The IWG 2024 Lexicon
The three diagnostic categories proposed by the International Working Group to characterise individuals along the Alzheimer disease continuum.
The IWG defines Alzheimer disease as a clinical-biological construct: a diagnosis of AD requires both a recognised clinical phenotype and supportive biomarker evidence. In cognitively unimpaired individuals, biomarker positivity defines a state of risk — not disease.
No symptoms Biomarker positive
Uncertain progression High-risk biomarker profile
Near-deterministic progression Clinical phenotype
Biomarker positive
Asymptomatic at Risk for AD Cognitively normal · Biomarker positive
- Isolated amyloid positivity (A+ T−)
- Amyloid + tau limited to medial temporal lobe
- Positive p-tau fluid biomarker (e.g. plasma p-tau 217)
Presymptomatic AD Cognitively normal · Near-deterministic profile
- Autosomal dominant mutations (APP, PSEN1, PSEN2)
- Persons with Down syndrome (trisomy 21)
- APOE ε4 homozygotes with SORL1 loss-of-function
- Sporadic AD with amyloid PET(+) and tau PET(+) in neocortical regions
Alzheimer Disease (AD) Cognitively impaired · Phenotype + Biomarkers
- Common: amnestic syndrome of the hippocampal type
- Common: logopenic variant primary progressive aphasia
- Common: posterior cortical atrophy
- Uncommon: corticobasal syndrome, behavioural / dysexecutive variant
Asymptomatic at-Risk and Presymptomatic AD are not stages of Alzheimer disease — they are categories of risk. The diagnostic label "Alzheimer disease" is reserved for individuals who present with both a recognised clinical phenotype and supportive biomarker evidence.
Glossary of Terms
The broader terminology of Alzheimer disease diagnosis, as defined in the 2025 Lancet Series.
Alzheimer's Association Workgroup 2024 Revised Criteria
An integrated biological and clinical staging scheme with six clinical stages (graphically represented in left-to-right columns) and four biological stages (top-to-bottom rows). Biological Alzheimer's disease stage and clinical severity are related, but do not travel in lockstep. The typical or average relationship between biology and symptoms can be envisioned as moving along an upper-left to lower-right diagonal, following the steps of the amyloid cascade — from A−T− to A+T− to A+T+ in the medial temporal lobe, A+T+ with moderate neocortical burden, and A+T+ with high neocortical burden. A = β-amyloid, T = tau pathology. The criteria are conceptual and await validation.
Alzheimer's disease
There is no unanimity on the epistemological definition of Alzheimer's disease, reflected in sets of different diagnostic criteria (Alzheimer's Association Workgroup 2024 Revised Criteria and International Working Group 2024 diagnostic criteria). Disagreements extend to the existence of presymptomatic or preclinical Alzheimer's disease, and to the interpretation of Alzheimer's disease biomarker positivity in the absence of objective cognitive impairment or deterioration. However, for all practical purposes Alzheimer's disease can be operationalised as cognitive impairment due to Alzheimer's disease pathology, evolving in stages of increasing cognitive and functional severity.
Alzheimer's pathology
Alzheimer's disease pathology, or Alzheimer's disease neuropathological changes, consists of the cortical deposition of aggregates of β-amyloid and hyperphosphorylated tau proteins.
Amyloid-targeting therapy
Pharmacological products aimed at decreasing the load of aggregated β-amyloid in the brain or preventing aggregation, such as monoclonal antibodies directed towards different forms of aggregated or soluble amyloid. Two of these (lecanemab and donanemab) have been found effective in registration phase 3 trials at reducing cognitive progression by 27% to 39% in patients with Alzheimer's disease operationalised as cognitive impairment and β-amyloid pathology; tau biomarkers are also ameliorated. Lecanemab and donanemab are approved for clinical use in the USA and other countries.
Biomarker
An objectively measurable substance, characteristic, or other parameter of a biological process that enables assessment of disease risk or prognosis and provides guidance for diagnosis or monitoring of treatment.
Braak stages
In Alzheimer's disease, a method to classify the progressive degree of neurofibrillary tangle involvement due to tau pathology.
Cognitive disorders
All conditions that can cause cognitive impairment. These include neurodegenerative conditions such as Alzheimer's disease, but also vascular disease, traumatic brain injury, substance use, infections, disturbances of cerebrospinal fluid dynamics, psychiatric conditions, secondary or reversible cognitive disorders, and more. DSM-5 refers to "neurocognitive disorders" to differentiate cognitive impairment from psychoses. The authors believe the "neuro" prefix does not add meaningful information, as by definition the brain is the organ responsible for all cognitive disorders.
Cognitive impairment
Problems with thinking, learning, remembering, using judgment, and making decisions that cannot be accounted for by age alone. In the differential diagnosis of cognitive disorders, it is used to infer change from a normal aging trajectory to an abnormal trajectory of decline. In highly educated or performant patients still scoring in the normal range of cognitive tests, clinical judgement can occasionally help identify those on a trajectory of cognitive decline based on a clear history of progressive and consistent decline.
Delirium
A syndrome of acute confusion due to the direct physiological consequence of medical conditions, the effects of psychoactive substances, acute brain diseases, or multiple causes affecting brain functioning. It often develops on a brain weakened by age-associated or neurodegeneration-associated pathology, and usually develops over the course of hours to days with disturbances in attention, awareness, and higher-order cognition. Other neuropsychiatric disturbances are often associated, such as changes in psychomotor activity (e.g. hyperactive, hypoactive, or mixed level of activity), a disrupted sleep–wake cycle, emotional disturbances, an altered state of consciousness, and perceptual disturbances (e.g. hallucinations and delusions).
Dementia
A syndrome referring to acquired cognitive impairment affecting disability in daily activities. The term is largely regarded as stigmatising, of limited clinical usefulness (it fails to capture cognitive impairment with no loss of function), and imprecise (singular "dementia" denotes the syndrome, plural "dementias" the diseases and conditions underlying the syndrome). For this reason, while acknowledging that the term is widely used in neurology, psychiatry, and geriatrics, the authors endorse the terms cognitive impairment and cognitive disorders. Major neurocognitive disorder is the synonym for dementia in DSM-5.
International Working Group 2024 diagnostic criteria
Developed for clinical practice and research, the criteria postulate that Alzheimer's disease is a clinical–biological construct consisting of the association of Alzheimer's pathology (brain amyloidosis and tauopathy) with cognitive impairment of specific profiles. Presymptomatic individuals are cognitively unimpaired people who are carriers of fully penetrant autosomal dominant monogenic Alzheimer's disease mutations. Alzheimer's pathology in the absence of cognitive impairment defines the asymptomatic at-risk individuals.
Lewy body disease
A spectrum of conditions due to the accumulation, in the central and autonomic nervous system, of Lewy bodies and Lewy neurites, whose primary structural component is α-synuclein. The spectrum includes Parkinson's disease (the main cerebral affected structure being the substantia nigra), dementia with Lewy bodies (early involvement of the neocortex), and Parkinson's disease dementia (early involvement of the substantia nigra and later of the neocortex).
Mild cognitive impairment (MCI)
A syndrome referring to acquired and progressive cognitive impairment. The person may be slower and less efficient but can still function independently. It is commonly associated with neuropathology (e.g. Alzheimer's disease), but it could be due to anything, including physical and psychiatric conditions. Mild neurocognitive disorder is the synonym for MCI in DSM-5.
Proteinopathies
Refers to certain proteins whose three-dimensional folding conformation becomes abnormal and disrupts cellular function. In Alzheimer's disease and related neurodegenerative diseases, the most frequent are β-amyloid and 3R-4R hyperphosphorylated tau (typical of Alzheimer's disease), α-synuclein (Parkinson's disease, dementia with Lewy bodies, and Parkinson's dementia), TAR DNA-binding protein-43 (TDP-43, in some forms of frontotemporal lobar degeneration), 4R hyperphosphorylated tau (typical of progressive supranuclear palsy and corticobasal degeneration), polyglutamine (Huntington's disease), and superoxide dismutase-1 (SOD1, in some forms of amyotrophic lateral sclerosis).
Staging
In Alzheimer's disease and the dementias in general, staging consists of assigning a degree of severity to the main clinical dimensions of the disease: cognitive, behavioural and psychiatric, functional, and motor or other neurological symptoms. Each should be rated as none, minimal, mild, moderate, or severe. For cognitive or functional staging, the Clinical Dementia Rating Scale is largely used.
Subjective cognitive decline (SCD)
A clinical construct referring to complaints of progressive cognitive problems with formal cognitive testing revealing unimpaired performance. "SCD plus" refers to certain features of SCD which increase the likelihood that the condition is related to Alzheimer's disease pathology and that there is a higher risk of objective cognitive decline in the future. The currently proposed SCD plus criteria are: subjective decline in memory irrespective of function in other cognitive domains; onset of SCD within the past 5 years; onset of SCD at 60 years or older; concern (worry) associated with SCD; persistence of SCD over time; seeking of medical help; and confirmation of cognitive decline by an observer.
Worried well
Individuals who do not experience subjective cognitive decline themselves but are concerned about cognitive deterioration or Alzheimer's disease in the future. The label is controversial in the literature, as it might lead to genuine concerns or pathology being dismissed.