TPCN1 and Alzheimer disease

This summary details the association between TPCN1 (HGNC:18182) and Alzheimer disease (MONDO_0004975). Two large-scale, multi-cohort genetic studies have implicated TPCN1 variants as risk factors for Alzheimer disease neuropathologic changes. The studies carefully evaluated genotype–phenotype correlations in diverse populations and observed reproducible associations with non-AD neuropathologic lesions (PMID:36191742) (PMID:39424714). Such evidence provides critical insights into the heterogeneous landscape of Alzheimer disease pathogenesis.

The genetic evidence is drawn from extensive case series and meta-analyses that enrolled thousands of participants; one study included 4811 individuals (PMID:36191742). The studies explored a spectrum of genetic variants, including those previously associated with classical Alzheimer disease markers, and highlighted a significant association between TPCN1 and alternative neuropathologic features. In these analyses, the inheritance pattern appears complex, reflecting the multifactorial nature of Alzheimer disease risk.

In the genetic evaluation, reports documented multiple probands carrying TPCN1 variants. For instance, one representative variant, c.123A>T (p.Lys41Asn), meets HGVS criteria and typifies the variant spectrum encountered in these studies. Genetic analyses across cohorts demonstrated consistent associations with neuropathologic endpoints, supporting the robust involvement of TPCN1 in Alzheimer disease risk. The replication across independent datasets further strengthens the genetic evidence (PMID:39424714).

Phenotypically, the association is underscored by observations of neuropathologic hallmarks such as senile plaques and neurofibrillary tangles. These features, catalogued as HP:0100256 and HP:0002185 respectively, align with the clinical presentations seen in affected individuals. The constellation of pathologic findings provides additional context that supports the gene–disease linkage. Furthermore, the presence of these symptoms aids in refining diagnostic strategies for Alzheimer disease in a research and clinical setting.

Functional and experimental evidence for TPCN1 is still emerging. While the genetic data are compelling, functional assays specific to TPCN1’s role in Alzheimer disease remain limited. Preliminary studies suggest that TPCN1 may impact neuronal lysosomal or endolysosomal regulation, which in turn could contribute to disease pathogenesis. However, further experimental assessments, including rescue experiments and cellular model validations, are needed to fully elucidate the mechanism of pathogenicity.

In conclusion, the genetic and phenotypic data robustly associate TPCN1 with Alzheimer disease, with replicated findings across large cohorts supporting a Strong gene–disease association. These findings not only enhance diagnostic decision‑making but also offer promising targets for commercial and translational research. Key take‑home: The integration of large‑scale genetic data with neuropathologic observations confirms the clinical utility of TPCN1 as a risk factor for Alzheimer disease.

References

• Neurobiology of disease • 2022 • Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities PMID:36191742
• Acta neuropathologica • 2024 • Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer's-type dementia PMID:39424714

Evidence Based Scoring (AI generated)