Marks JD, Ayuso VE, Carlomagno Y, Yue M, Todd TW, Hao Y, Li Z, McEachin ZT, Shantaraman A, Duong DM, Daughrity LM, Jansen-West K, Shao W, Calliari A, Bejarano JG, DeTure M, Rawlinson B, Casey MC, Lilley MT, Donahue MH, Jawahar VM, Boeve BF, Petersen RC, Knopman DS, Oskarsson B, Graff-Radford NR, Wszolek ZK, Dickson DW, Josephs KA, Qi YA, Seyfried NT, Ward ME, Zhang YJ, Prudencio M, Petrucelli L, Cook CN. TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Sci Transl Med. 2024 Jan 17;16(730):eadf9735. PubMed.
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University of Kentucky
Genetic variation at the TMEM106B locus is a massively under-appreciated risk factor for dementia, with a large impact on public health. TMEM106B variance was identified as a genetic modifier of dementia risk in the context of FTLD/FTD, as re-emphasized with new insights by the strong, recently published work by Jordan Marks and colleagues.
FTLD/FTD is a ~1:1,000 lifetime risk disease that often affects persons in advanced middle age, and each case is a tragedy. Moreover, TMEM106B (predicated on the same risk allele) also appears to stimulate TDP-43 proteinopathy in the far more prevalent condition limbic-predominant age-related TDP-43 encephalopathy (LATE)—a 1 in 3 lifetime risk disease that usually affects older persons.
Another interesting thing about the disease-driving TMEM106B haplotype: it appears to be differently inherited in persons of different ethnoracial backgrounds. For example, in persons with European ancestry, the risk allele is actually represented in the majority (more white people are at risk from TMEM106B genotype than are not at risk), whereas in persons of African ancestry the TMEM106B risk allele is in the minority.
By contrast, the other important risk factor for LATE-NC (GRN gene variant rs5848) is far more common in persons with African ancestry than in persons of European ancestry (Katsumata et al., 2023). These observations, coupled with the large apparent impact of these alleles, suggest that future therapeutic strategies for FTLD/FTD and LATE-NC may have some differences based on the patient populations that are being served.
References:
Katsumata Y, Fardo DW, Shade LM, Alzheimer’s Disease Genetics Consortium, Nelson PT. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry. J Neuropathol Exp Neurol. 2023 Aug 21;82(9):760-768. PubMed.
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