Two new studies appear to lend strong support for the theory that an overabundance of the amyloid-beta protein is the root cause of Alzheimer’s disease.
A genetic study of 1,800 residents of Iceland discovered a rare mutation that apparently protects against the disease in those who carry it, and even staves off the disease in those genetically programmed to develop it – probably by blocking the formation of amyloid-beta.
A second study, published July 11 in the New England Journal of Medicine, found that a processed fragment of amyloid-beta, called amyloid-beta-42 (Abeta42), begins to accumulate in the brain 25 years before symptoms appear in people with a mutation in one of three genes that is known to cause early-onset Alzheimer’s disease, suggesting that amyloid deposition initiates the cascade of physiologic and cognitive changes that culminate in full-blown AD.
"Our data suggest that amyloid deposition will develop and be detectable in all persons with a mutation while they are still asymptomatic," wrote Dr. Randall J. Bateman, professor of neurology at Washington University, St. Louis, and his colleagues. "These findings suggest that targeting amyloid-beta earlier in the course of the disease may provide better clinical outcomes than the treatment of mild to moderate dementia after substantial neuronal and synaptic loss has occurred" (N. Engl. J. Med. 2012 July 11 [doi: 10.1056/NEJMoa1202753]).
Dr. Kari Stefansson, chief executive officer of deCODE Genetics in Reykjavik, led the Icelandic study. He and his colleagues sought to discover any unusual genetic risk factors for AD in a group of about 1,800 subjects. The researchers focused on variants of the amyloid precursor protein gene (APP), because different enzymes can either split this protein into a harmless fragment or change it into Abeta42 – the form that aggregates into AD brain plaques.
In the initial group, Dr. Stefansson and his colleagues looked for every APP variant that occurred in more than one person, and then imputed these into a database of 72,000 Icelanders who had already been genotyped. A computer program estimated how many times each allele might occur in almost 300,000 relatives of these subjects (Nature 2012 July 11 [doi: 10.1038/nature11283]).
The researchers found a mutation (A673T) in APP that was significantly more common in those without AD than in those with it. The variant was rare, occurring in 0.14% of those with Alzheimer’s, 0.45% of overall population-based controls, 0.62% of controls aged 85 years or older, and 0.79% of controls older than 85 who were still cognitively intact. Nevertheless, the authors concluded, the presence of the variant exerted a protective effect against the disease.
This was even more apparent in risk analyses. Compared with the group of people with AD, the gene was four times more likely to appear in the general population, five times more likely to occur in those 85 years or older, and nearly eight times more common among a group of cognitively healthy subjects who were 85 or older.
The allele also appeared to protect against expected age-related cognitive decline in elderly people who did not have AD, the authors noted. In a comparison of 41 allele carriers and 3,700 noncarriers, all of whom were 80-100 years old, those with the protective allele had significantly better cognitive ability. The relationship remained strong even after removal of patients with AD from the noncarrier group.
"Removing known Alzheimer’s disease cases [from this analysis] suggests that the protective effect of A673T extends beyond the boundaries of the Alzheimer’s disease phenotype," the investigators wrote.
The mutation’s benefit probably arises from its influence over APP fragmentation, the researchers said. Three enzymes – alpha-, beta-, and gamma-secretase – can cleave the APP protein. If alpha-secretase splits the protein, no further fragmentation occurs. When gamma-secretase splits APP, it sets the stage for beta-secretase (BACE1) to finish the job, producing Abeta42, the form most likely to aggregate into brain plaques.
In vitro experiments indicated that the allele blocked the effect of BACE1, reducing the production of Abeta42 by up to 50%. This suggests that a well-tolerated BACE1 inhibitor might have a place in any future Alzheimer’s treatment regimen.
The New England Journal of Medicine study examined Abeta42 levels and cognitive function in 128 subjects enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. The 6-year, cross-sectional, longitudinal study is examining members of families who carry a mutation in one of the three genes that affect amyloid processing, including APP. All subjects have at least one parent with a mutation known to cause early-onset AD.
The study group’s mean age at enrollment was 39 years. About half of the carriers are symptomatic, compared with just 2% of the noncarriers. Parents of these subjects developed AD at a mean age of 46 years.