Alzheimer Disease

Alzheimer disease is a progressive neurodegenerative disorder and the most common cause of dementia. Its neuropathology is defined by two protein aggregates - extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau - accompanied by synaptic and neuronal loss that begins in medial temporal structures and spreads through the cerebral cortex.

Definition

Alzheimer disease is a neurodegenerative proteinopathy characterised pathologically by extracellular amyloid-beta plaques, intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau, and progressive synaptic and neuronal loss, clinically manifesting as a slowly progressive dementia.

Scope

The entry covers the defining lesions of Alzheimer disease (amyloid plaques and tau tangles), the staging of their anatomical spread, and the principal hypothesis linking amyloid accumulation to downstream injury. It treats Alzheimer disease as a neuropathological entity for reference and education and does not provide diagnostic or treatment recommendations.

Core questions

• What are the defining histopathological lesions of Alzheimer disease, and how are they staged?
• How does the amyloid cascade hypothesis frame the relationship between amyloid-beta and tau pathology?
• Why does the disease show a characteristic anatomical progression through the cortex?

Key concepts

• Amyloid-beta plaques
• Neurofibrillary tangles and hyperphosphorylated tau
• Braak staging of tau pathology
• Synaptic and neuronal loss
• Neuroinflammation
• Medial temporal and cortical involvement

Key theories

Amyloid cascade hypothesis

Proposes that accumulation and aggregation of amyloid-beta peptide is an early and driving event in Alzheimer disease, initiating a cascade that includes tau pathology, neuroinflammation, synaptic dysfunction, and neuronal death; it remains influential but is debated.

Mechanisms

Alzheimer disease pathology centres on two aggregating proteins. Amyloid-beta, a fragment of the amyloid precursor protein, accumulates extracellularly as diffuse and neuritic plaques, while the microtubule-associated protein tau becomes hyperphosphorylated and forms intraneuronal neurofibrillary tangles. The amyloid cascade hypothesis holds that amyloid-beta deposition is an early driver that promotes tau pathology, synaptic failure, neuroinflammation, and neuronal death. Tau pathology spreads in a stereotyped anatomical sequence - captured by Braak staging - beginning in the transentorhinal and limbic regions and progressing to the neocortex, paralleling the clinical evolution from memory impairment to broader cognitive decline.

Clinical relevance

The neuropathological features of Alzheimer disease underlie its presentation as a progressive amnestic dementia and inform how the disease is defined and diagnosed. This entry is provided for reference and education; it describes disease mechanisms and is not a source of diagnostic or treatment advice.

Epidemiology

Alzheimer disease is the leading cause of dementia and a major contributor to disability in older populations, with prevalence rising sharply with age. Increasing age is the strongest risk factor, and the absolute number of affected people is growing as populations age.

Evidence & guidelines

The anatomical staging of Alzheimer-related neurofibrillary pathology is codified in the Braak staging scheme, and authoritative reviews synthesise the molecular pathobiology. The amyloid cascade hypothesis provides the dominant interpretive framework, while remaining an area of active scientific debate.

History

The disease was first described in the early twentieth century from a case combining progressive dementia with characteristic plaques and tangles seen at autopsy. Later identification of amyloid-beta and tau as the molecular constituents of these lesions, the formulation of the amyloid cascade hypothesis, and the Braak staging of pathological spread established the modern neuropathological understanding.

Debates

Is amyloid-beta the primary driver of Alzheimer disease?

The amyloid cascade hypothesis places amyloid-beta upstream of tau pathology and neurodegeneration, but the imperfect correlation between amyloid burden and clinical severity, and the central role of tau spread in tracking symptoms, have led to ongoing debate about the relative primacy of amyloid and tau.

Key figures

• Heiko Braak
• Eva Braak
• John Hardy

Seminal works

• braak-1991
• hardy-higgins-1992

Frequently asked questions

What are the two defining lesions of Alzheimer disease?

Extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles made of hyperphosphorylated tau, together with progressive synaptic and neuronal loss. These are the hallmark neuropathological features.

What is Braak staging?

Braak staging is a system that describes the stereotyped anatomical progression of tau (neurofibrillary) pathology in Alzheimer disease, from transentorhinal and limbic regions to the neocortex. It is a descriptive staging scheme used in neuropathology, not a clinical treatment tool.