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Investigating the Causal Relationship between Neuroticism and Alzheimer’s Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors
Akbarian N, Ebrahimi M, Dos Santos FC, Afjeh SS, Abdelhack M, Diaconescu AO, Felsky D, Zai CC et al.. medRxiv, 2026-08-04
Topic: Genetics and APOE
Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer’s disease (AD). However, the mechanisms underlying this association remain unclear. Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk. To assess causality, a two-sample Mendelian randomization (MR) was employed using publicly available genome-wide association studies (GWAS) for neuroticism (Nagel et al., 2018) and AD (Bellenguez et al., 2022). Mediation analysis was conducted in a subset of UK Biobank participants aged 60 and older, including 121,825 controls (mean age = 63.9 ± 2.81; 61,993 females or 50.9%) and 1,277 individuals with AD (mean age = 65.6 ± 2.71; 628 females or 49.2%). All participants had complete data on neuroticism and the potential mediators. MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal. However, depression (β=0.048, p=3×10⁻⁴), hypertension (β=0.005, p=2×10⁻⁴), and alcohol consumption (β=0.001, p=1×10⁻ 5 ) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk. Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect. A better understanding of these mediating pathways may inform targeted prevention and therapeutic strategies to reduce AD risk.
Key findings
- Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer’s disease (AD).
- Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk.
- MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal.
- However, depression (β=0.048, p=3×10⁻⁴), hypertension (β=0.005, p=2×10⁻⁴), and alcohol consumption (β=0.001, p=1×10⁻ 5 ) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk.
- Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect.
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Study details
- Participants1,277
- Effect sizeor 50.9; or 49.2
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 34 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design 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 21 of the 62 points we could judge it on, which is 34 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 | 1,277 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 21 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 21 of the 62 points we could judge it on is 34 out of 100. |
| Total | 34 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Akbarian, N., Ebrahimi, M., Dos Santos, F. C., Afjeh, S. S., Abdelhack, M., Diaconescu, A. O., et al. (2026). Investigating the Causal Relationship between Neuroticism and Alzheimer’s Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors. medRxiv. https://doi.org/10.64898/2026.08.01.26359481
Vancouver
Akbarian N, Ebrahimi M, Dos Santos FC, Afjeh SS, Abdelhack M, Diaconescu AO, et al. Investigating the Causal Relationship between Neuroticism and Alzheimer’s Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors. medRxiv. 2026. doi:10.64898/2026.08.01.26359481.
BibTeX
@article{akbarian2026-0d107df7,
author = {Akbarian, N. and Ebrahimi, M. and Dos Santos, F. C. and Afjeh, S. S. and Abdelhack, M. and Diaconescu, A. O. and Felsky, D. and Zai, C. C. and others},
title = {{Investigating the Causal Relationship between Neuroticism and Alzheimer’s Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.08.01.26359481},
url = {https://doi.org/10.64898/2026.08.01.26359481}
}
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