PSEN2 gene mutation
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Epidemiology
- case report* of an exceptional resilience mutation carrier, an individual with p.Asn141Ile PSEN2 gene mutation, surviving to mid 70's without neurofibrillary tangles* or cognitive impairment[3]
- his brain was full of amyloid plaques[3]
* Neurofibrillary tangles in the exceptional resilience carrier were confined to the occipital cortex Interpretion:
- this case report of an exceptional resilience mutation carrier[3] provides strong evidence that PHF-tau & neurofibrillary tangles define Alzheimer pathology as describedby Braak & Braak in 1991[4] (see histopathology of Alzheimer's disease)
- this case report[3] did not identify any previously described protective factors present in the genome of the exceptional resilience mutation carrier
Pathology
- a point mutation resulting in ~1.2-3x increase production of A-beta 42 & is associated with early onset Alzheimer's disease[1][2]
Genetics
- autosomal dominant presenilin 2 p.Asn141Ile mutation
- candidate protective genes
* MRPL15P1 mitochondrial ribosomal protein L15 pseudogene 1
* The exceptional resilience mutation carrier also with
- TREM2 p.Asp87Asn variant (association with AD unclear)
- MAPT variant p.Tyr441His (reportedly protective)
- CD33 p.Gly304Arg (putative protective effect)
* The exceptional resilience mutation carrier exhibits a lower abundance for almost 200 proteins & higher abundance for almost 300 proteins vs other carriers of the PSEN2 gene mutation
- the highly abundant proteins are enriched in pathways affecting protein folding
- include multiple members of the heat shock protein family
* The exceptional resilience mutation carrier exhibits upregulation of GPCPD1, an enzyme involved in choline production (reportedly associated with cognitive resilience in patients with Alzheimer's disease)
Clinical manifestations
- carriers are genetically destined to develop Alzheimer's while still young (by age 52 years)[3]
Notes
- the DIAN investigators have established a platform at the Dominantly Inherited Alzheimer Network (DIAN) for interested investigators to access the data, propose studies & suggest collaboration ideas aimed at understanding how this individual has resisted the clinical onset of Alzheimer's disease
More general terms
Additional terms
References
- ↑ 1.0 1.1 Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7638622
- ↑ 2.0 2.1 Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7651536
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Reardon S A man was destined for early Alzheimer's - these genes might explain his escape Nature News. Feb 10 2025 https://www.nature.com/articles/d41586-025-00398-4
Llibre-Guerra JJ, Fernandez MV, Joseph-Mathurin N et al Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med. 2025 Feb 10. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39930140 https://www.nature.com/articles/s41591-025-03494-0 - ↑ 4.0 4.1 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82(4):239-59. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1759558