Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: From biological biomarkers to clinical syndromes
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BACKGROUND: According to the 2018 NIA-AA research framework, Alzheimer's disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition-assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis-is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers. METHODS: We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated. RESULTS: Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers' profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%. CONCLUSIONS: The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.
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Following the 2018-NIA-AA-RF, Alzheimer's disease is defined by underlying pathology measured by lifetime biomarkers, and both Aβ and phosphorylated tau pathology are required for classification as AD, whereas Aβ deposition alone is an early sign.
“Following the new research framework (2018-NIA-AA-RF), AD is not defined by its clinical consequences but by its underlying pathology measured by lifetime biomarkers. Regardless of the presence of clinical symptoms, both Aβ and phosphorylated tau pathology are required for classification as AD, whereas Aβ deposition alone is an early sign, labelling the pathologic change towards AD [9].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [9]
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- Authors
- Carandini, T., Arighi, A., Sacchi, L., Fumagalli, G. G., Pietroboni, A. M., Ghezzi, L., Colombi, A., Scarioni, M., Fenoglio, C., De Riz, M. A., Marotta, G., Scarpini, E., & Galimberti, D.
- Affiliations
- University of Milan (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Corresponding author
- Carandini, Tiziana
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2019-10-15
- Volume
- 11
- Issue
- 1
- Pages
- 84-84
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC6794758
- OpenAlex
- W2980693448
- Cited by
- 36
- References
- 49
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 7 · 2018: 1
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministero della Salute
- Associazione Italiana Ricerca Alzheimer
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, amyloid-beta, phosphorylated tau, cerebrospinal fluid biomarkers, amyloid PET, clinical syndromes, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, atypical parkinsonism, mild cognitive impairment, dementia, neurodegenerative dementia
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments, Retrospective Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Neuroimaging, Cognitive Dysfunction
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