eaks through in a person, Goate said.
One such gene is ApoE, insofar as APP/PSEN mutation carriers with the ApoE2 variant tend to get the family disease later than relatives with the ApoE4 variant. Another AD risk gene that preoccupies scientists is TREM2. It encodes a receptor protein sitting on microglia, the immune cells of the brain. What TREM2 risk variants do in DIAN families is unknown, but it is known that they speed up amyloid plaque formation in the brains of mice made to express DIAD mutations. Bits of the TREM2 protein are detectable in CSF of DIAN participants, and levels rise as people approach the symptomatic stage. “TREM2 probably influences progression of your family disease. The wide spread in age at onset that we see may be partly due to which TREM2 variant a person has,” Goate said.
Besides ApoE and TREM2, many additional AD risk genes may play into age at onset. In toto, geneticists to date have identified 41 spots, or loci, along the human genome that harbor risk variants for late-onset AD (see image above). When they compute all of these variants into one number—called a polygenic risk score, or PRS—they can see that this score partially accounts for the age at onset of dominantly inherited AD. In other words, the PRS score does not determine whether a DIAN participant will develop AD. That is largely due to the powerful APP or presenilin mutations. Rather, the other AD genes combined affect at what age that happens (Cruchaga et al., 2018).
Using blood from both DIAN and API participants, geneticists are hot on the trail of protective genes. Addressing DIAN families in L.A., Ken Kosik of the University of California, Santa Barbara, emphasized that no gene mutation is 100 percent deterministic. Scientists know that besides ApoE2, certain variants of the genes TMEM106B, phospholipase C, Rab10, and the Icelandic APP mutation delay Alzheimer’s onset (May 2019 news; Tavana et al., 2019; April 2016 news). And they are sure that more are yet to be found.
The DIAN families include several “escapees” 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