In What Could Be an Alzheimer's Breakthrough, UCLA Scientists Link Specific Gene Mutations to Dementia

_{Tau protein, which when accumulated abnormally may contribute to dementia.}

In Alzheimer’s disease, the most common type of dementia, scientists believe there are two primary mechanisms. The first is the development and accumulation of an abnormal protein, beta-amyloid. This starts early in the disease and is believed to cause much of the damage that leads to cognition and memory problems. Later in the disease, another abnormal protein called tau accumulates.

Researchers with the University of California, Los Angeles (UCLA) Health Sciences have identified two major groups of genes that, when mutated, results in overproduction of the tau protein, at least in mice. They published their research in the journal Nature Medicine.

The research was primarily conducted on mouse models of dementia. They then searched a database of the genetic effects of experimental drugs to try to find ones that might affect the loss of neurons.

“Our study is the most comprehensive published effort to date to identify the source of neurodegeneration across species and provides an important roadmap for the development of potentially effective new drugs for Alzheimer’s disease and other dementia,” stated senior author Daniel Geschwind, professor of neurology and psychiatry at the David Geffen School of Medicine at UCLA.

The most common gene associated with late-onset Alzheimer’s is apolipoprotein E (APOE), which has three common types: APOE e2, which seems to decrease the risk of Alzheimer’s; APOE e4, which seems to increase the risk of Alzheimer’s; and APOE e3, which is the most common type, and doesn’t seem to affect Alzheimer’s risk.

However, people who have two APOE e4 genes do not necessarily develop Alzheimer’s disease. And it does occur sometimes in people who have no APOE e4 gene.

Other genes linked to late-developing Alzheimer’s include ABCA7, CLU, CR1, PICALM, PLD3, TREM2 and SORL1. Others associated with early-onset Alzheimer’s are APP, PSEN1 and PSEN2.

The UCLA team identified MAPT and GRN genes. Their focus, however, was on frontotemporal dementia, which is a type of early-onset dementia. The processes involved are similar to those observed in Alzheimer’s disease and another type of dementia called supranuclear palsy.

Geschwind’s group hypothesized that mouse models of dementia often failed because the mouse models typically use a single inbred strain. They studied frontotemporal dementia in three genetically distinct strains of mice, looking at the genetic activity in different parts of the brain at different periods of time.

The mutation clusters they found were associated with neurodegeneration in all three mouse models. “There is still a significant amount of work that needs to be done to develop drugs that could be effectively used in humans against these targets, but this is an encouraging step,” Geschwind stated.

In September, researchers at Massachusetts General Hospital (MGH) and Johns Hopkins School of Medicine identified how the abnormal form of tau disrupts normal brain function. They published their research in the journal Neuron.

Much of their work revolved around a newly identified biochemical aspects of tau—under some conditions, tau can form microscopic droplets. Their search for other proteins with the same property led them to the nuclear pore complex, a structure on the nuclear membrane that manages the transport of proteins and RNA between the nucleus and the cytoplasm.

“Communication between the nucleus and the rest of the cell is usually a tightly regulated process,” stated co-senior author Bradley Hyman, director of the MGH-based Massachusetts Alzheimer’s Disease Research Center. “Our work shows a new way tau might cause brain cells to become impaired. In other systems, disruption of this communication causes cell misfunction and even cell death, so we think this might contribute to neuronal dysfunction and death in Alzheimer’s disease as well.”

Although this basic research is good—the more we know, the better the odds of developing preventions or treatments for dementias and Alzheimer’s disease—a recent study pointed out that between 1998 and 2017 there were 146 failed attempts at developing drugs for Alzheimer’s disease.

Although discouraging, most researchers in the field, and the report itself, expressed cautious optimism. The study noted, “In fact, a recent analysis of late-stage Alzheimer’s drugs, conducted by ResearchersAgainstAlzheimer’s, a global network of leading researchers, found nearly a hundred treatments in Phase II and III development in 2018. The analysis demonstrates that the drugs in development are increasingly attacking the disease in different ways—an important fact given that successful future treatments will likely rely on multiple therapies to stop the disease.”