Alzheimer Disease

Alzheimer disease is the most common neurodegenerative cause of dementia, a slowly progressive disorder of memory and other cognitive domains driven by the accumulation of amyloid-beta plaques and tau neurofibrillary tangles in the brain. It typically begins with episodic memory impairment and advances over years to widespread cognitive and functional decline.

Definition

Alzheimer disease is a progressive neurodegenerative disorder defined neuropathologically by extracellular amyloid-beta plaques and intracellular tau neurofibrillary tangles, and clinically by an insidious, progressive decline in memory and other cognitive abilities sufficient to impair daily function.

Scope

This topic covers Alzheimer disease as a clinical and biological entity: its defining amyloid and tau pathology, the typical amnestic clinical course and its atypical variants, the move toward biomarker-based biological definition, and its epidemiology as the leading cause of dementia. It is a reference overview and does not provide diagnostic protocols or treatment guidance.

Core questions

• How do amyloid-beta and tau pathology relate to each other and to symptoms?
• Can the disease be defined biologically by biomarkers before symptoms appear?
• Why does episodic memory tend to be affected first?
• How do atypical (non-amnestic) presentations fit the same disease?

Key concepts

• Amyloid-beta plaques
• Tau neurofibrillary tangles
• AT(N) biomarker classification
• Episodic memory impairment
• Atypical and early-onset variants
• Cerebrospinal fluid and PET biomarkers
• Mixed and co-occurring pathology

Key theories

Amyloid cascade hypothesis

The amyloid cascade hypothesis proposes that accumulation of amyloid-beta is an early and upstream event that triggers downstream tau pathology, synaptic loss, and neurodegeneration; it remains influential but is debated given the imperfect correlation between amyloid burden and clinical severity.

Biological (biomarker-based) definition

The NIA-AA research framework reframes Alzheimer disease as a biological construct defined by amyloid, tau, and neurodegeneration biomarkers (the AT(N) system) rather than by clinical syndrome alone, separating the underlying pathology from the staging of symptoms.

Mechanisms

Alzheimer disease is characterised by the extracellular aggregation of amyloid-beta into plaques and the intracellular aggregation of hyperphosphorylated tau into neurofibrillary tangles, accompanied by synaptic loss, neuroinflammation, and progressive neuronal death. Tau pathology spreads in a stereotyped pattern that begins in the medial temporal lobe and extends through the cortex, paralleling the clinical progression from memory impairment to broader cognitive decline. The amyloid cascade hypothesis links these processes by positing amyloid as an upstream driver, although the relationship between molecular pathology and clinical severity is imperfect, motivating the biomarker-based AT(N) framework (Scheltens et al., 2021; Jack et al., 2018).

Clinical relevance

Alzheimer disease is the leading cause of dementia, and understanding its amyloid and tau pathology underlies the interpretation of cognitive assessment, imaging, and fluid biomarkers in research and clinical reasoning. This entry describes how the disease is defined and studied; it is not a basis for individual diagnosis or treatment decisions.

Epidemiology

Alzheimer disease accounts for the majority of dementia cases worldwide, and its prevalence rises steeply with age, making it a dominant contributor to the growing global dementia burden as populations age. Most cases are late-onset and sporadic, with age as the strongest risk factor; a minority of early-onset cases are associated with autosomal-dominant mutations (Scheltens et al., 2021).

History

Alois Alzheimer described the disease in 1906-1907 in a patient with progressive dementia whose brain showed plaques and tangles. Over the twentieth century the disease was recognised as a common cause of dementia rather than a rare presenile condition, the amyloid and tau proteins were molecularly characterised, and the field progressively moved toward defining the disease biologically through biomarkers, culminating in research frameworks such as the NIA-AA AT(N) system (Scheltens et al., 2021; Jack et al., 2018).

Debates

Is the amyloid cascade hypothesis the right organising framework?

Amyloid-targeting strategies and the imperfect correlation between amyloid burden and symptoms have fuelled debate over whether amyloid is the primary driver of disease or one component of a more complex process involving tau and other factors.

Should Alzheimer disease be defined biologically or clinically?

The shift toward a biomarker-based biological definition separates pathology from symptoms and raises questions about how to classify people with biomarker evidence of disease who have no or minimal cognitive impairment.

Key figures

• Alois Alzheimer
• Philip Scheltens
• Clifford Jack
• Dennis Dickson

Seminal works

• scheltens-2021
• jack-2018
• dugger-dickson-2017

Frequently asked questions

What is the difference between Alzheimer disease and dementia?

Dementia is a clinical syndrome of acquired cognitive decline with many possible causes; Alzheimer disease is a specific neurodegenerative disease, defined by amyloid and tau pathology, that is the most common cause of dementia.

What are amyloid plaques and tau tangles?

They are the two hallmark protein aggregates of Alzheimer disease: amyloid-beta plaques form outside neurons, and tau neurofibrillary tangles form inside them, and together they define the disease neuropathologically.