Each year, the DIAD family conference held in advance of the Alzheimer's Association International Conference features a science update, and this year the focus was on genetics. DIAN families know that the modern era of Alzheimer’s research started when blood given by their parents enabled the discovery of mutations in APP, presenilin 1 and 2 (Goate et al., 1991; Sherrington et al., 1995; Rogaev et al., 1995; Levy-Lahad et al., 1995). They may not know that Alzheimer’s genetics research today continues to draw on dominantly inherited AD. “The discoveries go back to the samples you donated in the 1980s, but they really do not end there,” Alison Goate told the families. Goate, who was at University College London when she discovered the first APP mutation, is now at Icahn School of Medicine, Mount Sinai, New York.
- Twenty-eight years after first gene was found, dominantly inherited AD still devastates families.
- Genes discovered for late-onset AD influence age of symptom onset in APP, PSEN mutation carriers.
- Geneticists are on the hunt for protective genes that delay onset.
By the late 1990s, after scientists had fingered ApoE as a risk gene for late-onset AD (Corder et al., 1993), progress in AD genetics overall slowed to a crawl for a decade or so. Scientists knew that APP and presenilin mutations caused rare, dominantly inherited AD on the one hand, and that ApoE4 explained a small piece of the common, late-onset form of AD on the other hand. However, in between these two was a large unexplained gap they were unable to close with the techniques at the time. They were stuck. Then, with the advent of GWAS and new sequencing and analysis methods, AD genetics research revived—and once again, dominantly inherited mutations are part of the progress.
Nowadays, scientists use the term “genetic architecture” to convey that the genetic basis of Alzheimer’s disease is more like a complex assembly of many elements than the product of a single gene. The respective “power” of different gene mutations, or variants, falls onto a spectrum. On one end are dominantly inherited variants in a single gene that are powerful enough to cause AD in early adulthood; they are rare. On the other end are variants that raise a person’s Alzheimer’s risk by only a smidgen; they occur commonly among the different world populations. In between these extremes of severity and frequency, however, are known to be many variants in many additional genes that are more or less pathogenic and more or less frequent. This in-between group contains ApoE and many other genes, including Trem2, CD33, and Sorl1, for example (Campion et al., 2019). For every given person, it is their inherited unique combination of variants from this collection of genes that determine if and when they develop dementia.
This much-cited image from a paper by Teri Manolio and colleagues depicts how disease variants of genes fall onto a spectrum defined by strength (effect size) and frequency in the population. DIAD mutations would crowd the top left corner. Many of the weaker, and more common, gene variants that are still being discovered likely influence when Alzheimer’s dementia develops in a given APP and PSEN mutation carrier. [Manolio et al., Nature, 2010.]
How does this play out in reality? For example, the 501 families who are in DIAN all have a known pathogenic mutation in APP, PSEN1, or PSEN2, and almost all carriers get the disease. Even so, age of onset varies from one person to the next. This is especially true of PSEN1, which, at 392 families with 177 different mutations, is the most commonly mutated gene in DIAD. While many mutations cause symptoms by one’s 40s, the spread across PSEN1 mutations ranges from age 20 to 80, and even within a given family’s single mutation, onset can differ by a decade. Indeed, when scientists looked among non-DIAN families who had clusters of late-onset AD (LOAD), 3.4 percent of these people turned out to carry a “DIAD” mutation (e.g., Cruchaga et al. 2012). This means that other genes influence when a pathogenic APP or presenilin mutation br