) than noncarriers. Courtesy of Carlos Cruchaga and Oskar Hariri.
This type of genomics work is in its infancy, but so far, it appears that people with dominantly inherited AD have fewer excitatory neurons and more neuronal death at the same disease stage than people with late-onset AD (see image above; Del-Aguila et al., 2019; Li et al., 2018). If this trend holds up, it would confirm at the level of gene expression that dominantly inherited Alzheimer’s disease is a more aggressive form of AD. “These are examples of the work we do with the tissue you donate,” Goate told the families.
Mutations Keep On Coming
Incidentally, pathogenic APP and presenilin mutations are popping up anew in people at a rate scientists can measure. While current DIAN members have (or had) a parent with the disease, separate collections of sporadic, i.e. non-familial, early onset AD cases turn out to contain people who carry known pathogenic mutations in APP or PSEN1 or 2. In Los Angeles, Goate cited a study that included 10 such cases in whom that known mutation had newly arisen, i.e., the patient’s biological parents had not had AD (Lanoiselée et al., 2017). “These mutations look sporadic now, but in future generations they will look familial,” Goate said. Luciana, an at-risk DIAN participant living in Argentina, showed such an example at the family conference. A journalist herself, she traced her family’s mutation to her Lebanese great-grandfather. He likely suffered what looked like sporadic early onset dementia in his day, but passed on a presenilin mutation to at least 10 descendants to date (see Part 1 of this series).
In fact, a growing number of APP and presenilin mutations—some familial, some sporadic—have become known in Central and South American countries in recent years. Jorge Llibre-Guerra at WashU told Alzforum that people afflicted with the A431E PSEN1 mutation, first discovered in the Mexican state of Jalisco, may turn out to be as numerous as those carrying the E280A “Paisa” mutation in Colombia, for whom Francisco Lopera and his team at University of Antioquia in Medellin have been providing care, support, and now a first prevention trial. At 1,192 mutation carriers, the Colombian cohort is the largest known in the world today.
Affected (black) and unaffected members of a Brazilian family carrying the “Iranian” APP mutation T714A. Courtesy of Leonel Takada.
At the DIAD family meeting, Leonel Takada, University of São Paulo Medical School, showed a poster of the first Brazilian study assessing how frequently mutations can be found in autosomal-dominant AD at his clinic. Of the 17 probands from different families in Takada’s study, five had a mutation in PSEN1, of which four were previously described and one is new. Two probands from unrelated families had the same T714A APP mutation, known as the Iranian mutation. In one of the families, six of eight children of an affected mother had the disease, and the sixth sibling alone passed the mutation on to six of her 10 children (see image above).
Llibre-Guerra, Lopera, Takada, Ana Luisa Sosa-Ortiz of the National Institute of Neurology and Neurosurgery in Mexico City, and Ricardo Allegri of FLENI in Buenos Aires are working with the Alzheimer’s Association to obtain funding for a DIAN site to bring services, research, and eventually also prevention trials to families in this part of the world.
- The Mutation You Want: It Protects the Brain, Extends Life
- Genetic Resilience—Can We Find Treatments for the Sick by Studying the Healthy?
- ASOs: Wave of the Future in Alzheimer’s Therapeutics?
- As DIAN Wraps Up Anti-Aβ Drug Arms, it Sprouts Tau, Primary Prevention Arms
- Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.
- Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, R