Heterozygous TREM2 (p.W44X) and PSEN1 (p.A431T) mutations in two Peruvian Families with Familial Alzheimer's Disease: Expanding the Genetic Landscape in Underrepresented Populations

Claudio Villegas-Llerena^1*Solange Paredes Moscosso¹María Luisa Guevara-Fujita¹Daisy Obispo¹Nilton Custodio²Rosa Montesinos²Jose Francisco Parodi³Oscar Flores-Flores³John Hardy^4,5Ricardo Fujita¹

• ¹Centro de Investigación de Genética y Biología Molecular (CIGBM), Instituto de Investigación, Facultad de Medicina Humana, Universidad de San Martin de Porres, Lima, Peru., Lima, Peru
• ²Research unit, Instituto Peruano de Neurociencias, Lima, Peru
• ³Universidad de San Martín de Porres, Facultad de Medicina, Centro de Investigación del Envejecimiento., Lima, Peru
• ⁴UK Dementia Research Institute, London, United Kingdom
• ⁵Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London,, London, United Kingdom

Alzheimer's disease (AD) accounts for up to 70% of all dementia cases, affecting an estimated 23–35 million people worldwide. According to the World Health Organization (WHO), the number of AD cases in Latin America, including Peru, is expected to quadruple by 2050. However, these populations remain underrepresented in research, diagnostics, and care. Early-onset Alzheimer's disease (EOAD), characterized by symptom onset before the age of 65, has been shown to have a strong genetic component, making it valuable for genetic studies. Identifying EOAD-associated mutations in underrepresented populations is crucial for uncovering pathogenic variants that may provide new insights into the disease's mechanisms. In this article, we present two Peruvian families with early and late onset AD in whom whole-exome sequencing (WES) revealed heterozygous variants associated with AD. In family AD002, we found a heterozygous variant in TREM2 (c.132G>A; p.W44X), a protein-truncating mutation. The proband and 17 family members participated in genetic testing, of which 04 members were variant carriers.. This is the first TREM2-associated mutation reported in the Peruvian population. In family AD009, a novel heterozygous variant in PSEN1 (c.1291G>A; p.A431T) is reported. The proband and 11 family members participated in genetic testing, of which 05 were carriers of the mutation (02 affected siblings and 03 unaffected relatives). This is the first report of PSEN1 A431T associated with AD. Overall, our findings suggest that TREM2 p.W44X is a likely-pathogenic variant whilst PSEN1 p.A431T is a candidate variant of uncertain significance (VUS) associated with AD; both genetic variants warrant further investigation.