nto 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 breaks 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