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Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors
Eva Bagyinszky, Seong Soo A An. International journal of molecular sciences, 2024-11-07
Topic: Genetics and APOE
Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as Sortilin-related receptor 1 (SORL1), Phospholipid-transporting ATPase ABCA7 (ABCA7), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Phosphatidylinositol-binding clathrin assembly protein (PICALM), and clusterin (CLU) were implicated. These genes contribute to neurodegeneration through both gain-of-function and loss-of-function mechanisms. While it was traditionally thought that heterozygosity in autosomal recessive mutations does not lead to disease, haploinsufficiency was linked to several conditions, including cancer, autism, and intellectual disabilities, indicating that a single functional gene copy may be insufficient for normal cellular functions. In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles. Paradoxically, heterozygous knockouts of PSEN1 or PSEN2 can impair synaptic plasticity and alter the expression of genes involved in oxidative phosphorylation and cell adhesion. Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation. Conversely, haploinsufficiency in APOE, beta-secretase 1 (BACE1), and transmembrane protein 59 (TMEM59) was reported to confer neuroprotection by potentially slowing amyloid deposition and reducing microglial activation. Given its implications for other neurodegenerative diseases, the role of haploinsufficiency in AD requires further exploration. Modeling the mechanisms of gene knockout and monitoring their expression patterns is a promising approach to uncover AD-related pathways. However, challenges such as identifying susceptible genes, gene-environment interactions, phenotypic variability, and biomarker analysis must be addressed. Enhancing model systems through humanized animal or cell models, utilizing advanced research technologies, and integrating multi-omics data will be crucial for understanding disease pathways and developing new therapeutic strategies.
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APA 7th
Bagyinszky, E., & An, S. S. A. (2024). Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors. International journal of molecular sciences. https://doi.org/10.3390/ijms252211959
Vancouver
Bagyinszky E, An SSA. Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors. International journal of molecular sciences. 2024. doi:10.3390/ijms252211959. PMID: 39596030.
BibTeX
@article{bagyinszky2024-39596030,
author = {Bagyinszky, Eva and An, Seong Soo A},
title = {{Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors}},
journal = {International journal of molecular sciences},
year = {2024},
doi = {10.3390/ijms252211959},
pmid = {39596030},
url = {https://doi.org/10.3390/ijms252211959}
}
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Key findings
- In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles.
- Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. 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 journal's citation record, 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, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International journal of molecular sciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 4 / 5 | 2024 — within 3 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 | 2 / 2 | Indexed in PubMed (PMID 39596030) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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