What Causes Alzheimer's Disease
Alzheimer's disease is a multifactorial neurodegenerative disorder resulting from complex interactions among genetic, biological, and environmental factors, with amyloid-β (Aβ) peptide accumulation representing the key upstream initiating event that triggers a downstream cascade of tau pathology, synaptic dysfunction, neuronal loss, and ultimately cognitive decline. 1, 2
Primary Pathological Mechanisms
The core pathophysiology centers on two hallmark protein abnormalities that work synergistically:
- Amyloid-β accumulation occurs first, beginning 25-30 years before symptoms appear, and represents the upstream initiating factor in the disease cascade 1, 2
- Hyperphosphorylated tau protein forms neurofibrillary tangles that correlate more strongly with clinical impairment than amyloid plaque burden alone 1, 2
- Synaptic depletion and neuronal loss constitute the final common pathway leading to clinical symptoms, with these changes invariably occurring in AD 1, 2
- Neuroinflammation with glial activation and elevated proinflammatory cytokines contributes to progressive neuronal damage 2
The pathological process follows a predictable sequence: Aβ accumulation → tau pathology → neurodegeneration → clinical symptoms, though the exact mechanism by which Aβ triggers downstream changes remains incompletely understood 1, 2
Genetic Causes and Risk Factors
All autosomal dominant early-onset forms of AD are caused by alterations in amyloid precursor protein (APP) production or cleavage 1, 2:
- Mutations in APP, PSEN1, and PSEN2 genes cause early-onset familial AD with accelerated disease progression 3, 4, 5
- Trisomy 21 invariably results in AD pathology due to three intact copies of the APP coding region on chromosome 21 1, 2
- APOE ε4 allele is the major genetic risk factor for late-onset AD, directly affecting amyloid trafficking and plaque clearance 1, 2, 3
Environmental and Modifiable Risk Factors
Multiple environmental factors alter the pace of clinical disease expression 1:
- Vascular risk factors (hypertension, hypercholesterolemia, diabetes) increase dementia risk and directly contribute to AD pathology effects on the aging brain 1, 2
- Head trauma, malnutrition, and environmental exposures may influence disease progression, though evidence remains less definitive 5
- Depressive symptomatology, apathy, and chronic psychological distress have been linked to increased risk of manifesting MCI and dementia 1
Protective factors include cognitive, physical, leisure, and social activities, which associate with decreased risk of MCI and AD dementia 1, 2
Age as the Primary Risk Factor
Advanced aging is the greatest risk factor for developing AD, with Aβ42 accumulation increasing with age 1:
- Most AD cases are sporadic, with disease risk increasing dramatically with age 1
- Approximately 30% of clinically normal individuals aged 65+ have biomarker evidence of amyloid accumulation 1, 2
- Two-thirds of individuals aged 70+ show all stages of AD brain lesions on systematic post-mortem examination regardless of clinical status 2
The Role of Reserve Capacity
Brain reserve and cognitive reserve explain why pathological burden does not always correlate with clinical symptoms 1, 2:
- Brain reserve (greater synaptic density, larger neuronal populations) allows tolerance of higher pathological burden without symptoms 1, 2
- Cognitive reserve (alternate neural networks, compensatory strategies) enables coping with encroaching pathology 1, 2
- Higher education and socioeconomic status associate with lower age-adjusted incidence of AD diagnosis, though rapid decline may occur after compensatory mechanisms fail 1
Critical Clinical Pitfalls
Do not diagnose AD based solely on biomarker positivity in cognitively unimpaired individuals, as the majority remain stable over years and current evidence cannot reliably predict progression 2. The temporal lag between pathology appearance and clinical symptoms varies substantially based on reserve capacity and modulating factors 2.
Recognize that positive AD biomarkers may represent copathology in other neurodegenerative diseases rather than primary AD 2, and CSF biomarker changes occur in other disorders requiring consideration of the overall clinical presentation 2.