Amyloid-Negative, Tau-Positive Profiles Not Associated With Increased Cognitive Decline

Henrik Zetterberg, MD, PhD

Recently published findings from large, real-world, clinical routine data set showed that the prevalence of individuals with an amyloid-ß-negative, tau-positive (A–T+) cerebrospinal fluid (CSF) biomarker profile was 4.1%, which was far lower than the prevalence of other CSF profiles. In comparison with those with A–T– biomarker profiles, those with A–T+ profiles were not associated with higher rates of cognitive deterioration, Aß accumulation, tau PET pathology, or neurodegeneration.

Published in JAMA Neurology, a total of 7679 individuals from the cross-sectional multicenter University of Gothenberg (UGOT) cohort, 970 from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort, and 519 individuals from the Wisconsin Registry for Alzheimer Prevention (WISC) were included in the analysis. The ADNI featured individuals with mild cognitive impairment (MCI) and no cognitive impairment while the 2 Wisconsin cohorts included individuals without cognitive impairment.

Senior investigator Henrik Zetterberg, MD, PhD, professor of neurochemistry, UGOT, and colleagues included patients with 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. In the UGOT cohort, A– T+ profiles were found in 4.1% of patients, whereas the prevalence of A–T– was 42%, the prevalence of A+T– was 17%, and the prevalence of A+T+ was 36%. Similar estimates were found in the ADNI and WISC cohorts.

The findings also highlighted the importance of lower levels of Aß42 in the association with cognitive decline even in the presence of tau alteration. If determining amyloid by CSF Aß42 alone, the prevalence of an A–T+ profile would be 19% (95% CI, 18-20), and 37% (95% CI, 36-38), 22% (95% CI, 21-23), and 21% (95% CI, 20-22) for A–T–, A+T–, and A+T+ profiles, respectively.

"Interestingly, in the UGOT and ADNI cohorts, concentrations of Aβ40 and Aβ42 were clearly higher in the A−T+ group, compared with the A−T− group,” Zetterberg et al noted. "This could potentially suggest that the CSF A−T+ profile is indeed associated altered CSF dynamics, given that within 2 Aβ-negative groups as defined by the Aβ42/Aβ40 ratio, it would not be expected that Aβ42 and Aβ40 values alone would differ between groups."

Using mPACC, findings from the ADNI cohort showed that an A–T+ profile was not associated with significantly different rates of decline as compared with A–T+ individuals, regardless of baseline cognitive status (cognitive unimpaired [CU], ß = –0.09 [95% CI, –0.3 to 0.1; P = .27] MCI: ß = –0.01 [95% CI, –0.4 to 0.4] P = .99). In both the ADNI and WISC cohorts, individuals with A+T– and A+T+ profiles had faster cognitive decline in comparison with those with an A–T– profile.

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In terms of assessing disease progression over time, regardless of baseline cognitive status, individuals with an A–T+ profile did not significantly differ from those with A–T– in longitudinal rates of change in Aß-PET (CU: β = 0.002 [95% CI, −0.01 to 0.01; P = .44] MCI: β = 0.002 [95% CI, −0.01 to 0.01; P = .44], FDG-PET CU: β = −0.002 [95% CI, −0.01 to 0.001] P = .28, MCI: β = −0.002 [95% CI, −0.005 to 0.002] P = .39), or hippocampal volume (CU: β = −19 mm3 per year [95% CI, −40 to 1.0; P = .06] MCI: β = 3.9 mm3 per year [95% CI, −29 to 37] P = .82). in comparison with A–T– profiles, those with MCI and A+T+ or A+T– profiles displayed significant changes in markers of hippocampal volume and glucose metabolism, contrasting previous studies.

In CU individuals with an A+T– profile, investigators observed no significant changes in FDG PET, whereas there was a slight decrease in hippocampal volume when comparing individuals with an A–T– profile. Using a subset of participants with tau-PET data (ADNI: n = 192; WISC: n = 227), data showed that the A+T+ group had higher tau PET standardized uptake value ratio (ADNI: EM, 1.54 [SE, 0.03]; P <.001; WISC: EM, 1.5 [SE, 0.04]; P = .002) when compared with the A–T+ group.

Above all, Zetterberg et al concluded that those with CSF A–T+ patterns are not associated with higher rates of cognitive decline or AD biomarker progression than an A–T– profile. “We suggest that practitioners encountering this pattern in daily clinical practice should interpret such a finding similarly to CSF biomarker-negative results during the diagnostic workup of patients with cognitive complaints, and unusually high CSF Aβ42 and Aβ40 concentrations could be a recognizable feature of such a profile,” they concluded.

REFERENCE
1. Erickson P, Simren J, Brum WS, et al. Prevalence and clinical implications of a ß-amyloid-negative, tau-positive cerebrospinal fluid biomarker profile in Alzheimer disease. JAMA Neurol. Published online July 31, 2023. doi:10.1001/jamaneurol.2023.2338