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Natural Alzheimer’s Protection

Researchers identify a gene variant that reduces risk of Alzheimer’s disease.

By | July 11, 2012

image: Natural Alzheimer’s Protection Dreamstime, Tomasz Parys

Researchers have identified a mutation in the amyloid precursor protein (APP) that provides protection against Alzheimer’s disease, according to a study published today (July 11) in Nature. The mutation, which reduces cleavage of APP into the amyloid β fragments that aggregate in the brains of Alzheimer’s patients, appears to protect against the disease and age-related cognitive decline.

“We already knew that factors that increase the amount of amyloid β are risk factors, but this study demonstrates a rare variant that decreases the amount of amyloid β,” said Alison Goate, a geneticist at Washington University in St. Louis. Although a few other protective mutations have been identified, most notably those underlying the ApoE2 isoform of apolipoprotein E, most researchers have focused on genetic risk factors.

The value of looking beyond risk factors to protective mutations is “an important message for future studies,” said Fabrizio Tagliavini, who researches prion and prion-like diseases, including Alzheimer’s, at the Istituto Nazionale Neurologico Carlo Besta in Milan, Italy. Tagliavini’s own work on APP identified a different substitution, A673V, which occurs at the same site as the newly discovered protective mutation, but increases Alzheimer’s risk in homozygous individuals, by increasing generation and aggregation of amyloid β.

APP is a membrane protein expressed in many tissues but especially prevalent on the surfaces of neurons, extending into synapses. It can be cleaved at several sites, most notably by the aspartyl protease β-site APP cleaving enzyme 1 (BACE1). According to the amyloid hypothesis for Alzheimer’s disease development, processing of APP into amyloid β, and its subsequent aggregation into tangled fibrils, underlies disease development. The fibrils kill neurons, leading to the cognitive declines associated with Alzheimer’s.

In order to identify mutations in APP that could protect against Alzheimer’s development, the researchers, led by Kári Stefansson of the University of Iceland and genomics company deCODE genetics, performed a genome-wide association study to correlate mutations with reduced risk of late-onset Alzheimer’s disease.  One mutation stood out—a single nucleotide polymorphism that resulted in the substitution of a threonine amino acid for an alanine at position 673 in APP.

They found that people without Alzheimer’s disease, especially those over 85, had the allele about 4 to 5 times more frequently than those with Alzheimer’s disease. Interestingly, the mutation also appeared to protect against age-related decline in octogenarians without Alzheimer’s disease, suggesting that “they share mechanisms,” said Stefansson. If this is the case, therapies to impede Alzheimer’s progression could be generally useful to the ageing population. “The ability to maintain cognitive function and brain health is the essence of a meaningful longevity,” he said.

The mutation is near the location where BACE1 cleaves APP, so Stefansson and his colleagues examined whether the mutation affected efficiency enzyme cleavage of APP. Using human kidney embryonic cells, they expressed wild type and mutant alleles of APP. Cells expressing the mutant APP produced about half the amyloid β fragments as cells expressing normal APP. Looking in vitro, the team saw that BACE1 cleaved the mutant APP about half as efficiently as wild type APP, suggesting that the mutation may protect against Alzheimer’s by reducing amount of amyloid protein, and fibrils, produced in neurons.

By highlighting the association between decreased APP processing and protection against Alzheimer’s disease, the research strongly supports the amyloid hypothesis, which has suffered recently, said Goate. “A lot of ongoing therapeutic work based on the amyloid hypothesis has failed,” she explained, “so people were worried that modulating amyloid might not work.” But the current study suggests that reducing amyloid β may play a role in preventing Alzheimer’s development. In addition, the data also support continued investigation of BACE inhibitors as possible therapeutic drugs to treat Alzheimer’s, she added.

Of course, by the time Alzheimer’s is diagnosed, it may be too late for therapeutics that interfere with APP cleavage to be effective. People with the A673T variant have shown protection from Alzheimer’s after carrying the allele their whole lives, Goate noted, and the neurological changes that lead to Alzheimer’s, like the fibrils, begin to form about 10 to 15 years before clinical signs emerge.

T. Jonsson et al., “A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline,” Nature, doi: 10.1038/nature11283, 2012.

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