The fundamental principle
Alzheimer disease is a clinical-biological construct. The diagnostic meaning of any biomarker depends on the clinical context in which it was measured. The same biomarker result does not carry the same weight in a patient with cognitive symptoms and in a cognitively normal individual.
Biomarkers SUPPORT an AD diagnosis
Use as diagnostic markersThe patient presents with a specific Alzheimer disease clinical phenotype:
- Common phenotypes: amnestic syndrome of the hippocampal type, logopenic variant PPA, posterior cortical atrophy
- Uncommon phenotypes: behavioural / dysexecutive variant, corticobasal syndrome, non-fluent or semantic variant PPA
Positive pathophysiological biomarkers of amyloid and tau pathology — either CSF (low Aβ42, increased phospho-tau or Aβ40/Aβ42 ratio) or PET (amyloid and tau tracer retention).
Biomarkers indicate RISK only
Interpret as risk markers — not diagnosticThe individual is cognitively unimpaired on objective testing — no AD clinical phenotype is present.
- No measurable cognitive deficit
- Activities of daily living preserved
- Subjective complaints may or may not be present
Positive amyloid PET / CSF, isolated amyloid positivity, or full A+T+ profile — measured for screening, family history, or research purposes.
The IWG 2024 lexicon
Three categories to distinguish when communicating with patients.
Cognitively normal · Biomarker positive · Uncertain progression
Isolated amyloid positivity, or amyloid + limited tau (medial temporal only). Lifetime risk is increased compared with biomarker-negative individuals, but far from deterministic. Not a diagnosis of AD.
Cognitively normal · Near-deterministic biomarker profile
Autosomal dominant mutations (APP, PSEN1, PSEN2), Down syndrome, APOE ε4 homozygous with SORL1 loss-of-function, or amyloid+ and tau+ in neocortical regions. Progression to symptoms is very likely.
Cognitively impaired · Specific clinical phenotype · Biomarker positive
Common or uncommon AD clinical phenotype plus positivity of CSF or PET pathophysiological biomarkers. Covers the prodromal (MCI) and dementia stages.
Do
- Always start with a careful clinical assessment — cognitive testing, history, examination — before interpreting biomarker results.
- Identify the clinical phenotype first, then assess whether biomarker results are congruent with that phenotype.
- Order biomarkers in patients with cognitive impairment, where they can answer a meaningful diagnostic question.
- Communicate risk — not disease — to cognitively unimpaired biomarker-positive individuals.
- Consider copathologies (Lewy, TDP-43, vascular, etc.) when the clinical phenotype is incongruent with the biomarker profile.
Don't
- Don't diagnose AD on biomarker positivity alone in a cognitively normal individual.
- Don't assume A+T+ means AD regardless of phenotype — in Lewy body, Richardson, or Huntington syndromes, this profile likely reflects copathology, not the primary diagnosis.
- Don't routinely screen cognitively unimpaired individuals with biomarkers outside a research context.
- Don't disclose biomarker results without a structured discussion of what they do and do not predict for that individual.
- Don't ignore a clinical phenotype because biomarkers are negative — pursue full investigation of cause.