Rare genetic coding variants associated with age-related episodic memory decline implicate distinct memory pathologies in the hippocampus
Ali, A.; Milman, S.; Weiss, E. F.; Gao, T.; Napolioni, V.; Barzilai, N.; Zhang, Z. D.; Lin, J.-R.
Show abstract
BackgroundApproximately 40% of people aged 65 or older experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. MethodsWe investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom MD simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. ResultsIn addition to the common polygenic risk of Alzheimers Disease (AD), we identified and replicated rare variant association in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. DiscussionOur study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease 97%
- An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration 96%
- Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease 96%
Similar papers in this journal
- Genetic architecture of brain age and its casual relations with brain and mental disorders 97%
- Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer's disease and epilepsy 96%
- Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2 94%
Similar papers in this journal
- Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis 95%
- Scalable Bayesian functional GWAS method accounting for multivariate quantitative functional annotations with applications to studying Alzheimer’s disease 95%
- Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range 93%
Similar papers in this journal
- Large meta-analysis of genome-wide association studies expands knowledge of the genetic etiology of Alzheimer’s disease and highlights potential translational opportunities 97%
- Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies 97%
- The impact of rare protein coding genetic variation on adult cognitive function 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.