Depressive Symptoms and APOE ε2 Broad the Natural History in Presenilin-1 E280A Familial Early-Onset Alzheimer's Disease

Abstract

Background: Meta-analysis have associated depression with Alzheimer's disease, but it has not been easy to clarify whether it is a trigger or only a consequence. A longitudinal follow-up of depressive symptoms in carriers of the presenilin 1 (PSEN) E280A mutation, the biggest cohort in the world with a single genetic cause, help to understand this relationship. Methods: After 20-years of studying the PSEN1-E280A cohort, carriers of the mutation were retrospectively analysed for identifying depressive symptoms and other possible risk factors associated to the age of onset and progression at each clinical stage of the disease using Cox proportional hazards models. Clinically relevant depressive symptoms were identified according to three criteria: Structured medical interview, Geriatric depression scale short form, and Neuropsychiatric inventory-affective score. We analysed potential confounders: APOE, sex, hypothyroidism, educational level, marital status, rural residence, tobacco use, alcohol and drug abuse. Findings: Out of 6737 identified subjects in our database, 190 symptomatic carriers met the inclusion criteria and were analyzed. Participants exhibiting depressive symptoms prior to the appearance of amnesic symptoms were more prone to reach a faster onset of dementia stage. Hazard Ratio (HR)= 1,67; 95% Confidence Interval (CI), 1.01 to 2.76. Apolipoprotein E (APOE)e2 is a protective modifier of the age of onset in all stages: MCI HR= 0.48 (95% CI 0.24-0.98), dementia HR= 0.41 (95% CI 0.20-0.81); death HR = 0,28 (95% CI 0.09-0.84). Interpretation: Apolipoprotein Ee2 delay the onset of familial EOAD, PSEN1 E280A mutation. Important depressive symptom before the amnesic signs is triggering factor of earlier dementia stage, even in presence of APOE e2. These findings help to understand the magnitude of this complex genetic characteristic. Further studies are required to identify interventions capable of at least to delay the onset of dementia, modifying individual outcomes and decrease the social, family and economic impact. Funding Statement: This work was conducted with support from Universidad de Antioquia and Universidad Nacional de Colombia Declaration of Interests: None of the authors have any financial interests or affiliations relevant to the subject of this manuscript. Ethics Approval Statement: The execution of the study was approved by the ethics research committee of the Universidad de Antioquia. All Individuals authorized their participation and signed an informed consent. The confidentiality of their medical records was preserved.