Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology
Vijay K Ramanan, Timothy G Lesnick, Scott A Przybelski, Michael G Heckman, David S Knopman, Jonathan Graff-Radford, Val J Lowe, Mary M Machulda et al.. Acta neuropathologica communications, 2021-03-23
Topic: Genetics and APOE
Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10-8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
Key findings
- Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET).
- Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses.
- Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10-8, β = 0.23), and demonstrated replication in an independent cohort.
- Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory.
- Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for 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 32 of the 56 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Acta neuropathologica communications) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over 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 | 2021 — 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 | 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 33757599) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 32 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 32 of the 56 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
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APA 7th
Ramanan, V. K., Lesnick, T. G., Przybelski, S. A., Heckman, M. G., Knopman, D. S., Graff-Radford, J., et al. (2021). Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology. Acta neuropathologica communications. https://doi.org/10.1186/s40478-021-01154-1
Vancouver
Ramanan VK, Lesnick TG, Przybelski SA, Heckman MG, Knopman DS, Graff-Radford J, et al. Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology. Acta neuropathologica communications. 2021. doi:10.1186/s40478-021-01154-1. PMID: 33757599.
BibTeX
@article{ramanan2021-33757599,
author = {Ramanan, Vijay K and Lesnick, Timothy G and Przybelski, Scott A and Heckman, Michael G and Knopman, David S and Graff-Radford, Jonathan and Lowe, Val J and Machulda, Mary M and others},
title = {{Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology}},
journal = {Acta neuropathologica communications},
year = {2021},
doi = {10.1186/s40478-021-01154-1},
pmid = {33757599},
url = {https://doi.org/10.1186/s40478-021-01154-1}
}