A blood DNA methylation marker of cognitive ability is associated with six-year cognitive performance independent of blood Alzheimer's disease biomarkers

Penanda metilasi DNA darah untuk kemampuan kognitif berasosiasi dengan performa kognitif enam tahun, terlepas dari biomarker penyakit Alzheimer dalam darah

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ID: 327921
2026
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Abstract
MethylCog is a 29-CpG blood DNA methylation (DNAm) score developed to index general cognitive ability (g). Whether it captures cognition-related information associated with later cognitive performance that is not fully represented by blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) remains unclear. Using the held-out Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) test set from the original MethylCog study (N = 605), we examined associations with baseline g after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), and amyloid-β 42/40 ratio (Aβ42/40). Prospective associations with six-year follow-up g were examined after adjustment for baseline g, age, sex, education, and APOE ε4 carrier status, with additional adjustment for the ADRD biomarker panel. MethylCog remained associated with baseline g in the fully adjusted cross-sectional model (standardized β=.178, 95% CI: .111-.244, p<.001; ΔAdjR²=.025). MethylCog was also associated with six-year follow-up g after adjustment for baseline g and all covariates and biomarkers (standardized β=.101, 95% CI: .033-.170, p=.004; N = 331; ΔAdjR²=.007). Findings were similar among participants without baseline cognitive impairment. These findings provide preliminary evidence that a cognition-trained DNAm signature captures variation in later cognitive performance not fully represented by baseline cognition or available ADRD blood biomarkers.
MethylCog adalah skor metilasi DNA (DNAm) darah 29-CpG yang dikembangkan untuk mengindeks kemampuan kognitif umum (g). Masih belum jelas apakah skor ini menangkap informasi terkait kognisi yang berasosiasi dengan performa kognitif di kemudian hari yang tidak sepenuhnya direpresentasikan oleh biomarker berbasis darah untuk penyakit Alzheimer dan demensia terkait (ADRD). Menggunakan set uji *held-out* dari Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) dari studi asli MethylCog (N = 605), kami meneliti asosiasi dengan g baseline setelah penyesuaian terhadap usia, jenis kelamin, pendidikan, status pembawa apolipoprotein E (APOE) ε4, *neurofilament light chain* (NfL), *glial fibrillary acidic protein* (GFAP), tau terfosforilasi 181 (p-tau181), dan rasio amiloid-β 42/40 (Aβ42/40). Asosiasi prospektif dengan g pada tindak lanjut enam tahun diteliti setelah penyesuaian terhadap g baseline, usia, jenis kelamin, pendidikan, dan status pembawa APOE ε4, dengan penyesuaian tambahan untuk panel biomarker ADRD. MethylCog tetap berasosiasi dengan g baseline dalam model potong-lintang yang disesuaikan secara penuh (β terstandarisasi = 0,178, 95% CI: 0,111–0,244, p < 0,001; ΔAdjR² = 0,025). MethylCog juga berasosiasi dengan g pada tindak lanjut enam tahun setelah penyesuaian terhadap g baseline serta seluruh kovariat dan biomarker (β terstandarisasi = 0,101, 95% CI: 0,033–0,170, p = 0,004; N = 331; ΔAdjR² = 0,007). Temuan serupa juga diperoleh pada partisipan tanpa gangguan kognitif pada baseline. Temuan-temuan ini memberikan bukti awal bahwa profil DNAm yang dilatih berdasarkan kognisi menangkap variasi dalam performa kognitif di kemudian hari yang tidak sepenuhnya direpresentasikan oleh kognisi baseline atau biomarker darah ADRD yang tersedia saat ini.
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Authors Deirdre M O'Shea, Lily Wang, David Lukacsovich, Wei Zhang, James E Galvin
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Journal the journals of gerontology series a, biological sciences and medical sciences
Year 2026
DOI
10.1093/gerona/glag222
URL
https://doi.org/10.1093/gerona/glag222
Keywords Keywords not found

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