Home › Research › Disease mechanisms
Ion modulation restores local synaptic function in APOE4 neuronal networks despite persistent impairments in global network organization
Grønlie MB, Mikalsen Kollstrøm A, Sandvig A, Sandvig I.. bioRxiv, 2026-09-14
Topic: Genetics and APOE
The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD), which accounts for the vast majority of AD cases. Ion dysfunction has emerged as a central mechanism involved in APOE4-related pathology, reflecting the importance of ion homeostasis for cell membrane excitability, synaptic transmission, and plasticity. We have previously demonstrated that ion dysfunction contributes to early AD-related network vulnerability, and that engaging synaptic plasticity mechanisms via ion modulation can restore network balance in neurodegenerative disease. Here, we investigated whether synaptic mobilization by ion modulation could ameliorate APOE4-associated dysfunction in human neuronal networks compared with isogenic APOE3 controls. APOE4 networks exhibited progressive structural and functional deterioration, manifesting as increased neurite length, reduced neurite branching, and reduced firing rate and number of active recording electrodes. This was accompanied by compensatory hypersynchronization, rendering networks vulnerable to pathological spread, and reduced synaptic AMPAR levels compared with isogenic APOE3 control networks. Modulating ion homeostasis restored the local firing dynamics and stabilized synaptic AMPAR levels. However, the elevated synchronization and aberrant morphology of APOE4 networks were not alleviated by engaging synaptic plasticity mechanisms, demonstrating that APOE4 networks retain a capacity for adaptive plasticity enabling restoration of local neuronal function, but that this recovery does not extend to higher-order network organization.
Key findings
- We have previously demonstrated that ion dysfunction contributes to early AD-related network vulnerability, and that engaging synaptic plasticity mechanisms via ion modulation can restore network balance in neurodegenerative disease.
- Here, we investigated whether synaptic mobilization by ion modulation could ameliorate APOE4-associated dysfunction in human neuronal networks compared with isogenic APOE3 controls.
- This was accompanied by compensatory hypersynchronization, rendering networks vulnerable to pathological spread, and reduced synaptic AMPAR levels compared with isogenic APOE3 control networks.
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. |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
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
Grønlie, M. B., Mikalsen Kollstrøm, A., Sandvig, A., & Sandvig, I. (2026). Ion modulation restores local synaptic function in APOE4 neuronal networks despite persistent impairments in global network organization. bioRxiv. https://doi.org/10.64898/2026.09.08.750089
Vancouver
Grønlie MB, Mikalsen Kollstrøm A, Sandvig A, Sandvig I. Ion modulation restores local synaptic function in APOE4 neuronal networks despite persistent impairments in global network organization. bioRxiv. 2026. doi:10.64898/2026.09.08.750089.
BibTeX
@article{gronlie2026-816ff7e2,
author = {Grønlie, M. B. and Mikalsen Kollstrøm, A. and Sandvig, A. and Sandvig, I.},
title = {{Ion modulation restores local synaptic function in APOE4 neuronal networks despite persistent impairments in global network organization}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.08.750089},
url = {https://doi.org/10.64898/2026.09.08.750089}
}