Alzheimer’s disease is a progressive neurodegenerative disorder that slowly destroys memory and thinking skills. It is the most common cause of dementia and affects more than 6 million Americans. Alzheimer’s has no current cure, so understanding risk factors for developing the disease is critically important.
Genetic Risk Factors
The biggest risk factor for Alzheimer’s disease is advancing age, with most cases occurring after age 65. However, genetics also play a major role. Certain gene variants can significantly increase or decrease a person’s risk. The key genes involved are:
- Apolipoprotein E (APOE) – This gene comes in several forms, with APOE e4 being the highest risk variant. Each inherited copy of APOE e4 increases Alzheimer’s risk 2 to 3 fold compared to the most common e3 form.
- APP – Rare mutations in this gene can virtually guarantee early-onset Alzheimer’s, usually before age 65.
- PSEN1/PSEN2 – Mutations also cause early-onset Alzheimer’s, often in the 30s to 50s.
- TREM2 – Variants increase risk 2 to 4 times for common late-onset Alzheimer’s.
In addition, researchers have identified over 40 other gene loci associated with altered Alzheimer’s risk. Carrying more of these risk variants can have an additive effect.
Family History
Beyond specific high-risk genes, simply having a parent or sibling with Alzheimer’s increases your risk. The more closely related family members that have the disease, the higher your risk. For example:
- With an affected parent, risk is 1.5 times higher.
- With an affected sibling, risk is 3 times higher.
- With 2 or more affected relatives, risk is 4 to 5 times higher.
Overall, genetics account for 60-80% of Alzheimer’s risk. However, not all inheritance is due to known genes. Much of the increased risk associated with family history may be caused by shared environmental factors or other genetic influences not yet identified.
Down Syndrome
People with Down syndrome, a chromosomal disorder caused by an extra copy of chromosome 21, have a significantly increased risk for early-onset Alzheimer’s. Up to 75% of individuals over age 60 with Down syndrome have Alzheimer’s dementia due to the extra copy of the APP gene on chromosome 21.
Cardiovascular Disease Risk Factors
Many conditions that damage blood vessels and lead to strokes or heart attacks also increase the risk of Alzheimer’s and other dementias. These include:
- High blood pressure
- High cholesterol
- Diabetes
- Obesity
- Smoking
Maintaining heart health through diet, exercise, and medication use lowers dementia risk by improving blood flow to the brain.
Traumatic Brain Injury
Moderate and severe traumatic brain injuries, such as from combat or sports, increase the risk of Alzheimer’s and other dementias. Mild TBI does not appear to increase risk. Proposed mechanisms include damaging nerve cell connections or triggering inflammation and oxidative damage.
Education Level
Higher educational attainment has been associated with decreased dementia risk. Proposed protective factors include:
- Increased “cognitive reserve” to better tolerate damage
- Healthier lifestyle habits
- Reduced vascular disease risk
- Hormone changes
- Stronger brain connectivity
However, evidence also suggests highly educated individuals may exhibit more cognitive impairment than expected because early symptoms disrupt their superior mental functioning.
Social and Cognitive Engagement
An engaged, active lifestyle seems to help prevent Alzheimer’s and dementia. Activities such as learning new skills, traveling, volunteering, puzzles, games, reading, playing music, and visiting friends may build cognitive reserve and strengthen brain networks.
Depression
Late-life depression significantly increases dementia risk, potentially due to effects on thinking, memory, vascular health, hippocampal volume, and amyloid beta plaques. Effective depression treatment may reduce this risk.
Sleep Disorders
Disrupted sleep due to conditions such as sleep apnea may raise Alzheimer’s risk through effects on clearing waste proteins, circadian rhythms, and neuroinflammation. Treating sleep disorders may be an important preventive strategy.
Diet
Some dietary components may influence Alzheimer’s risk, such as:
- Fats – Saturated and trans fats may increase risk, while omega-3 and monounsaturated fats may be protective.
- Carbohydrates – Diets high in sugars and refined carbs may increase risk.
- Fruits and Vegetables – Antioxidants like vitamin E, vitamin C, and flavonoids may reduce risk.
- Vitamin D and Folate – Deficiencies are linked to increased risk.
Overall, a Mediterranean-style diet high in plant foods is associated with lower dementia risk.
Obesity and Metabolic Syndrome
Midlife obesity and metabolic diseases like diabetes significantly increase risk for Alzheimer’s and vascular dementia. Proposed mechanisms include insulin resistance, inflammation, blood vessel damage, and lipid abnormalities. Maintaining normal weight and metabolic health is important.
Alcohol Use
Heavy alcohol consumption may elevate Alzheimer’s risk, while light to moderate intake may be protective. Proposed mechanisms include influences on cardiovascular health, cholesterol levels, inflammation, and insulin resistance.
Smoking
Current smoking increases dementia risk by around 40%, while quitting may return risk to normal after 5-10 years. Tobacco smoke contains hundreds of toxic chemicals that promote vascular disease and inflammation.
Air Pollution
Exposure to air pollution including particulate matter, ozone, nitrogen oxides, and metals has been associated with higher dementia risk. Pollutants may promote neuroinflammation, oxidative stress, cerebrovascular damage, and neurodegeneration.
Pesticide Exposure
Exposure to certain pesticides has been linked to increased Alzheimer’s risk. Proposed mechanisms include interference with neurotransmission, inflammation, oxidative stress, mitochondrial dysfunction, and accumulation of amyloid beta.
Hormone Replacement Therapy
Use of hormone replacement therapy in menopausal women for more than 10 years may slightly increase Alzheimer’s risk, potentially due to pro-inflammatory effects.
Infections
Certain chronic infections like gum disease and Helicobacter pylori have been associated with elevated Alzheimer’s risk, potentially by triggering inflammation.
Oral Hygiene
Poor oral hygiene resulting in tooth loss and gum disease has been linked to increased dementia risk. Proposed mechanisms involve bacteria entering the bloodstream and triggering inflammation.
Hearing Loss
Hearing loss in older adults correlates with higher dementia risk, potentially due to social isolation and cognitive load from straining to hear. Hearing aids may help reduce this risk.
Frailty
Physical frailty markers including slow gait speed and grip strength predict increased Alzheimer’s risk. Frailty may reflect processes like inflammation, hormones, nutrition, and vascular health affecting cognition.
Low Testosterone
Age-related testosterone deficiency in men has been associated with about twice the risk of Alzheimer’s disease. Possible mechanisms include vascular, metabolic, and neuroprotective effects.
Conclusion
In summary, many genetic and lifestyle factors influence Alzheimer’s disease risk. The most important controllable risk factors include vascular health, education, cognitive activity, diet, metabolic factors like obesity and diabetes, smoking, and physical frailty. While some risk factors like genetics cannot be changed, focusing on living an overall healthy lifestyle can significantly help reduce risk of developing Alzheimer’s and other dementias.
Risk Factor Summary Table
| Risk Factor | Level of Risk |
|---|---|
| Age over 65 years old | High |
| APOE e4 gene variant | High |
| Rare APP, PSEN1, PSEN2 mutations | Very high |
| First-degree relative with Alzheimer’s | Moderate |
| Down syndrome | Very high |
| Cardiovascular disease | Moderate |
| Traumatic brain injury | Moderate (severe TBI) |
| Less education | Moderate |
| Social/cognitive inactivity | Moderate |
| Depression | Moderate |
| Sleep disorders | Moderate |
| Unhealthy diet | Moderate |
| Obesity, metabolic syndrome | Moderate |
| Heavy alcohol use | Moderate |
| Smoking | Moderate |
| Air pollution | Low |
| Pesticide exposure | Low |
| Chronic bacterial infections | Low |
| Hearing loss | Low |
| Low testosterone | Low |