What Causes Alzheimer's Disease
Alzheimer's disease is a multifactorial neurodegenerative disorder caused by complex interactions among genetic factors, biological mechanisms (primarily amyloid-β accumulation and tau pathology), and environmental influences. 1
Primary Pathophysiological Mechanisms
The disease fundamentally results from two synergistic pathological processes in the brain 2:
- Amyloid-β (Aβ) plaques accumulate as the upstream initiating event, with all autosomal dominant early-onset forms linked to alterations in amyloid precursor protein (APP) production or cleavage 2
- Hyperphosphorylated tau protein tangles form intracellularly and correlate more strongly with clinical impairment than amyloid plaque burden alone 1, 2
- These pathological changes lead to synaptic dysfunction, neuronal loss, and progressive cognitive decline 2
The temporal sequence matters: amyloid accumulation occurs first, followed by tau pathology that progresses to the highest stages (Braak 5 or 6) through synergistic interactions with amyloid-β, producing the most severe cognitive decline 2.
Genetic Causes and Risk Factors
Early-Onset Alzheimer's Disease (Before Age 65)
Autosomal dominant mutations in three genes directly cause early-onset AD, inherited in a Mendelian fashion 3:
- APP (amyloid precursor protein gene)
- PSEN1 (presenilin 1 gene)
- PSEN2 (presenilin 2 gene)
Trisomy 21 (Down syndrome) invariably results in Alzheimer's pathology due to three intact copies of the APP coding region on chromosome 21 2.
Late-Onset Alzheimer's Disease (After Age 65)
- APOE ε4 allele is the major genetic risk factor, directly affecting amyloid trafficking and plaque clearance 2
- Having a first-degree relative with AD at least doubles the average lifetime risk from 10-12% 1
- However, the APOE ε4 allele and traditional AD pathological biomarkers are likely not the major factors accounting for observed differences in risk among underrepresented populations 1
Environmental and Modifiable Risk Factors
Vascular and Metabolic Factors
Cardiovascular risk factors increase dementia risk and directly contribute to how Alzheimer's pathology affects the aging brain 1:
- Hypertension
- Hypercholesterolemia
- Diabetes mellitus
Lifestyle and Occupational Exposures
Environmental factors that increase risk include 1, 3:
- Chronic stress
- Smoking
- Exposure to pollution
- Inequitable access to education, healthy diet, and healthcare
- Occupational exposures (pesticides, electromagnetic fields, organic solvents, volatile anesthetics) 3
- Head trauma 3
Protective Factors
Engagement in specific activities associates with decreased risk 1:
- Cognitive activity
- Physical activity
- Leisure activities
- Social activity
Age as the Primary Risk Factor
Age is the best-studied and strongest risk factor for dementia 1. The disease risk increases dramatically with age, with approximately 30% of clinically normal individuals aged 65 years and older having biomarker evidence of amyloid accumulation 1, 2.
Modulating Factors: Reserve Capacity
Brain reserve and cognitive reserve allow individuals to tolerate higher levels of pathological burden without exhibiting clinical symptoms 1, 2:
- Brain reserve refers to greater synaptic density or larger numbers of healthy neurons that provide sufficient neural substrate to support normal function 1, 2
- Cognitive reserve represents the ability to engage alternate brain networks or cognitive strategies to cope with encroaching pathology 1, 2
- Higher education and socioeconomic status have been associated with lower age-adjusted incidence of AD diagnosis 1
Critical Clinical Context
Most AD cases are sporadic rather than inherited, with disease risk increasing with age 1. The pathophysiological changes occur in the brain decades before the first memory complaints appear 1. Approximately 30% of clinically normal individuals aged 65+ have biomarker evidence of amyloid accumulation, yet the majority remain clinically stable, highlighting the complex interplay between pathology and clinical expression 1, 2.
The differences in incidence and prevalence across racial and ethnic groups likely relate to variations in medical comorbidities, health-related behaviors, and sociocultural and environmental factors that confer increased AD vulnerability, rather than solely genetic differences 1.