What Causes Alzheimer’s Disease?

Alzheimer’s disease is a progressive neurological (brain) disease that leads to dementia, which is the loss of cognitive functions such as memory, thinking, and reasoning. It’s most common in people ages 65 or older; in fact, age is the biggest known risk factor for Alzheimer’s.

Aging itself does not cause Alzheimer’s. Complex brain changes can begin years or even decades before you begin any symptoms. Researchers believe a combination of genetics plus lifestyle and environmental factors leads to the development of this condition.

There are two types of Alzheimer’s: early-onset and late-onset. People with late-onset disease get symptoms at ages 65 or older. It’s by far the most common type of Alzheimer's. Less than 10% of people with Alzheimer’s have early-onset, developing symptoms between their 30s and mid-60s.

It’s still impossible to predict who will get Alzheimer’s. Researchers are actively studying risk factors and have come up with several hypotheses for what brain changes cause the disease. Here’s what they’ve proposed so far.  

Hypotheses

Alzheimer’s results in a major loss of brain cells (neurons) and their connections (synapses), starting in the areas of the brain that control memory. As damage spreads throughout the brain, more cognitive and physical abilities are affected. This causes the brain to physically shrink.

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. Cholinergic neurons throughout the brain play an important role in cognition (learning and understanding). People with Alzheimer’s disease show a severe loss of cholinergic neurons and a deficiency of acetylcholine (ACh)—a brain chemical messenger that is important for learning, memory, and other functions. 

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 the nerve cells) formed amyloid plaques in the brain. It is thought that these plaques are what contribute to the cognitive loss associated with Alzheimer’s. The beta-amyloid hypothesis was based on an influential 2006 paper published in the journal Nature.   

However, medications targeting beta-amyloid did not improve Alzheimer’s symptoms. Additionally, researchers found that amyloid plaques can also be found in people without Alzheimer's as they age.

Then, in July 2022, a Science magazine report cast doubt on this major hypothesis. One neuroscientist found that the images in the 2006 study were altered. Since then, researchers have approached the beta-amyloid hypothesis with caution. 

In November 2022, results from the clinical trial of a medication called Leqembi (lecanemab) showed some renewed support for the role of beta-amyloid in Alzheimer’s 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 now-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 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 in your family.

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

The gene that can affect your risk of late-onset Alzheimer’s the most is apolipoprotein E (APOE). Everyone has some form (or variant) of APOE in their DNA. However, 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.

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. But 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. Recent studies have also revealed sex and gender bias in older research. 
• Ethnicity: Black and Hispanic populations may be at a higher risk but, as with sex and gender, newer studies have challenged this idea. When researchers consider socioeconomic factors and health conditions (such as the high rates of heart disease and diabetes in Black and Hispanic populations), the differences in risk go away. Structural racism can affect other social and environmental risk factors for Alzheimer’s as well.

Risk Factors

While the cause of Alzheimer’s disease is unknown, researchers have identified different conditions, injuries, and other circumstances that can also contribute to the development of Alzheimer’s.

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. 

Metabolic Conditions

These include type 2 diabetes, high LDL cholesterol, and obesity. Specifically, 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. 

Fortunately, getting back into social activities can help protect you. You can improve your mood, cognition, and overall well-being by talking to others or volunteering.

Traumatic Brain Injury (TBI)

Traumatic brain injury happens when you experience a blow or jolt to the head. A history of TBIs (for example, in people who play sports) can increase the risk of Alzheimer’s. 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. If you don’t stop smoking completely, decreasing the habit can still reduce your risk. 

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

Hearing Loss

Alzheimer’s is associated with hearing loss, but 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. Another hypothesis is that people with hearing loss require more cognitive resources in order to process sounds, which leaves fewer resources for other cognitive functions.

Air Pollution

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

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.

Physical Inactivity

Being active reduces your risk of Alzheimer’s (and all other causes of dementia). One 2022 review considered studies that followed participants for at least 20 years and found that physical activity could help protect against Alzheimer’s 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. Studies have shown that higher education can reduce your risk of dementia, but so 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 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 develops, though it’s likely because of a combination of genetic and environmental factors. 

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

It can be scary to live with a disease that doesn’t have a known cause but remember: Alzheimer’s research is always ongoing. A healthcare provider can help explain what to expect if you or a loved one are diagnosed.