UK DRI at UCL Guest Seminar: Diego Sepulveda-Falla

Mechanisms for phenotypic heterogeneity in Familial Alzheimer's disease

In Colombia, we have been following up during the last 35 years the largest known population suffering familial Alzheimer’s disease (FAD). All members of this kindred are descendants of a single founder back in the XVIII century. Almost 25% of members of this population carry a PSEN1 mutation, E280A, and half of the mutation carriers are symptomatic for mild cognitive impairment or dementia. Finally, we have collected 145 brains, all PSEN1 E280A FAD carriers. These cases are as similar as human cases can be, belonging to the same family, inhabiting the same region with similar dietary and environmental factors, and carrying the same PSEN1 pathological mutation. However, we have identified wide phenotypic variability in disease presentation, ages of disease onset, clinical features, and other pathological hallmarks. During the neuropathological characterization of disease heterogeneity, we have identified molecular and cellular modifying factors explaining delay of disease onset and localized sparing of Alzheimer’s pathology. The identification of molecular mechanisms of disease protection in FAD-affected populations can lead to the potential development of therapies against the more common sporadic AD and a better understanding of this disorder.