Structured Metabolic Genetic Axes Reveal Distinct Lipid and Ketone-Body Programs in Alzheimer’s and Parkinson’s Disease
Shen J, Shen Y, Yu G, Pang L, Xiao C.. Research Square, 2026-10-19
Topic: Genetics and APOE
Background Metabolic dysregulation has been implicated in Alzheimer disease (AD) and Parkinson disease (PD), yet circulating metabolites are embedded within highly correlated metabolic networks. This structure complicates single-metabolite analyses and motivates genetic approaches that model shared metabolic architecture directly. Methods We applied Genomic SEM to NMR metabolite GWAS summary statistics to construct lipid and non-lipid latent metabolic factor GWAS. Six factors were screened against AD, PD, and Lewy body dementia using cross-trait LDSC, followed by MiXeR, pleiotropy-informed locus discovery, colocalization, transcriptomic prioritization, single-cell projection, virtual knockout, and target annotation. Results Among 18 factor-disease comparisons, three survived FDR correction: an HDL-core axis positively correlated with AD (rg = 0.142, FDR = 0.002), a ketone-body axis inversely correlated with PD (rg = -0.106, FDR = 0.015), and a TG-rich/VLDL-remodeling axis inversely correlated with PD (rg = -0.072, FDR = 0.031). Component-level LDSC supported the biological traceability of these axes. Downstream analyses linked HDL-core/AD to perivascular support, ketone-body/PD to distributed neuronal-glial energy adaptation, and TG/VLDL-remodeling/PD to lysosomal and membrane-trafficking programs. Target annotation prioritized experimentally approachable genes including GRK4 , PRMT7 , and TMEM175 . Conclusions Structured metabolic genetic axes reveal selective and biologically distinct links between circulating metabolism and neurodegenerative disease, providing a framework for mechanism-focused follow-up beyond single-metabolite association.
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APA 7th
Shen, J., Shen, Y., Yu, G., Pang, L., & Xiao, C. (2026). Structured Metabolic Genetic Axes Reveal Distinct Lipid and Ketone-Body Programs in Alzheimer’s and Parkinson’s Disease. Research Square. https://doi.org/10.21203/rs.3.rs-11247856/v1
Vancouver
Shen J, Shen Y, Yu G, Pang L, Xiao C. Structured Metabolic Genetic Axes Reveal Distinct Lipid and Ketone-Body Programs in Alzheimer’s and Parkinson’s Disease. Research Square. 2026. doi:10.21203/rs.3.rs-11247856/v1.
BibTeX
@article{shen2026-ca8d722a,
author = {Shen, J. and Shen, Y. and Yu, G. and Pang, L. and Xiao, C.},
title = {{Structured Metabolic Genetic Axes Reveal Distinct Lipid and Ketone-Body Programs in Alzheimer’s and Parkinson’s Disease}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11247856/v1},
url = {https://doi.org/10.21203/rs.3.rs-11247856/v1}
}
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Key findings
- Results Among 18 factor-disease comparisons, three survived FDR correction: an HDL-core axis positively correlated with AD (rg = 0.142, FDR = 0.002), a ketone-body axis inversely correlated with PD (rg = -0.106, FDR = 0.015), and a TG-rich/VLDL-remodeling axis inversely correlated with PD (rg = -0.072, FDR = 0.031).
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people 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 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| 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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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