The Alzheimer's Association has published revised criteria for the diagnosis and staging of Alzheimer's disease that are based on the biology of the disease and reflect recent advancements in research, diagnostics and treatment.

"Defining diseases biologically, rather than based on symptoms, has long been standard in many areas of medicine — including cancer, heart disease and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases," says Clifford Jack Jr., M.D., a Mayo Clinic neuroradiologist, part of a workgroup convened by the Alzheimer's Association and lead author on the criteria published in Alzheimer's & Dementia. "An unchanging principle is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process."

The revised criteria define Alzheimer's disease as a biological process that happens in the brain before people exhibit symptoms of cognitive impairment, such as memory and thinking problems. However, the workgroup does not recommend diagnostic testing in cognitively unimpaired people who are not in research studies. No treatments have been approved for cognitively unimpaired people.

Updating the criteria was prompted by approval of the first disease-modifying treatments for Alzheimer's and emerging Alzheimer's blood tests. "These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer's, and we are able to measure those (brain) changes," Dr. Jack says.

Treatments that target the toxic amyloid protein that builds up in the brain recently have been approved for patients with mild Alzheimer's disease who meet specific criteria. To be eligible for treatment, biomarker proof — from blood, cerebrospinal fluid and brain images — is needed, showing that the underlying biology is present in a person's brain.

"Clinical use of (Alzheimer's) biomarkers is presently intended for the evaluation of symptomatic individuals, not cognitively unimpaired individuals," the authors note. "At the present time, disease-targeted therapies have not been approved for cognitively unimpaired individuals with (Alzheimer's). For this reason, we currently recommend against diagnostic testing in cognitively unimpaired individuals (outside of research studies)."

For more information on the criteria and the importance of the clinician's role in an Alzheimer's diagnosis, see the Alzheimer's Association news release.

For a full list of authors, funding and disclosures, see the journal article. Dr. Jack is the Alexander Family Professor of Alzheimer's Disease Research. He will present on the revised criteria in July at the Alzheimer's Association International Conference in Philadelphia.

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Early diagnosis will ultimately be essential in the management and treatment of Alzheimer’s disease. Examination of Alzheimer’s biomarkers can improve the prediction of short-term memory decline in middle-age and elderly individuals, according to new research from Mayo Clinic.

A new diagnostic framework developed in collaboration with the National Institute on Aging and the Alzheimer’s Association, paired with new tools at Mayo Clinic, is showing promise in diagnosing Alzheimer’s earlier and more accurately, researchers write in “Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia” in the Journal of the American Medical Association (JAMA).

In exploring associations between beta-amyloid, tau and neurodegeneration, or AT(N), biomarkers and memory decline in a population-based cohort, Clifford Jack Jr., M.D., and colleagues write, “This study illustrates the potential clinical utility of AT(N) biomarkers to improve prediction of short-term memory decline over commonly available clinical and genetic information.”

AT(N) is the classification of the major existing Alzheimer’s disease biomarkers into three categories: A, the beta-amyloid biomarker; T, the tau biomarker; and (N), the biomarkers of neurodegeneration or neuronal injury, Dr. Jack writes.

The study consisted of 480 Mayo Clinic Study of Aging participants without dementia age 60 or older in Olmsted County, Minnesota, with 99 percent self-reporting as white. Using the Rochester Epidemiology Project enumeration, participants for the Mayo Clinic Study of Aging are randomly selected by 10-year age and sex strata to equally represent both males and females. Read the rest of the article on Advancing the Science.
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JACKSONVILLE, Fla. — In collaboration with the University of Kentucky, the University of Texas Southwest Medical Center, Rush University Medical Center, the University of Cambridge in the U.K., and other institutions, Mayo Clinic researchers helped to establish a name for a degenerative brain disease that afflicts the elderly and mimics features of Alzheimer’s disease. This working group describes "limbic-predominant age-related TDP-43 encephalopathy," or LATE, as an underrecognized risk for public health and calls for an urgent focus on research to improve prevention, diagnosis and treatment of the disease. The report appears in the journal, Brain.

"LATE is a prevalent but underrecognized condition in the elderly," says Dennis Dickson, M.D., a Mayo Clinic neuropathologist. "We have been studying this protein for many years, but now we have a common goal to target, which is something we want to make clinicians aware of. LATE needs to be recognized and differentiated from Alzheimer's disease."

Researchers from Mayo Clinic were among the leaders of the working group, with the University of Kentucky leading the study. Dr. Dickson and colleagues identified the first pathological manifestation of LATE in 13 elderly patients with dementia and brain changes in 1994. Other groups have built and expanded on his and others' early work.

"Given that persons of advanced age (past 80 years) are at greatest risk for LATE and constitute a rapidly growing demographic group in many countries, LATE has an expanding but underrecognized impact on public health," the report says.

The report is a call to action, says Melissa Murray, Ph.D., a Mayo Clinic molecular neuroscientist. "This consensus paper is an accumulation of research from multiple groups that have spent the past decade working on this. We've come together to declare that LATE is its own disease entity — a disease in and of itself."

Clifford Jack Jr., M.D., a Mayo Clinic neuroradiologist, and Rosa Rademakers, Ph.D., a Mayo Clinic neurogeneticist, also are co-authors of the report.

Among the goals of the working group was to agree to a name and common nomenclature for the disease. Age-related TDP-43 proteinopathy has been known to clinicians for about a decade, but a common terminology was lacking. Identifying the disease is an important step in catalyzing future research, the report says.

The working group recommends that TDP-43 testing be performed as part of routine autopsy evaluation in all older patients. Also, more investigation is needed to test for memory and nonmemory symptoms that distinguish LATE from other degenerative disorders. No diagnostic tests are available to identify patients with LATE, though an exciting area of research will be the development of biomarkers for brain imaging, with the goal of revealing the disease early in the patient’s progression, Dr. Murray says.

Research on neurological diseases such as LATE has been made possible by resources in the Brain Bank at Mayo Clinic's Florida campus. This Brain Bank, which contains more than 6,000 specimens, is one of the largest repositories of brain tissue specimens in the world.

The LATE research, says Dr. Murray, is an "example of how crucial organ donation programs are to advancing scientific knowledge."

Funding included grants from the National Institute on Aging, National Institutes of Health. Full funding and conflict of interest information can be found in the publication.

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On this week's Mayo Clinic Radio program, Dr. Clifford Jack Jr., a radiologist at Mayo Clinic, will explain the importance of the new Alzheimer's framework for improving research. Also on the program, Vivien Williams, medical reporter with the Mayo Clinic News Network, will discuss "Health + Happiness With Mayo Clinic," the weekly program she co-hosts on NBC. And Dr. Thomas Brott, a neurologist at Mayo Clinic, will look back the advances he's seen in his 40 years of treating stroke.

Here's your Mayo Clinic Radio podcast.

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The findings, published in Brain, offer new and valuable information in the long and ongoing debate about the relative contribution of amyloid and tau to the development and progression of cognitive dysfunction in Alzheimer’s, says the study’s lead author, Melissa Murray, Ph.D., a neuroscientist at Mayo Clinic in Jacksonville.

MEDIA CONTACT: Kevin Punsky, Mayo Clinic Public Affairs, 904-953-0746, punsky.kevin@mayo.edu

Journalists: Video is available in the downloads.

The findings also suggest that halting toxic tau should be a new focus for Alzheimer’s treatment, the researchers say.

“The majority of the Alzheimer’s research field has really focused on amyloid over the last 25 years,” Dr. Murray says. “Initially, patients who were discovered to have mutations or changes in the amyloid gene were found to have severe Alzheimer’s pathology — particularly in increased levels of amyloid. Brain scans performed over the last decade revealed that amyloid accumulated as people progressed, so most Alzheimer’s models were based on amyloid toxicity. In this way, the Alzheimer’s field became myopic.”

But researchers at Mayo Clinic were able to simultaneously look at the evolution of amyloid and tau using neuropathologic measures. “Imagine looking at the rings of a tree — you can identify patterns, like the changing seasons and the aging of the tree, when viewing the tree’s cross-section,” Dr. Murray says. “Studying brains at different stages of Alzheimer’s gives us a perspective of the cognitive impact of a wide range of both amyloid and tau severity, and we were very fortunate to have the resource of the Mayo brain bank, in which thousands of people donated their postmortem brains, that have allowed us to understand the changes in tau and amyloid that occur over time.”

“Tau can be compared to railroad ties that stabilize a train track that brain cells use to transport food, messages and other vital cargo throughout neurons,” Dr. Murray says. “In Alzheimer’s, changes in the tau protein cause the tracks to become unstable in neurons of the hippocampus, the center of memory. The abnormal tau builds up in neurons, which eventually leads to the death of these neurons. Evidence suggests that abnormal tau then spreads from cell to cell, disseminating pathological tau in the brain’s cortex. The cortex is the outer part of the brain that is involved in higher levels of thinking, planning, behavior and attention — mirroring later behavioral changes in Alzheimer’s patients.”

“Amyloid, on the other hand, starts accumulating in the outer parts of the cortex and then spreads down to the hippocampus and eventually to other areas,” she says. “Our study shows that the accumulation of amyloid has a strong relationship with a decline in cognition. When you account for the severity of tau pathology, however, the relationship between amyloid and cognition disappears — which indicates tau is the driver of Alzheimer’s,” Dr. Murray says.

Amyloid brain scanning has been used for only about a decade, and “so there are still many unanswered questions about what it is measuring,” she adds. “Investigating what brain pathology underlies the amyloid brain scanning threshold indicative of Alzheimer’s can only be addressed in patients who underwent scanning and donated their brain for research.”

The study was conducted in two parts. Researchers at Mayo Clinic in Florida examined 3,618 brains in its postmortem brain bank, of which 1,375 brains were Alzheimer’s confirmed. These patients died at different ages and different stages of dementia, providing a valuable timeline into disease progression.

The researchers used recommended scoring systems to examine the evolution of amyloid and tau in dissected brain tissue. They found that the severity of tau, but not amyloid, predicted age onset of cognitive decline, disease duration and mental deterioration.

The second part of the study was conducted with their collaborators at Mayo Clinic in Rochester. Together the team examined amyloid brain scans taken of patients prior to death and compared the scans to measures of tau and amyloid brain pathology.

The investigators found that the signal from amyloid brain scans corresponded with amyloid pathology specific to the brain and not amyloid found in vessels, and did not correspond to tau pathology. The brains of some participants had amyloid visible at pathology that did not reach the threshold for what would be found in Alzheimer’s brain scans. This is important, as amyloid can be found in brains of older individuals who have not experienced cognitive decline, researchers say.

“Our findings highlight the need to focus on tau for therapeutics, but it also still indicates that the current method of amyloid brain scanning offers valid insights into tracking Alzheimer’s,” Dr. Murray says. “Although tau wins the ‘bad guy’ award from our study’s  findings, it is also true that amyloid brain scanning can be used to ensure patients enrolling for clinical trials meet an amyloid threshold consistent with Alzheimer’s — in lieu of a marker for tau.”

Co-authors of the study are, from Mayo Clinic in Jacksonville: Neill Graff-Radford, M.D., Amanda Liesinger, Ashley Cannon, Ph.D., Bhupendra Rawal, M.S., Owen Ross, Ph.D., and Dennis Dickson, M.D.; from Mayo Clinic in Rochester: Val Lowe, M.D., Scott Przybelski, Joseph Parisi, M.D., Ronald Petersen, M.D., Ph.D., Kejal Kantarci, M.D., David Knopman, M.D., and Clifford Jack, Jr., M.D.; and Ranjan Duara, M.D., from Mount Sinai Medical Center.

The study was funded by the National Institutes of Health (R01-AG040042, R01-AG011378, R01-AG041851, P50- AG016574, U01-AG006786, P50-NS072187), The Mangurian Foundation, the Robert H. and Clarice Smith and Abigail vanBuren Alzheimer’s Disease Research Program, the Elsie and Marvin Dekelboum Family Foundation, the Donors Cure Foundation New Vision Award, and The Alexander Family.

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Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit mayoclinic.com or newsnetwork.mayoclinic.org.

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Radiologist and noted Alzheimer’s disease researcher at Mayo Clinic Clifford Jack Jr., M.D., has been elected to the Institute of Medicine, part of the National Academies. John Noseworthy, M.D., president and CEO of Mayo Clinic, says, "This is a great recognition for Dr. Cliff Jack and an honor that is well deserved. He is internationally known for his discoveries in radiology and imaging and for his impact on Alzheimer’s disease analysis. Much of what we know about how Alzheimer’s develops is because Cliff Jack found a way to visualize it.”

Read news release.

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