Alzheimer Risk Variants Identified With Genetic Markers

Targeting a reduction in levels of the tau protein is likely to be a useful therapeutic approach in Alzheimer disease in parallel with efforts to target amyloid beta levels, according to research that has identified a new set of genetic markers for the disease.

“We identified several genes that modulate tau levels in the cerebrospinal fluid. These genes may be useful therapeutic targets for Alzheimer disease,” senior investigator Alison M. Goate, DPhil, Professor of Genetics in Psychiatry at Washington University School of Medicine in St. Louis, told ConsultantLive.

Dr Goate and colleagues conducted a large genome-wide association study on tau in cerebrospinal fluid. They analyzed points along the genomes of 1269 patients who had undergone spinal taps as part of ongoing Alzheimer research. They identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimer disease progresses and dementia develops.

The apolipoprotein E (APOE) gene has been identified as a risk factor for Alzheimer disease and has been linked to amyloid beta, a key component of brain plaques that build up in the brains of persons with the disease.

“Targeting APOE may be an effective way to treat Alzheimer disease,” Dr Goate said. “APOE likely has a strong effect on the risk of Alzheimer disease because of its effects on two independent pathways, one that involves reduced amyloid beta clearance and a second that affects tau levels and tangle formation. This may also explain why APOE is such a strong risk factor for Alzheimer disease.”

Higher levels of tau and a phosphorylated version of tau (p-tau) in the cerebrospinal fluid are thought to reflect both tangle formation and neuronal cell death. Because tau levels are proportional to the cell death, higher tau levels are associated with more severe dementia, Dr Goate noted.
 
“Because of the known association between tau, tangles, and neuronal cell death, tau has long been considered a useful target for Alzheimer disease drugs,” said Dr Goate. “Previous attempts to target tau have focused on kinases that phosphorylate tau. However, since these kinases likely phosphorylate many proteins, this has not been a fruitful approach.”

Dr Goate and colleagues identified several genes that are associated with tau levels, and “thus targeting these pathways may provide a more specific means of reducing tau or p-tau levels,” she said.

Even though APOE has been known to be a strong risk factor for Alzheimer disease for more than a decade, “little research has focused on APOE as a target for treatment of Alzheimer disease,” said Dr Goate. “Earlier work has focused on the link between APOE4 and differences in amyloid beta clearance. Our work suggests that APOE also influences tau levels and tangle formation. Understanding this connection might lead to drug targets that reduce tau levels.”

If drugs could be developed to target tau, they might prevent much of the neurodegeneration that characterizes Alzheimer disease and, in that way, help prevent or delay dementia, Dr Goate suggested.

The researchers reported their results online April 24 in the journal Neuron.