Updated diagnostic criteria for Alzheimer's disease will allow physicians to identify patients in the earliest possible stages of the disease, capitalizing on the treatments now available and enriching therapeutic research.
Unveiled at the meeting, the proposed criteria are the first updates to Alzheimer's diagnosis in 25 years, Dr. Ronald Peterson said in an interview.
“Our current criteria were established in 1984,” said Dr. Peterson, director of the Mayo Clinic Alzheimer Disease Research Center, Rochester, Minn. “They functioned well for 25 years, but they were completely syndromic. The field has moved on. There has been an explosion of information, including neuroimaging and biomarkers, which allows us to recognize a milder state of clinical impairment and is informing us about the underlying pathology. These need to be included in our diagnostic workups.”
The new criteria form the basis of a more flexible diagnostic tool—one that can be annually revisited and updated as new data demand, he said.
The National Institute on Aging and the Alzheimer's Association agreed last year to examine how to better incorporate new knowledge into the existing diagnostic criteria. The agencies created work groups to explore this idea in three stages of the disease process—preclinical, mild cognitive impairment, and Alzheimer's dementia.
Dr. Reisa Sperling, director of clinical research at the Memory Disorders Unit, Brigham and Women's Hospital, Boston, headed the preclinical group. “For me, this is the most exciting area, because it's the newest,” she said in an interview. “We have never tried to set criteria to diagnose Alzheimer's before there is significant clinical impairment.”
And yet, she said, this period may be the most crucial, for two reasons. First, because the earlier existing treatments are employed, the more effective they are. Second, because identifying a prodromal stage of Alzheimer's will, eventually, be key to developing new therapies.
Alzheimer's has never been viewed as a disease with an identifiable, but asymptomatic, prodromal state. “Our best chance at treating the disease and changing its course will be to treat before any symptoms appear, or when there are only very mild symptoms,” Dr. Sperling said.
The preclinical group identified three diagnostic criteria for the earliest stage of Alzheimer's:
▸ Asymptomatic amyloidosis, defined by evidence of abnormal levels of amyloid in the spinal fluid or on a brain scan, but no cognitive or functional symptoms.
▸ Amyloidosis plus one other marker of disease, which could be brain atrophy on imaging, functional abnormalities on positron emission tomography (PET), or abnormal levels of phosphorylated tau in spinal fluid.
▸ Amyloidosis plus a biomarker and slight cognitive symptoms. “This may be the most important stage, because there is good evidence that people experience cognitive changes years before they progress to mild cognitive impairment,” Dr. Sperling said. “Right now, we can't differentiate normal aging from the very beginning of Alzheimer's. But the combination of these biomarkers and memory trouble will allow us to predict who is on the Alzheimer's trajectory.”
Research may especially benefit from this identification, because drugs to slow or halt disease progression will be most effective in patients with the least neuronal damage, she added.
Dr. Peterson is a member of the work group that examined diagnostic criteria for mild cognitive impairment (MCI). That group also identified three criteria:
▸ The already-established clinical syndrome of MCI in which patients are aware of their memory problem and have a measurable deficit, but other cognitive and functional skills are preserved.
▸ In addition to MCI, there is some evidence of change in brain topography—either hippocampal atrophy or hypometabolic brain regions.
▸ In addition to MCI and topographical brain changes, a confirmed measure of amyloid abnormality, including reduced amyloid-beta42 in cerebrospinal fluid (indicating its accumulation in the brain) or positive amyloid brain imaging.
“This represents the progression in a perfect world,” Dr. Peterson said. “But the devil is in the details. What if you have the clinical syndrome but your biomarkers go in the opposite direction, or you have an incomplete set? That is where research is going to fill in the gaps in our knowledge.”
Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis, is a member of the dementia working group. Because diagnostic algorithms for dementia were already in place—albeit 25 years old—his group made modifications to the existing criteria.
“With the addition of biomarkers to support the clinical suspicion of dementia, we have been able to strengthen those criteria substantially, giving physicians the ability to be much more confident in their diagnoses,” Dr. Morris said.