” who remain cognitively healthy long after their family’s age at onset. One, Doug Whitney, is a regular at the family meeting; this year again, he was as well as ever despite his presenilin 2 “Volga German" mutation. The Colombian cohort includes at present seven carriers of the E280 mutation whose dementia did not start until old age, even though it usually begins in the 40s. Kosik and others are searching for the genes that held their disease at bay. One such gene was grist for the rumor mill at AAIC; its publication is currently embargoed but due out soon. About the others, all Kosik knows so far is that their protective variants do not lie in protein-coding regions. “They are more complicated to find, but we will,” Kosik said. Noncoding mutations tend to work by controlling the expression of other genes.
To understand gene expression in AD, DIAN is proving important in genomics research, as well. Genomics takes the study of genetics beyond a single gene. For example, scientists compare brain tissue from dominantly inherited to that of late-onset AD, and ask in which particular cell types a disease mutation does its damage. Is it neurons? Is it glial cells? At the DIAD family meeting, Goate cited studies by WashU’s Carlos Cruchaga, Oskar Harari, and others. They use pieces of postmortem brains donated by participants in DIAN and other AD studies, physically separate out the nuclei of the different cell types, and quantify which genes each individual cell had been expressing, and in what amounts, while the person was still alive. This is a step forward from mushing up bits of brain tissue and analyzing all the component cell types together, an older practice that obscured big differences between them.
Fewer Neurons in ADAD? An example of single-cell RNA analysis comparing brain tissues from a PS1 mutation carrier and noncarriers. Software named after the French pointillist painter Georges Seurat sorts gene-expression data into clusters. In this study, the carrier had fewer excitatory neurons (red, ochre, green) 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 Lop