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Background <p>Studies linking mitochondrial DNA (mtDNA) variants to cognition yielded inconsistent findings, and the underlying mechanisms remain unclear. We investigated whether mtDNA heteroplasmic variants were associated with cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), in 197 late midlife adults from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with complete data.</p> Methods <p>MtDNA was sequenced from blood using targeted deep sequencing. Adjusted linear and mixed-effects models examined the associations by functional regions, genes, total variant burden, nonsynonymous variants, and control regions.</p> Results <p>Heteroplasmic variants in the control region (β = -0.44, 95% CI: -0.83, -0.05, <i>p</i> = 0.027) and transfer RNA (tRNA) genes (β = -1.34, 95% CI: -2.58, -0.11, <i>p</i> = 0.034) were associated with MoCA baseline scores. Individual variants in cytochrome c oxidase subunit 1 (<i>CO1</i>) (β = -1.51, 95% CI: -2.54, -0.47, <i>p</i> = 0.005), NADH dehydrogenase subunit 1 (<i>ND1</i>) (β = -2.63, 95% CI: -4.56, -0.70, <i>p</i> = 0.008), and Displacement Loop <i>(D-LOOP2)</i> (β = -2.25, 95% CI: -4.20, -0.30, <i>p</i> = 0.025) was associated with reduced baseline MoCA scores. The <i>ND6</i> (β = −1.23, 95% CI: −2.09, − 0.37, <i>p</i> = 0.006), <i>ND4</i> (β = −1.11, 95% CI: −2.02, − 0.20, <i>p</i> = 0.018), ATP Synthase Membrane Subunit 8 (<i>ATP8</i>; β = −1.38, 95% CI: −2.63, − 0.13, <i>p</i> = 0.031), and <i>D-LOOP1</i> (β = −0.61, 95% CI: −1.20, − 0.01, <i>p</i> = 0.045) genes suggested a potential association with executive function. Longitudinal Animal Fluency Test (AFT) scores were inversely associated with heteroplasmic variants in coding regions (β = -0.10, 95% CI: -0.19, -0.006, <i>p</i> = 0.049), the total number of variants (β = -0.06, 95% CI: -0.11, -0.003, <i>p</i> = 0.037) and total nonsynonymous variants (β = -0.11, 95% CI: -0.21, -0.01, <i>p</i> = 0.040). Variants in the control region were associated with the greatest decline in verbal fluency (β = −0.20, 95% CI: −0.39 to − 0.002, <i>p</i> = 0.049). No associations were observed between mitochondrial variants and verbal memory performance or the MoCA composite scores.</p> Conclusions <p>Our study indicates that mitochondrial variants measured in blood may provide insight into cognitive function during midlife. However, additional studies are needed to validate these associations and to address potential power limitations in our study.</p>

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Blood mitochondrial heteroplasmic variants and cognitive performance in late midlife: REGARDS study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Diddier Prada,
  • Eva Morava -Kozicz,
  • Aravind Lathika Rajendrakumar,
  • Allison Kupsco,
  • Corina Lesseur,
  • Haritz Irizar,
  • David Cantú-de-Leon,
  • Claudia García-Cuellar,
  • Andrea Ramírez,
  • Jonathan González-Ruíz,
  • Carol R. Horowitz,
  • Mary Cushman,
  • Jennifer Manly,
  • Suzanne Judd,
  • Emilia Bagiella,
  • Andrea Baccarelli,
  • Robbie Parks

摘要

Background

Studies linking mitochondrial DNA (mtDNA) variants to cognition yielded inconsistent findings, and the underlying mechanisms remain unclear. We investigated whether mtDNA heteroplasmic variants were associated with cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), in 197 late midlife adults from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with complete data.

Methods

MtDNA was sequenced from blood using targeted deep sequencing. Adjusted linear and mixed-effects models examined the associations by functional regions, genes, total variant burden, nonsynonymous variants, and control regions.

Results

Heteroplasmic variants in the control region (β = -0.44, 95% CI: -0.83, -0.05, p = 0.027) and transfer RNA (tRNA) genes (β = -1.34, 95% CI: -2.58, -0.11, p = 0.034) were associated with MoCA baseline scores. Individual variants in cytochrome c oxidase subunit 1 (CO1) (β = -1.51, 95% CI: -2.54, -0.47, p = 0.005), NADH dehydrogenase subunit 1 (ND1) (β = -2.63, 95% CI: -4.56, -0.70, p = 0.008), and Displacement Loop (D-LOOP2) (β = -2.25, 95% CI: -4.20, -0.30, p = 0.025) was associated with reduced baseline MoCA scores. The ND6 (β = −1.23, 95% CI: −2.09, − 0.37, p = 0.006), ND4 (β = −1.11, 95% CI: −2.02, − 0.20, p = 0.018), ATP Synthase Membrane Subunit 8 (ATP8; β = −1.38, 95% CI: −2.63, − 0.13, p = 0.031), and D-LOOP1 (β = −0.61, 95% CI: −1.20, − 0.01, p = 0.045) genes suggested a potential association with executive function. Longitudinal Animal Fluency Test (AFT) scores were inversely associated with heteroplasmic variants in coding regions (β = -0.10, 95% CI: -0.19, -0.006, p = 0.049), the total number of variants (β = -0.06, 95% CI: -0.11, -0.003, p = 0.037) and total nonsynonymous variants (β = -0.11, 95% CI: -0.21, -0.01, p = 0.040). Variants in the control region were associated with the greatest decline in verbal fluency (β = −0.20, 95% CI: −0.39 to − 0.002, p = 0.049). No associations were observed between mitochondrial variants and verbal memory performance or the MoCA composite scores.

Conclusions

Our study indicates that mitochondrial variants measured in blood may provide insight into cognitive function during midlife. However, additional studies are needed to validate these associations and to address potential power limitations in our study.