'Natural' protection against Alzheimer’s disease

July 11, 2012

deCODE Genetics, together with their colleagues from the pharmaceutical company Genentech, reported today in the journal Nature the discovery of a variant of the amyloid precursor protein (APP) gene that confers protection against both Alzheimer's disease (AD) and cognitive decline in the elderly. The findings also indicate a linkage between age-related cognitive decline and late-onset forms of AD, the most common cause of dementia.

"Our results suggest that late-onset Alzheimer's disease may represent the extreme of more general age-related decline in cognitive function," said study lead author Kari Stefansson, M.D., Dr. Med., CEO of . "Also important, these data support certain Alzheimer's disease drug development programs--some of which are already in human clinical trials."

Alzheimer's disease is a progressive neurodegenerative disease associated with the production and accumulation of beta-amyloid produced by cleaving bits off the APP. While several mutant forms of the APP gene have been linked to early-onset, aggressive forms of AD, there is limited evidence supporting a role for mutations in the gene in the more common late-onset form of the disease.

In searching for low-frequency variants of the APP gene associated with AD, deCODE scientists found a significant association with a mutation in whole from 1,795 Icelanders. The research team showed that the mutation is significantly more common in the study's elderly control group than in those with AD, suggesting that the mutation confers protection against the disease.

The Genentech team then tested these findings using in vitro with wild-type APP and APP enriched with A673T, the mutation allele. Importantly, they showed a significantly reduced production of amyloid beta in cells with A673T.

"Our indicate that the mutation is protective against Alzheimer's disease," said Stefansson. "Our findings and the in vitro work done by also provide a proof of principle for the idea that blocking BACE1 cleavage of APP may protect against Alzheimer's, offering greater confidence to pharmaceutical companies with active BACE1 inhibitor drug development programs."

To study the association of the protective mutation with general cognitive decline, the research team examined the frequency of the mutation in the original Icelandic control group of those cognitively intact at age 85. The team found an enrichment of the mutation in this group, consistent with its protective effect against AD.

Extending this work further, the team investigated cognitive function using a seven-category test in carriers of the mutation and non-carriers in the age range of 80 to 100 years old. The research team found a statistically significant difference between carriers and non-carriers, with the carriers of the mutation having a score indicative of better-conserved cognition. After removing known AD cases, the team again found that carriers had better cognitive function, suggesting that the mutation extends its protective effect to the elderly in general.

"The implication of these data is that general and late-onset Alzheimer's disease share biological pathways," said Stefansson. "It also suggests that approaches to treating Alzheimer's may have benefit to those elderly who do not carry the protective mutation, and do not suffer from AD."

Alzheimer's disease, a progressive neurodegenerative disorder, is the most common form of dementia that affects four to eight percent of the elderly population worldwide. The neuropathological features of AD are the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles in the hippocampus and cortical grey matter of the AD brain.

Age-specific prevalence of AD nearly doubles after age 65, leading to a prevalence of greater than 25 percent in those over the age of 90.

Explore further: Overlooked peptide reveals clues to causes of Alzheimer's disease

More information: DOI: 10.1038/nature11283

Related Stories

Overlooked peptide reveals clues to causes of Alzheimer's disease

July 3, 2011
Researchers at the RIKEN Brain Science Institute (BSI) and their collaborators have shed light on the function of a little-studied amyloid peptide in promoting Alzheimer's disease (AD). Their surprising findings reveal that ...

A new gene thought to be the cause in early-onset forms of Alzheimer's disease

April 4, 2012
A new gene that causes early-onset of Alzheimer's disease has been discovered by the research team of Dominique Campion at the Insert unit 1079 "Genetics of cancer and neuropsychiatric diseases" in Rouen. The research scientists ...

Active lifestyle associated with less Alzheimer disease-related brain change among persons with APOE epsilon4 genotype

January 16, 2012
A sedentary lifestyle is associated with greater cerebral amyloid deposition, which is characteristic of Alzheimer’s disease (AD), among cognitively normal individuals with the ε4 allele of the apolipoprotein E ...

Same genes linked to early- and late-onset Alzheimer's disease

February 1, 2012
The same gene mutations linked to inherited, early-onset Alzheimer's disease have been found in people with the more common late-onset form of the illness.

Case of mistaken identity: Study questions role of A-beta molecules in Alzheimer's disease pathology

June 28, 2011
Increasingly, researchers are suggesting that amyloid plaques and neurofibrillary tangles may be relatively late manifestations in the course of Alzheimer's disease (AD) pathology. Identifying earlier events in the development ...

Recommended for you

Personality changes don't precede clinical onset of Alzheimer's, study shows

September 21, 2017
For years, scientists and physicians have been debating whether personality and behavior changes might appear prior to the onset of Alzheimer's disease and related dementias.

Newly ID'd role of major Alzheimer's gene suggests possible therapeutic target

September 20, 2017
Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer's disease—one that increases a person's chances of developing the neurodegenerative disease by up to 12 ...

Is the Alzheimer's gene the ring leader or the sidekick?

September 15, 2017
The notorious genetic marker of Alzheimer's disease and other forms of dementia, ApoE4, may not be a lone wolf.

Potential noninvasive test for Alzheimer's disease

September 6, 2017
In the largest and most conclusive study of its kind, researchers have analysed blood samples to create a novel and non-invasive way of helping to diagnose Alzheimer's disease and distinguishing between different types of ...

Researchers unlock the molecular origins of Alzheimer's disease

September 6, 2017
A "twist of fate" that is minuscule even on the molecular level may cause the development of Alzheimer's disease, VCU researchers have found.

Is dementia declining among older Americans?

September 5, 2017
(HealthDay)—Here's some good news for America's seniors: The rates of Alzheimer's and other forms of dementia have dropped significantly over the last decade or so, a new study shows.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.