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Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease
Schultz SA, Shirzadi Z, Schultz AP, Liu L, Fitzpatrick CD, McDade E, Barthelemy NR, Renton A et al.. Aging cell, 2023-06-08
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
What this study adds
Evidence grade: Moderate
This is a cross-sectional study. Among carriers of inherited PSEN1 variants in the DIAN study, those whose variant affects the transmembrane part of the protein had worse thinking, smaller hippocampus and higher phosphorylated tau than carriers of cytoplasmic variants, despite similar amyloid levels. The authors say variant location may explain much of the person-to-person difference in disease course, which matters for designing and interpreting clinical trials in inherited Alzheimer's.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Schultz, S. A., Shirzadi, Z., Schultz, A. P., Liu, L., Fitzpatrick, C. D., McDade, E., et al. (2023). Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease. Aging cell. https://doi.org/10.1111/acel.13871
Vancouver
Schultz SA, Shirzadi Z, Schultz AP, Liu L, Fitzpatrick CD, McDade E, et al. Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease. Aging cell. 2023. doi:10.1111/acel.13871. PMID: 37291760.
BibTeX
@article{schultz2023-37291760,
author = {Schultz, S. A. and Shirzadi, Z. and Schultz, A. P. and Liu, L. and Fitzpatrick, C. D. and McDade, E. and Barthelemy, N. R. and Renton, A. and others},
title = {{Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease}},
journal = {Aging cell},
year = {2023},
doi = {10.1111/acel.13871},
pmid = {37291760},
url = {https://doi.org/10.1111/acel.13871}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1.
- While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data.
- As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
Why it matters
Among carriers of inherited PSEN1 variants in the DIAN study, those whose variant affects the transmembrane part of the protein had worse thinking, smaller hippocampus and higher phosphorylated tau than carriers of cytoplasmic variants, despite similar amyloid levels. The authors say variant location may explain much of the person-to-person difference in disease course, which matters for designing and interpreting clinical trials in inherited Alzheimer's.
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Study details
- Study designcross-sectional
- Evidence strengthModerate
How this study scored 52/100
Published in a peer-reviewed journal, and it is a snapshot of people at one point in time. Scored zero for sample size, effect reported and randomized / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 50 of the 96 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Aging cell) |
| Journal's citation record | 2 / 4 | Aging Cell: journal h-index 216 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 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 | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 12 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.4 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 2 / 6 | Cited 1.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 31 institution(s) in 9 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37291760) |
| Free to read | 2 / 2 | Free to read |
| Points | 50 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 50 of the 96 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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