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Johns Hopkins Pediatric

The Quest to Determine Earliest Stages of Alzheimer’s Disease

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When Johns Hopkins geriatrician Esther Oh and psychiatrist Kostas Lyketsos directed a clinical study to see if a test for Alzheimer’s disease could identify which patients with cognitive impairment had the disease, they also hoped the biomarker would tell them who didn’t have it.

The ultimately fatal form of dementia currently afflicts more than 6.5 million Americans and their families, a population projected to grow to 12.7 million by 2050, according to the Alzheimer’s Association.

In the Johns Hopkins study, 112 participants were referred by consented dementia practitioners from the Johns Hopkins Memory and Alzheimer’s Treatment Center and the Eastern Virginia Medical School Comprehensive Memory Center for brain scan testing in 2016 and 2017.

The report, Utility of amyloid PET Imaging in a Memory Clinic, published last year in Alzheimer Disease & Associated Disorders, showed that 74 patients carried evidence of amyloid, the hallmark of the progressive neurodegenerative disease, while 38 did not.

For those patients with clinically ambiguous cases of cognitive impairment, the negative test led to more precise diagnoses, says Oh, who co-directs the Johns Hopkins Memory and Alzheimer’s Treatment Center.

“At the time, because there weren’t any medications to slow progression of the disease, the negative reading that ruled out Alzheimer’s disease was more informative,” Oh says.

Last year, however, that landscape changed dramatically when the Food and Drug Administration (FDA) approved the medication lecanemab for people with early-stage Alzheimer’s.

Although the new drug does not cure the disease, will not improve patients’ memories or cognitive abilities and will not stop the disease from progressing, it can moderately slow cognitive and functional decline in early-stage cases. It is also the only disease-modifying drug for the neurodegenerative condition to obtain Medicare coverage.

Delivered by an intravenous infusion every two weeks, lecanemab works by removing the forms of amyloid protein from the brain that are believed to cause Alzheimer’s disease to advance.

To prescribe the medication, however, physicians must show results from tests confirming there is an amyloid buildup in the patient’s brain.

While positron emission tomography (PET) scans — the kind of scans that the Johns Hopkins researchers used in their study — and cerebrospinal fluid testing (CSF) by lumbar puncture (LP) can be helpful in diagnosing early-stage Alzheimer’s, PET scans can cost thousands of dollars and LPs can be invasive.

Johns Hopkins neurologist Abhay Moghekar, who works on developing tests for neurodegenerative diseases, says newly available blood tests for amyloid biomarkers are quite effective as well.

“My guess is that in 50% to 75% of the patients, the blood test will provide an answer as to whether or not they have Alzheimer’s,” he says. “The others will need further testing.”

Moghekar says the tests are markers of the amyloid plaques and tau tangles that build up in the brain in people with Alzheimer’s disease.

“While some of these correlate very well with PET and CSF markers, defining normal versus abnormal values in blood remains a challenge that should be sorted out in the next couple of years,” Moghekar says. “None of the blood tests are FDA-approved yet, in contrast to PET and CSF markers.”

Oh says such tests should come into play only after a physician takes a “very careful history from the patient and also from their care partners,” as well as after performing traditional blood tests, MRI and neuropsychological testing.

She also cautions that there is no such thing as a “perfect test” for Alzheimer’s disease, and she worries that people who begin to experience a cognitive problem will press for a blood test that is more easily available than a brain scan or spinal tap.

“At this point, there is no treatment for cognitively normal adults who might also have amyloid positivity,” Oh says. “And you can always end up with a false positive result that will impact you, your family and maybe even your medical record.”

She believes that, at this time, biomarker testing should be used only for people who already have medical evidence of cognitive impairment.

Oh recalls one such patient she enrolled in the PET scan study. Although earlier tests indicated the woman’s problems were probably due to a seizure disorder she had since childhood, the patient feared she was also beginning to struggle with Alzheimer’s disease (AD).

The study ruled out that condition. However, Oh issued a caveat.

“The fact that you don’t have it now doesn’t mean that you won’t have it in the future,” she told her patient. “As we get older, we’re all at risk for AD.”

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