Biomarkers Show Who Faces Near-Term Cognitive Decline

Many cognitively normal people with positive amyloid and tau PET biomarkers appeared to be at imminent risk of cognitive decline, longitudinal data showed.

Across four independent cohorts, 33% to 83% of cognitively normal people positive for both amyloid and tau progressed to mild cognitive impairment within a mean of 2.00 to 2.72 years, compared with less than 20% in other groups (all P≤0.004), reported Cherie Strikwerda-Brown, PhD, of Douglas Mental Health University Institute in Montreal, at the 2022 Alzheimer’s Association International Conference.

These numbers increased across all four cohorts for cognitively unimpaired people who were positive for amyloid, tau, and neurodegeneration, reaching a progression rate of 43% to 100%.

“Our findings have potential implications for clinical trials,” Strikwerda-Brown told MedPage Today. “These biomarkers may be used to select individuals who are highly likely to develop symptomatic Alzheimer’s disease to target preventive interventions.”

The findings, published simultaneously in JAMA Neurology, supported the National Institute on Aging-Alzheimer’s Association (NIA-AA) research framework for Alzheimer’s disease, which is based on biomarkers of amyloid, tau, and neurodegeneration.

This scheme is intended to differentiate Alzheimer’s from other dementias. It classifies amyloid (A), tau (T), and neurodegeneration (N) measures as abnormal (+) or normal (−), resulting in eight possible clinical profiles.

“It’s currently unclear whether A+T+ cognitively unimpaired individuals are destined to show clinical progression or can preserve their cognitive abilities over time,” noted Rik Ossenkoppele, PhD, of Amsterdam University Medical Center in the Netherlands, who recently led another study about cognitively unimpaired people with Alzheimer’s pathology.

“This study and our preprint show that the risk of progression to a symptomatic stage of Alzheimer’s disease is substantially increased and nearly all A+T+ individuals show decline on cognitive tests assessing memory function and global cognition,” Ossenkoppele told MedPage Today.

“Together, these studies support the NIA-AA viewpoint that Alzheimer’s disease can be biologically defined and that considering A+T+ status just as a risk factor may be underestimating its malignancy,” he added.

Strikwerda-Brown and colleagues looked at four population-based cohorts of older adults without cognitive impairment who had data collected from 2003 to 2021. The researchers included 128 individuals from the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort; 153 from the Harvard Aging Brain Study (HABS); 48 from the Australian Imaging, Biomarkers & Lifestyle (AIBL) study; and 251 from the Knight Alzheimer Disease Research Center (ADRC) cohort.

Mean ages ranged from 67 to 76 across the cohorts, and 55% to 74% of participants were women. Neurodegeneration was assessed by cortical thickness. The primary outcome was clinical progression to mild cognitive impairment after amyloid and tau PET. Median clinical follow-up after PET ranged from 1.94 to 3.66 years.

Many A+T+ participants who didn’t progress to mild cognitive impairment showed longitudinal cognitive decline. Abnormalities in both amyloid and tau PET were associated with greater risk of near-term clinical progression than abnormal amyloid alone.

Study limitations included modest sample sizes in some biomarker groups. In addition, most participants were white; whether the findings apply to other populations is unknown.

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