Scientists have for the first time identified a timeline of early detectable biological changes that precede symptoms of Dominantly inherited Alzheimer’s disease by decades. They now plan to use these markers for prevention and treatment in affected families that have joined their study project.

The scientists, who belong to an international research partnership known as the Dominantly Inherited Alzheimer’s Network (DIAN) write about the timeline, which chronicles the human brain’s slow decline into full-blown Alzheimer’s, in a paper published online this week in the New England Journal of Medicine.

First author Randall Bateman is the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis, in the US. He told the press:

“A series of changes begins in the brain decades before the symptoms of Alzheimer’s disease are noticed by patients or families, and this cascade of events may provide a timeline for symptomatic onset.“

Dominantly Inherited Alzheimer’s is caused by three rare inherited gene mutations. Symptoms in this inherited form of Alzheimer’s often start affecting people in their 30s and 40s, at a much younger age than the more common form of Alzheimer’s, which typically strikes after the age of 65.

A person born with one of the mutations not only develops Dominantly Inherited Alzheimer’ disease, but has a 50-50 chance of passing the gene to each of his or her children.

This means that in families where Alzheimer’s is caused by one of these mutations, the disease will hit about 50% of the members in the family tree before they reach the age of 60.

Using cerebrospinal fluid and neuroimaging tests, the team, led by researchers at Washington University School of Medicine, evaluated a range of pre-symptomatic biomarkers in 128 people from families genetically predisposed to develop Dominantly Inherited Alzheimer’s disease who are taking part in the DIAN project.

Thus each of the 128 people in the study has a 50% chance of inheriting one of the three mutations that causes this early-onset form of the disease.

The researchers used parents’ medical histories to estimate the likely age of onset of symptoms in the (offspring) study participants. Using these timespans, and the results of the tests they carried out, they compiled a list, in time order, of the detectable changes that lead up to the memory loss and cognitive decline characteristic of Alzheimer’s.

These changes include:

  • A fall in spinal fluid levels of amyloid beta protein (a key ingredient of Alzheimer’s brain plaques), detectable some 25 years before symptoms.

  • Plaques visible on brain scans: 15 years before symptoms.

  • Elevated spinal fluid levels of tau, a structural protein in brain cells: 15 years before symptoms.

  • Shrinkage of key brain structures: 15 years before symptoms.

  • Brain starts using less glucose: 15 years before symptoms.

  • Slight impairments in a specific type of memory: detectable 10 years before symptoms.

Bateman said:

“As we learn more about the origins of Alzheimer’s to plan preventive treatments, this Alzheimer’s timeline will be invaluable for successful drug trials.”

For example, as the new the timeline shows plaques can be seen on brain scans 15 years before onset of memory problems, DIAN researchers now plan to give treatments that remove or block plaque formation at this early stage, and monitor participants closely to see not only if the plaques go away or diminish, but also to check whether the treatment improves other markers of the disease.

The DIAN partnership was set up by the National Institute on Aging of the National Institutes of Health (US) to bring together researchers who study genetic forms of Alzheimer’s. The partners are institutions across the United States, in the United Kingdom and Australia.

Laurie Ryan, clinical trials program director at the National Institute on Aging, said:

“These exciting findings are the first to confirm what we have long suspected, that disease onset begins years before the first sign of cognitive decline or memory loss.”

“And while DIAN participants are at risk for the rare, genetic form of the disease, insights gained from the study will greatly inform our understanding of late-onset Alzheimer’s disease,” said Ryan.

The DIAN researchers also tested participants from families that don’t carry any of the inherited Alzheimer’s mutations. Bateman said those participants showed no detectable changes in the markers they tested.

“It’s striking how normal the Alzheimer’s markers are in family members without a mutation,” he added.

The team hopes to begin prevention and treatment trials later this year.

Anyone whose family history has several generations of Alzheimer’s disease diagnosed before the age of 55 can join the DIAN Expanded Registry online. The researchers will contact them to find out if their family is eligible to take part in the DIAN studies.

Written by Catharine Paddock PhD