Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease
Wadhwani AR, Affaneh A, Van Gulden S, Kessler JA.. Annals of neurology, 2019-03-27
Topic: Brain proteins, microglia and lab models
Objective The apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem-cell-derived neurons predisposes them to injury and promotes the release of phosphorylated tau. Methods Induced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types. Results Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform-dependent manner by a heparin sulfate proteoglycan-dependent mechanism. Interpretation Our results demonstrate that endogenous expression of E4 by stem-cell-derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms. Ann Neurol 2019;85:726-739.
Key findings
- Results Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity.
- Interpretation Our results demonstrate that endogenous expression of E4 by stem-cell-derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death.
- This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau.
- These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms.
Why it matters
In neurons grown from stem cells of Alzheimer's patients, the APOE4 form of apolipoprotein E made the cells more vulnerable to injury and caused them to release more phosphorylated tau. This is laboratory work in cells, not a treatment or cure, and it suggests a possible mechanism by which APOE4 might help tau pathology spread.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 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 | 5 / 7 | Cited 145 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.1 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 4 / 6 | Cited 11.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 3 / 4 | Cited 56 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author John A. Kessler: h-index 86 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Northwestern University: institution h-index 1,592 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30840313) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Wadhwani, A. R., Affaneh, A., Van Gulden, S., & Kessler, J. A. (2019). Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease. Annals of neurology. https://doi.org/10.1002/ana.25455
Vancouver
Wadhwani AR, Affaneh A, Van Gulden S, Kessler JA. Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease. Annals of neurology. 2019. doi:10.1002/ana.25455. PMID: 30840313.
BibTeX
@article{wadhwani2019-30840313,
author = {Wadhwani, A. R. and Affaneh, A. and Van Gulden, S. and Kessler, J. A.},
title = {{Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease}},
journal = {Annals of neurology},
year = {2019},
doi = {10.1002/ana.25455},
pmid = {30840313},
url = {https://doi.org/10.1002/ana.25455}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 13.
Later studies that cite this one
7 studies in the alzhub library list this one in their references.