What are the risk factors for Alzheimer’s disease?

Risk Factors for Alzheimer's Disease

Age is the strongest risk factor for Alzheimer's disease, followed by genetic factors—particularly the APOE ε4 allele—with additional modifiable vascular and lifestyle factors contributing to disease risk. 1

Non-Modifiable Risk Factors

Age

• Age is the most powerful risk factor, with the general population having approximately 10-12% lifetime risk of developing AD 1
• The percentage of amyloid-positive individuals at a given age closely parallels the percentage diagnosed with AD dementia a decade later 1
• Risk increases exponentially with advancing age, particularly after age 65 1

Genetic Factors

APOE ε4 Allele (Most Important Genetic Risk Factor):

• Heterozygous APOE ε4 carriers have 3-4 times increased risk 2
• Homozygous APOE ε4 carriers have 8-12 times increased risk 1, 2
• APOE ε4 is the major late-onset AD susceptibility gene, though it increases risk without guaranteeing disease even in homozygosity 3
• The prevalence of ε4 decreases with age in AD cohorts, particularly for homozygotes, suggesting differential mortality or survival effects 2

Autosomal Dominant Mutations (Absolute Risk):

• Carriers of mutations in APP, PSEN1, or PSEN2 genes have absolute risk for early-onset AD (before age 65) 1
• Trisomy 21 (Down syndrome) is also an established genetic risk factor 1

Family History:

• Having a first-degree relative with AD increases risk 1
• Familial aggregation occurs even independent of APOE ε4 status, suggesting additional familial factors beyond APOE 4

Polygenic Risk Factors:

• Risk factors beyond APOE related to immunity, endocytosis, lipid metabolism, tau binding proteins, and amyloid precursor protein metabolism contribute to overall risk 1

Sex

• Female sex increases risk for progression to AD 1
• This may relate to longer lifespan, hormonal factors, or other sex-specific biological mechanisms 1

Modifiable Risk Factors

Vascular Risk Factors

• Elevated midlife systolic blood pressure (odds ratio 2.6) is an independent risk factor even after adjusting for APOE genotype 5
• Elevated midlife total cholesterol level (odds ratio 2.8) independently increases AD risk 5
• The risk from these treatable vascular factors appears greater than that from APOE ε4 alone 5
• Cardiovascular risk factors increase risk for both Alzheimer's disease and vascular dementia 1

Lifestyle and Environmental Factors

• Low education level increases risk, likely through reduced cognitive reserve 1
• History of head trauma may contribute to increased risk 1
• Lifestyle promoting good cardiovascular health may reduce risk or delay age of onset 1

Cognitive and Functional Markers

• Memory complaint or subjective cognitive decline increases risk of progression, even without objective impairment on testing 1
• Frailty is associated with increased risk of progression 1

Biomarker-Based Risk Stratification

High-Risk Biomarker Profiles

• Amyloid-positive AND tau-positive on CSF or PET imaging confers high risk 1
• Tau positivity outside the limbic cortex (Braak stage 5 or higher) indicates high risk 1
• Presence of neurodegeneration markers (hippocampal atrophy on MRI, FDG-PET hypometabolism, elevated CSF neurofilament light chain) increases risk 1
• APOE ε4 homozygosity combined with positive biomarkers represents particularly high risk 1

Important Caveat on Biomarker-Positive Individuals

• Lifetime dementia risk for cognitively unimpaired amyloid-positive individuals ranges from only 5% to 42% depending on age and sex 1
• A substantial proportion remain cognitively stable for years and may never develop symptoms 1
• Biomarker positivity alone does not predict when or whether progression will occur in a given individual 1

Protective Factors

• APOE ε2 allele provides genetic protection 1
• Higher cognitive reserve (related to education, occupational complexity, lifelong learning) decreases progression risk 1
• Rare protective mutations include APOE ε3 Christchurch mutation and A673T APP Icelandic mutation 1

Clinical Implications

The interaction between multiple risk factors determines individual risk, with age-adjusted polygenic hazard scores and modulating factors (cognitive reserve, vascular health, copathology) influencing whether and when disease manifests 1. Current individualized prediction models work better for prodromal AD than for cognitively unimpaired individuals, making patient-level risk disclosure premature outside of autosomal dominant mutation carriers 1.