What is Alzheimer's disease?

What is Alzheimer's Disease

Alzheimer's disease is a clinical-biological entity defined by a specific clinical phenotype of progressive cognitive and functional decline associated with in-vivo evidence of underlying brain pathology—specifically amyloid-β plaques and neurofibrillary tau tangles—that leads to neuronal degeneration and dementia. 1

Core Pathological Features

The neuropathological hallmarks that define Alzheimer's disease include:

• Extracellular amyloid-β (Aβ) plaques composed of aggregated amyloid-β protein 1, 2
• Intracellular neurofibrillary tangles comprised of hyperphosphorylated tau protein 1, 2
• Progressive neuronal and synaptic degeneration leading to brain atrophy 1, 3

These pathological changes can now be detected in living patients through biomarkers including low CSF Aβ42, increased CSF phosphorylated tau, elevated amyloid on PET imaging, and tau PET tracer retention 1.

Clinical Presentation and Disease Continuum

Alzheimer's disease exists along a continuum from preclinical to dementia stages 1:

Preclinical Stage

• Biomarker evidence of pathology is present but no cognitive symptoms 1
• This asymptomatic phase may last a decade or more before clinical symptoms emerge 1
• However, the 2021 International Working Group emphasizes that cognitively unimpaired individuals with positive biomarkers should be classified as "asymptomatic at risk" rather than having Alzheimer's disease, since many will never progress to clinical disease 1

Prodromal Alzheimer's Disease (MCI due to AD)

• Early symptomatic predementia phase with objective cognitive impairment 1
• Impairment in at least one cognitive domain (not necessarily memory) relative to age-matched norms 1
• Preserved independence in functional abilities, though mild problems with instrumental activities of daily living may be present 1
• Annual conversion rate to dementia is 5-10%, with approximately 35% progressing within 3 years 1

Alzheimer's Dementia

• Cognitive symptoms sufficiently severe to interfere with social functioning and activities of daily living 1
• Requires insidious onset with progressive cognitive decline 1
• Impairment in two or more cognitive domains 1
• While amnestic presentation is most common, nonamnestic presentations (executive dysfunction, visuospatial impairment, language problems) are recognized 1

Characteristic Neurodegeneration Pattern

Brain atrophy follows a predictable sequence 4:

• Medial temporal lobe atrophy affecting hippocampus and amygdala with temporal horn enlargement 4
• Paralimbic and temporoparietal cortical atrophy 4
• Enlarged sulcal spaces with gyral atrophy in frontal and temporal cortices 4
• These structural changes correlate closely with cognitive performance through MCI and dementia phases 4

Critical Diagnostic Principle

The 2021 International Working Group strongly recommends that clinical diagnosis of Alzheimer's disease must remain tied to the clinical phenotypic presentation, not biomarkers alone 1. This is because:

• Biomarker-positive cognitively unimpaired individuals have highly variable outcomes, with lifetime dementia risk ranging only 5-42% 1
• Many elderly individuals have pathological changes without clinical progression 1
• Defining disease by pathology alone risks diagnostic confusion, particularly in the oldest old where memory complaints and low amounts of pathology are nearly constant 1

Impact and Epidemiology

• Alzheimer's disease is the most common cause of dementia worldwide, affecting approximately 15 million people globally 3, 5
• It is progressive and irreversible, though treatments can enhance quality of life 5
• The disease exacts substantial societal costs and is the primary cause of cognitive decline in old age 5, 2