Application of the Nia-Aa Research Framework: Towards a Biological Definition of Alzheimer’s Disease Using Cerebrospinal Fluid Biomarkers in the Aibl Study

Abstract

BACKGROUND: The National Institute on Aging and Alzheimer’s Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer’s disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer’s disease. OBJECTIVES: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)). DESIGN: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers. SETTING: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study. PARTICIPANTS: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable. MEASUREMENTS: Three CSF biomarkers, namely amyloid β1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test – Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores. RESULTS: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework’s definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures. CONCLUSIONS: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…The results revealed that only subjects classified as A + T + N + show marked cognitive impairment compared to subjects classified as A − T − N −. The same data emerged using a previous classification of the NIA–AA group, based on the presence (or absence) of amyloidosis and tau, leading to the conclusion that the concomitant presence of amyloidosis and tau pathology is required to increase the risk of developing cognitive impairment in the future [ 394 ]. However, the high invasiveness and the elevated costs of CSF sampling, as well as the imaging methods, have recently led scientists to search for new minimally invasive and cost-effective blood-based biomarkers to be used in broad population screenings [ 11 ].…”

Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

“…The current work is largely consistent with several recent studies that have demonstrated generally poorer prognoses in groups with positive A, T, and N biomarkers relative to other groups ( Burnham et al, 2019 , Jack et al, 2019 , Yu et al, 2019 ). We extend these prior findings by providing support for the notion that the relative presence or absence of A/T/(N) biomarkers may provide insights into underlying drivers of cognitive impairment in MCI.…”

Connecting Cohorts to Diminish Alzheimer’s Disease (CONCORD-AD): A Report of an International Research Collaboration Network

“…F lived; a small number were also assessed at home by AIBL staff. The AIBL cohort has given rise to diverse research publications and further studies, including imaging studies exploring the relationship between aggregated amyloid-␤ (A␤) and gray matter atrophy [13], studies exploring the application of new research frameworks and analytical techniques in the AIBL cohort [14][15][16], cognition-function studies [17], and the potential for introducing physical activity interventions in participants at risk for AD or with subjective memory complaints [18].…”