UK DRI at UCL Guest Seminar: Francisco Lopera & Juan Pablo Sánchez Escudero

Early Onset Autosomal Dominant AD: E280A PS1 COHORT

In this talk, Dr. Francisco Lopera will take us on a remarkable journey through the ground-breaking discoveries resulting from his extensive research:

For 40 years, we have been studying the largest population in the world with early onset autosomal dominant Alzheimer's disease at Universidad de Antioquia in Medellin, Colombia. Approximately 40% of this population lives in rural areas and works in agriculture. For years we visited their homes to assess them and understand their cognitive profile.

As a result of collaboration with Ken Kosik, John Morris, and Alison Goete, we discovered that these families are affected by the pathogenic mutation E280A in Presenilin 1 gene located in chromosome 14, named Paisa mutation due to its geographic origin in Antioquia.

This population of 25 multigenerational families, comprising over 6,000 members, has been extensively studied to understand the natural history and evolution of this form of Alzheimer's disease, which typically progresses from mild cognitive impairment at 44 to dementia at 49, and death in the 60s. Currently, almost 1200 individuals live with the mutation and show signs of AD or will be affected in the following years as this mutation has a penetrance of about 100%.

Notably, carriers of the Paisa mutation show high levels of biomarkers such as ß42 in cerebrospinal fluid, NFL and phTAU in plasma at 24, 20 years before the first symptoms of Mild Cognitive Impairment. Additionally, neuroimaging studies have revealed that these individuals showed PET-amyloid positivity at 28 and pTAU positivity ten years later at 38. Regarding cognitive markers, decreased performance in the word-list test of CERAD battery around 32 years is the earliest sign of cognitive decline. Currently, new research using digital neuropsychology tools aims to investigate the suitability of performance in spatial navigation tasks as cognitive markers since the preclinical stage of AD. This information is crucial for designing primary and secondary prevention clinical trials for Alzheimer's.

In collaboration with Banner Institute, Genentech, and Roche, we developed the API Colombia clinical trial to test the safety and efficacy of the monoclonal anti-amyloid antibody Crenezumab. The trial was conducted over eight years but produced negative results. However, the API program resulted in a notable finding, the product of a natural experiment: the discovery of a woman and a man among the studied families who carried both the Paisa mutation and another protective mutation, such as the ApoE3ch mutation or a mutation in a different gene under study currently. These individuals remained protected from the onset of Alzheimer's disease symptoms for more than two decades. These findings provide valuable insights for future research on natural prevention or cure for Alzheimer's disease.