSENEN (presenilin enhancer, gamma-secretase subunit) [NCBI Gene 55851] {aka ACNINV2, MDS033, MSTP064, PEN-2, PEN2}, PCYT2 (phosphate cytidylyltransferase 2, ethanolamine) [NCBI Gene 5833] {aka ET, SPG82}, CEP250 (centrosomal protein 250) [NCBI Gene 11190] {aka C-NAP1, CEP2, CNAP1, CRDHL2}, KLHL4 (kelch like family member 4) [NCBI Gene 56062] {aka DKELCHL, KHL4}, CD226 (CD226 molecule) [NCBI Gene 10666] {aka DNAM-1, DNAM1, PTA1, TLiSA1}, OCRL (OCRL inositol polyphosphate-5-phosphatase) [NCBI Gene 4952] {aka DENT2, Dent-2, LOCR, OCRL-1, OCRL1}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, DNPH1 (2'-deoxynucleoside 5'-phosphate N-hydrolase 1) [NCBI Gene 10591] {aka C6orf108, RCL, dJ330M21.3}, FGFRL1 (fibroblast growth factor receptor like 1) [NCBI Gene 53834] {aka FGFR-5, FGFR5, FHFR}, SERPINH1 (serpin family H member 1) [NCBI Gene 871] {aka AsTP3, CBP1, CBP2, HSP47, OI10, PIG14}, ZSCAN2 (zinc finger and SCAN domain containing 2) [NCBI Gene 54993] {aka ZFP29, ZNF854}, KLRC1 (killer cell lectin like receptor C1) [NCBI Gene 3821] {aka CD159A, NKG2, NKG2A}, PCID2 (PCI domain containing 2) [NCBI Gene 55795], UBE2D3P2 (ubiquitin conjugating enzyme E2 D3 pseudogene 2) [NCBI Gene 100130139], ALCAM (activated leukocyte cell adhesion molecule) [NCBI Gene 214] {aka CD166, MEMD}, RPS13 (ribosomal protein S13) [NCBI Gene 6207] {aka S13, uS15}, NIPA2 (NIPA magnesium transporter 2) [NCBI Gene 81614] {aka SLC57A2}, TAS2R46 (taste 2 receptor member 46) [NCBI Gene 259292] {aka T2R46, T2R54}, RPS13P2 (ribosomal protein S13 pseudogene 2) [NCBI Gene 729236] {aka RPS13_1_51}, MYB (MYB proto-oncogene, transcription factor) [NCBI Gene 4602] {aka Cmyb, c-myb, c-myb_CDS, efg}, UBA5 (ubiquitin like modifier activating enzyme 5) [NCBI Gene 79876] {aka DEE44, EIEE44, SCAR24, THIFP1, UBE1DC1}, SUV39H2 (SUV39H2 histone lysine methyltransferase) [NCBI Gene 79723] {aka KMT1B}, PCNT (pericentrin) [NCBI Gene 5116] {aka KEN, MOPD2, PCN, PCNT2, PCNTB, PCTN2}, SMIM18 (small integral membrane protein 18) [NCBI Gene 100507341], FAM223A (family with sequence similarity 223 member A) [NCBI Gene 100132967] {aka CXorf52, LINC00204A, NCRNA00204, NCRNA00204A, SPCX}, RHOXF2 (Rhox homeobox family member 2) [NCBI Gene 84528] {aka CT107, PEPP-2, PEPP2, THG1}, ETF1 (eukaryotic translation termination factor 1) [NCBI Gene 2107] {aka D5S1995, ERF, ERF1, RF1, SUP45L1, TB3-1}, SGPP2 (sphingosine-1-phosphate phosphatase 2) [NCBI Gene 130367] {aka SPP2, SPPase2}, KBTBD11 (kelch repeat and BTB domain containing 11) [NCBI Gene 9920] {aka KLHDC7C}, ETF1P2 (eukaryotic translation termination factor 1 pseudogene 2) [NCBI Gene 6825] {aka SUP45L3}, UBXN10 (UBX domain protein 10) [NCBI Gene 127733] {aka UBXD3} - **Diseases:** neuroinflammation (MESH:D000090862), AD (MESH:D000544), Neurodegeneration (MESH:D019636), RESEARCH (MESH:D014947), inflammation (MESH:D007249), PACC (MESH:D058617), cognitive decline (MESH:D003072), ADRD (MESH:D003704), Amyloid (MESH:C000718787) - **Chemicals:** 18F-Florbetapir (MESH:C545186), solanezumab (MESH:C550616), NEO (-), 18F-flortaucipir (MESH:C000591008), lipid (MESH:D008055) - **Species:** Homo sapiens (human, species) [taxon 9606] - **Cell lines:** PACC — Mus musculus (Mouse), Hybridoma (CVCL_U609) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12928093/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12928093/full.md ## References 41 references — full list in the complete paper: https://tomesphere.com/paper/PMC12928093/full.md --- Source: https://tomesphere.com/paper/PMC12928093