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16/100

⚠ Preprint — not yet peer-reviewed alzhub usefulness score 16 out of 100. Biomarkers

Topic: Genetics and APOE

Background Accelerated biological aging can be assessed with DNA methylation (DNAm)-based epigenetic clocks. Research suggests that greater DNAm is associated with faster cognitive decline and risk of Alzheimer disease (AD) and other dementias. However, most studies have relied on single-time-point measurements of clocks, rather than evaluating dynamic changes over time. We examined the association between 15-year epigenetic aging trajectories and brain health outcomes in midlife. Methods We analyzed 2,833 middle-aged adults (mean baseline age 40 years, 59% female and 44% Black) with ≥ 3 DunedinPACE (a recently developed epigenetic clock) measurements, collected over 15 years. Using mixed-effects modeling, we derived individual-specific slopes of epigenetic aging trajectories and categorized participants as Fast Agers (slopes > 1 SD above the mean), Slow Agers (slopes < 1 SD below the mean), or Typical Agers (within ±1 SD of the mean). We examined associations between trajectory group and cognition on five cognitive domains as well as on plasma AD biomarkers (NfL, p-tau217, Aβ42/Aβ40), all assessed 15-20 years post-baseline. Models were adjusted for demographics, education, physical activity and APOE *ε4 carrier status (with additional adjustments for eGFRcr for biomarker outcomes). Results Epigenetic aging trajectories were associated with multiple domains of cognition and AD biomarkers (Figure 1). Compared to Typical Agers, Fast Agers showed worse processing speed, memory, executive function, and global cognition (all p<0.05), with no difference in verbal fluency. Slow Agers had better performance on memory and global cognition (both p < 0.05). Fast Agers also exhibited significantly lower Aβ42/Aβ40 levels (p = 0.011) compared to Typical agers; no significant associations with p-tau217 or NfL were observed in either group. Conclusion Middle-aged adults with faster 15-year epigenetic aging trajectories demonstrated worse cognitive performance, whereas those with slower biological aging trajectories exhibited cognitive resilience and more favorable AD biomarker profiles. By examining long-term trajectories rather than single timepoints, these findings identify individuals at differential risk for brain health outcomes.

Key findings

Research suggests that greater DNAm is associated with faster cognitive decline and risk of Alzheimer disease (AD) and other dementias.
Results Epigenetic aging trajectories were associated with multiple domains of cognition and AD biomarkers (Figure 1).
Compared to Typical Agers, Fast Agers showed worse processing speed, memory, executive function, and global cognition (all p<0.05), with no difference in verbal fluency.
Fast Agers also exhibited significantly lower Aβ42/Aβ40 levels (p = 0.011) compared to Typical agers; no significant associations with p-tau217 or NfL were observed in either group.
Conclusion Middle-aged adults with faster 15-year epigenetic aging trajectories demonstrated worse cognitive performance, whereas those with slower biological aging trajectories exhibited cognitive resilience and more favorable AD biomarker profiles.

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Study details

Participants2,833
Evidence strengthLow

How this study scored 16/100

Preprint — not yet peer-reviewed. It scored 31 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 19 of the 62 points we could judge it on, which is 31 out of 100.

Component	Points	Why
Journal tier	2 / 10	Tier 4 — not a peer-reviewed journal (medRxiv)
Journal's citation record	0 / 4	Not a journal article, so the journal's record does not count
Study design	0 / 12	No study design recorded — scores zero, not guessed (not stated in the record — scored 0)
Strength of evidence	1 / 5	Rated “low” in our summary
Peer-review validation	4 / 10	Preprint — not yet peer-reviewed. Hosted on a preprint server.
How recent	5 / 5	2026 — within 1 year(s) of the newest study here
Sample size	3 / 4	2,833 participants
Effect reported	0 / 3	No effect size reported — scores zero (not stated in the record — scored 0)
Studied in people	3 / 3	Studied in people (participant count stated)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	— / 7	No citation count (not found in OpenAlex) — left out of this score
Citations per year	— / 5	No citation count or no year — left out of this score
Impact for its field and year	— / 6	No field-weighted citation impact (OpenAlex has none yet) — left out of this score
Cited by studies here	— / 6	Not yet checked against this library's citation graph — left out of this score
Still being cited	— / 4	No yearly citation counts — left out of this score
Senior author's track record	— / 4	Senior author's record not available — left out of this score
Institution's track record	— / 3	No institution listed in OpenAlex — left out of this score
Multi-centre collaboration	— / 3	Institutions not listed — left out of this score
Indexed in PubMed	1 / 2	Not in PubMed, but has a DOI
Free to read	0 / 2	Behind a paywall — scores zero
Points	19 / 62	Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 19 of the 62 points we could judge it on is 31 out of 100.
Total	31 / 100	Capped to 16 because this is not a peer-reviewed article.

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Cite this study APA, Vancouver, BibTeX · download .bib or .ris

Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.

APA 7th

Boeriu, A. I., Andrews, S. J., Hoang, T., Bae, S., & Yaffe, K. (2026). Epigenetic Clock Trajectories and Brain Health in Midlife. medRxiv. https://doi.org/10.64898/2026.07.16.26358251

Vancouver

Boeriu AI, Andrews SJ, Hoang T, Bae S, Yaffe K. Epigenetic Clock Trajectories and Brain Health in Midlife. medRxiv. 2026. doi:10.64898/2026.07.16.26358251.

BibTeX

@article{boeriu2026-23452582,
  author  = {Boeriu, A. I. and Andrews, S. J. and Hoang, T. and Bae, S. and Yaffe, K.},
  title   = {{Epigenetic Clock Trajectories and Brain Health in Midlife}},
  journal = {medRxiv},
  year    = {2026},
  doi     = {10.64898/2026.07.16.26358251},
  url     = {https://doi.org/10.64898/2026.07.16.26358251}
}

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