The 7th Leonard Berg Symposium, Part 3

Abstract

One question that pervaded the 7th Leonard Berg Symposium is whether dominantly inherited AD really is the same disease as the common late-onset forms that afflict some 35 million people around the globe, according to a recent report. “Can we generalize from FAD to all AD?” asked Martin Rossor of University College, London. The question is important in part because the interest drug developers take in testing prevention in families with strong AD genetics hinges on their confidence that success in the few will translate into success in the many. In private, some industry leaders express doubt about that point, and some companies exclude eFAD families from their trials for this reason. That eFAD indeed models late-onset AD (LOAD) to a great extent, if not in all aspects, is a premise of DIAN, and the comparison of DIAN and ADNI data may settle the issue definitively. In the meantime, scientists at the Symposium discussed what clues they have so far. See below for talks taking stock of LOAD/eFAD similarities and differences in the clinic, pathology, biochemistry, genetics, and imaging. First, a word about nomenclature. Autosomaldominant AD is the form in which a child of an affected parent faces 50-50 odds of inheriting a pathogenic mutation in either the AβPP or the presenilin 1 or 2 genes. It is variously referred to as “familial” or “FAD,” “earlyonset” or “EOAD,” “early-onset familial” or “eFAD.” Strictly speaking, none of the terms is interchangeable. Familial AD often is merely a clustering, not a Mendelian autosomal-dominant inheritance pattern; early-onset AD is often sporadic in the sense that neither affected relatives, much less a gene mutation, is known. The term used in the Alzforum section on this set of aggressive forms of AD – eFAD – does not quite catch all people it means to include, either, because recently, autosomal-dominant pathogenic presenilin mutations were spotted in some rare families who get this form of AD in their seventies, i.e., with a late onset [1, 2]. The WashU researchers sidestepped this confusing nameology by using yet another term: “dominantly inherited Alzheimer disease.” DIAD conveniently stands opposite LOAD and echoes DIAN, making DIAN the network for the DIAD crowd. At the Leonard Berg Symposium, speakers stressed that DIAD/eFAD overall appears to model LOAD quite closely. However, it is not a carbon copy, and for the sake of discussion, the differences got center stage for a session. DIAD is heterogeneous. The way people decline can vary a bit from person to person, said Rossor, whose center follows members of 10 families with AβPP mutations and 34 families with presenilin 1 mutations. Certain clinical differences do track with genetic ones. For example, people who get DIAD because their AβPP gene is duplicated frequently have seizures, brain hemorrhages, and white matter changes. In these extremely rare families, some affected relatives start having seizures when they are teenagers, and depression and then dementia follow within a decade thereafter. With presenilin, some 175 different mutations are published, but clinicians have no comprehensive description of how their preclinical period unfolds. DIAN is aiming to accomplish that and in the process may match up genotypes to phenotypes. Based on what clinicians observe, it is already clear that some presenilin cases come with added signs that are atypical for AD.