What Causes Alzheimer’s Disease?

Medically reviewed by Smita Patel, DO

The causes of Alzheimer's disease are unknown, but the condition does have theorized causes like acetylcholine deficiency and risk factors related to its development. Alzheimer's disease is a progressive neurological (brain) disease that leads to the loss of cognitive functions such as memory, thinking, and reasoning.

Complex brain changes can begin years or even decades before you experience any symptoms. Researchers believe genetics combined with lifestyle and environmental factors leads to the development of this condition. Here's what you need to know.

Theories

Alzheimer’s disease results in a significant loss of brain cells called neurons and their connections, known as synapses. This loss starts in the areas of the brain that control memory.

As damage spreads throughout the brain, more cognitive and physical abilities are affected, causing the brain to shrink physically. There are two main hypotheses for the development of Alzheimer’s: cholinergic and amyloid.

Cholinergic Hypothesis

The cholinergic hypothesis is the earliest explanation of Alzheimer's disease. Cholinergic neurons throughout the brain play an essential role in cognition, including learning and understanding. People with Alzheimer's disease show a severe loss of cholinergic neurons.

Another theorized cause of Alzheimer's disease is a deficiency in the brain messenger chemical called acetylcholine (ACh). ACh plays a role in brain functions like learning and memory.

The only approved medications for Alzheimer's help maintain the level of ACh in the brain. These drugs can temporarily slow down cognitive symptoms, but they don't prevent long-term brain damage.

Amyloid Hypothesis

For many years, researchers believed that abnormally high levels of beta-amyloid—a protein that surrounds nerve cells—formed amyloid plaques in the brain. These plaques are thought to contribute to the cognitive loss associated with Alzheimer's disease. The beta-amyloid hypothesis was based on an influential 2006 research paper.

Treatment endeavors using medications to target beta-amyloid did not result in improved symptoms of Alzheimer's disease. In addition, researchers found that amyloid plaques can also be found in people without Alzheimer's disease as they age.

One report cast doubt on this hypothesis. One neuroscientist found that the images in the 2006 study were altered. Since then, researchers have approached the beta-amyloid hypothesis with caution.

Results from the clinical trial of a medication called Leqembi (lecanemab) showed some renewed support for the role of beta-amyloid in Alzheimer's disease development. Lecanemab reduced the amount of amyloid in participants' brains, resulting in a moderate improvement of symptoms after 18 months.

More research and trials are necessary to confirm the debated hypothesis. Investigators are also looking into new explanations for neuron loss as well.

Is Alzheimer’s Disease Hereditary?

Some cases of early-onset Alzheimer’s disease are familial, meaning children may inherit certain mutations from their parents. In those cases, gene mutations cause the disease. Consider speaking to a healthcare provider about genetic testing if you have a history of early-onset Alzheimer’s disease in your family.

About 70% of Alzheimer’s disease cases are related to genetic factors. The genetics of late-onset Alzheimer’s disease is less clear: It doesn’t seem to run in families.

The gene that can most affect your risk of late-onset Alzheimer’s is apolipoprotein E (APOE). Everyone has some form (or variant) of APOE in their DNA. You’re more likely to develop the disease if you inherit the ɛ4 variant. On the other hand, having the relatively rare APOE ε2 variant can actually help protect you from Alzheimer’s disease.

Who Gets Alzheimer’s Disease?

Some people are more likely to develop Alzheimer's than others. Factors that can contribute to risk include:

• Age: This is the most important risk factor; most Alzheimer's symptoms start after age 65, and the percentage of people who have Alzheimer's increases with age. Forty percent of people over the age of 85 have Alzheimer's.

• Biological sex and gender: Nearly two-thirds of Alzheimer's cases are in people assigned female at birth. However, women may not be at an increased risk of Alzheimer's. For example, the difference may appear because women live longer than men on average; in the United States, the rates of women and men who develop Alzheimer's at each age are the same. Other studies have also revealed sex and gender bias in older research.

• Ethnicity: Alzheimer's disease is common in Black and Hispanic populations. However, when researchers consider socioeconomic factors and health conditions, the differences in risk go away.

Risk Factors

Researchers have identified different conditions, injuries, and other circumstances that can also contribute to the development of Alzheimer’s disease.

Vascular (Blood Vessel) Conditions

These conditions include high blood pressure (hypertension), heart disease, and stroke. Issues with blood vessels (for example, because of heart failure) can affect the blood supply to the brain, which can lead to brain inflammation and eventually Alzheimer’s disease.

Metabolic Conditions

These include type 2 diabetes, high LDL cholesterol, and obesity. In particular, experiencing high LDL cholesterol levels and obesity during your midlife can increase your Alzheimer’s risk.

Depression

Depression can raise your risk of Alzheimer’s. Antidepressant treatment may reduce this risk, but there aren’t enough studies to say for sure. Depression can also be an early sign of Alzheimer’s, as dementia can cause similar mood symptoms.

Social Isolation and Loneliness

Social isolation means lacking social interaction. Loneliness is different—it’s feeling alone or separated, which can happen even when you’re around other people. Both are risk factors for Alzheimer’s disease.

Getting back into social activities can help protect you. Talking to others or volunteering can improve your mood, cognition, and overall well-being.

Traumatic Brain Injury (TBI)

Traumatic brain injury happens when you experience a blow or jolt to the head. A history of TBIs can increase the risk of Alzheimer’s disease. This is especially true for severe injuries, but even mild TBI (like a concussion) can have a long-term impact.

Heavy Alcohol Use

Heavy alcohol use is associated with changes in the brain and cognitive decline, though there’s not enough evidence to say that it causes these issues. This doesn’t mean you have to quit alcohol entirely—light to moderate drinking in middle to late adulthood has been shown to decrease the risk of cognitive decline and dementia.

Smoking

People who've never smoked or have quit smoking long-term may have a lower risk of developing Alzheimer's disease. Decreasing the habit can still reduce your risk if you don't stop smoking completely.

Secondhand smoke can also increase your chance of developing Alzheimer's—especially if you're exposed at home.

Hearing Loss

Alzheimer’s disease is associated with hearing loss. Researchers don’t know why or if one condition causes the other.

A major hypothesis is that hearing impairment may lead to social isolation, which is a risk factor for Alzheimer’s disease. Another hypothesis is that people with hearing loss require more cognitive resources to process sounds, which leaves fewer resources for other cognitive functions.

Air Pollution

Higher levels of tiny particulate matter (PM 2.5), which is pollution from sources like power plants, construction sites, and fires, are associated with higher rates of Alzheimer's disease.

Other types of pollution, such as nitrogen oxides (emitted from burning fuel in cars and power plants) and sulfur dioxide (emitted from burning fossil fuels at industrial facilities), can also cause brain damage similar to that seen in people with Alzheimer’s disease.

Physical Inactivity

Being active reduces your risk of Alzheimer’s disease and all other causes of dementia. One review considered studies that followed participants for at least 20 years and found that physical activity could help protect against Alzheimer’s disease in the long term.

Low Mental Engagement

Just like physical activity is important, staying mentally active—especially before age 20—can help protect you from Alzheimer’s disease. Studies have shown that higher education can reduce your risk of dementia, as can other cognitively stimulating activities like reading, speaking a second language, and playing music. Having a mentally challenging job can also help.

A Quick Review

Alzheimer’s disease results in the loss of cognitive functions like memory and thinking, typically in people aged 65 or older. Researchers don’t yet know how Alzheimer’s disease develops, though it’s likely because of a combination of genetic and environmental factors.

Age is the biggest risk factor for Alzheimer’s disease, and other known risks include heart disease, brain injury, and low mental or physical activity. Studies are beginning to include demographically diverse populations to better understand who gets Alzheimer’s disease, but there’s no way to predict exactly who will develop it at this time.

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