Uncovering Gene Variants Linked to Early Onset Alzheimer’s Disease: Insights and Implications

Understanding the Link Between Rare Gene Variants and Early-Onset Alzheimer’s Disease

Study Overview

A 2017 study explored the connection between rare gene variants and the risk of early-onset Alzheimer’s disease (EOAD). Researchers identified variants in several genes, notably PSD2, TCIRG1, and RIN3, which are essential for endolysosomal function. It is estimated that mutations in key genes contribute to 5-10% of EOAD cases. While most genetic risk factors remain unidentified, existing evidence indicates that genes and molecular pathways associated with late-onset Alzheimer’s disease (LOAD) may also play a role in EOAD. Identifying additional genetic risk factors could enhance the understanding of EOAD, providing crucial insights for screening, treatment, and management.

Details of the Research

The study, published in JAMA Neurology, defined early-onset Alzheimer’s as occurring before the age of 65. Between January 2013 and October 2016, researchers screened the genomes of 51 non-Hispanic White individuals diagnosed with EOAD, focusing on rare variants of genes linked to EOAD, including APP, PSEN1, and PSEN2. These individuals had previously tested negative for known variants in these genes as well as for two copies of the ε4 form of APOE, which is associated with a twelvefold increase in EOAD risk.

The study also included 53 Caribbean Hispanic participants, comprising 42 EOAD patients and 11 unaffected individuals from the same families, who tested negative for known variants in APP, PSEN1, PSEN2, MAPT, and GRN.

Key Findings

The research uncovered mutations in the gene SORL1 across three families, two of which had members with LOAD. The specific mutation SORL1-Cys1431fs was present in two sisters, one with an APOE-ε3/4 genotype and the other experiencing mild cognitive impairment at age 69. Additionally, the mutations PSEN1-R265G and PSEN2-M174V were identified in individuals with ages at onset (AAO) of 50 and 48, respectively, both with an APOE-ε3/3 genotype.

Among the EOAD patients, 26 rare variants were linked to LOAD, and the RIN3 variant notably increased the odds of EOAD. The PSEN1-A79V mutation, associated with Alzheimer’s disease, was identified in two unrelated individuals with AAOs of 54 and 56. Furthermore, MAPT-R406W, known to affect both Parkinson’s disease and Alzheimer’s, was found in two siblings and another individual, with AAOs of 52, 56, and 61. Due to their known effects on amyloid-beta plaques and tau protein tangles, these individuals were excluded from further analyses.

The study found that the likelihood of having EOAD was greater among those with specific mutations compared to those without. However, three of the four patients with these mutations also had a copy of APOE-ε4. Variants in PSD2, LIN37, SLC22A17, LRRC16B, and HSD17B were also detected in unrelated EOAD cases. Notably, 30 rare variants were shared between non-Hispanic White and Caribbean Hispanic participants, including TCIRG1, which is associated with both EOAD and LOAD.

Significance of Endolysosomal Transport Genes

The genes PSD2, TCIRG1, and RIN3 are involved in endolysosomal transport, a critical process through which cells absorb and degrade nutrients. Deficiencies in this process may lead to amyloid beta accumulation, suggesting that certain rare variants in these genes could contribute to Alzheimer’s disease development.

Future Research Directions

Further investigation is necessary to confirm whether the cellular pathways associated with PSD2, TCIRG1, and RIN3 influence amyloid-beta levels. Larger studies are needed to assess the risk of EOAD linked to rarer gene variants identified in this research.

In conclusion, this pivotal study highlights the potential involvement of PSD2, TCIRG1, RIN3, and RUFY1 in the endolysosomal transport system, essential for understanding Alzheimer’s disease. It also identifies shared genetic factors between early and late-onset Alzheimer’s, including SORL1, PSEN2, and TREM2, contributing to the knowledge of risk genes associated with both forms of the disease.

References

Kunkle, B.W. et al. (2017). Early Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport. JAMA Neurology. doi:10.1001/jamaneurol.2017.1518