Single-Nucleus Profiling Reveals Neuronal Metabolic Collapse During the Transition to Alzheimer’s Disease Dementia
Lu S, Enduru N, Citu C, Tung C, Zhao Z.. bioRxiv, 2026-10-28
Topic: Genetics and APOE
Current Alzheimer’s disease (AD) neuropathological metrics, including Thal phasing, and Braak staging, often do not accurately predict cognitive status: many cognitively resilient individuals have substantial pathological burdens, whereas some patients with dementia show minimal classical AD pathology. Here, we addressed this discrepancy by investigating the molecular mechanisms underlying AD dementia using single-nucleus RNA-sequencing and single-nucleus multiome datasets. To eliminate cross-modality scaling artifacts and compositional biases inherent in neurodegenerative tissues, we normalized the datasets using our novel framework, bypassing scaling issues of conventional methods that may obscure critical biological signals of interest. We identified neuron-specific suppression of nuclear-encoded mitochondrial genes and their upstream mitochondrial biogenesis signaling (MBS) as primary drivers of clinical dementia. By integrating multi-omic quantitative trait loci, genome-wide association studies, and epigenomic profiles, we delineated genetic and epigenetic changes underlying MBS suppression. This study provides a systematic genomic framework for understanding the mechanisms of cognitive resilience.
Key findings
- Here, we addressed this discrepancy by investigating the molecular mechanisms underlying AD dementia using single-nucleus RNA-sequencing and single-nucleus multiome datasets.
- To eliminate cross-modality scaling artifacts and compositional biases inherent in neurodegenerative tissues, we normalized the datasets using our novel framework, bypassing scaling issues of conventional methods that may obscure critical biological signals of interest.
- We identified neuron-specific suppression of nuclear-encoded mitochondrial genes and their upstream mitochondrial biogenesis signaling (MBS) as primary drivers of clinical dementia.
- By integrating multi-omic quantitative trait loci, genome-wide association studies, and epigenomic profiles, we delineated genetic and epigenetic changes underlying MBS suppression.
- This study provides a systematic genomic framework for understanding the mechanisms of cognitive resilience.
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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Preprint — not yet peer-reviewed.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 (bioRxiv) |
| 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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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Lu, S., Enduru, N., Citu, C., Tung, C., & Zhao, Z. (2026). Single-Nucleus Profiling Reveals Neuronal Metabolic Collapse During the Transition to Alzheimer’s Disease Dementia. bioRxiv. https://doi.org/10.64898/2026.10.26.761376
Vancouver
Lu S, Enduru N, Citu C, Tung C, Zhao Z. Single-Nucleus Profiling Reveals Neuronal Metabolic Collapse During the Transition to Alzheimer’s Disease Dementia. bioRxiv. 2026. doi:10.64898/2026.10.26.761376.
BibTeX
@article{lu2026-20c913a6,
author = {Lu, S. and Enduru, N. and Citu, C. and Tung, C. and Zhao, Z.},
title = {{Single-Nucleus Profiling Reveals Neuronal Metabolic Collapse During the Transition to Alzheimer’s Disease Dementia}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.26.761376},
url = {https://doi.org/10.64898/2026.10.26.761376}
}
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