What causes cognitive decline and brain damage in Alzheimer’s disease? Is it mostly genetic or are other factors more important? The story is more complicated than it seems at first glance. Read on to find out about the real drivers and risk factors of this disease.

Alzheimer’s Disease Causes

In this post, you will read not only about the hallmarks of Alzheimer’s disease but also about all how the modern lifestyle, your environment, and genetic factors that contribute to it.

The Brain’s Silent Battle

One fact is clear: Alzheimer’s disease is a result of gradual brain cell loss. Brain degeneration specific to the disease happens through a complex cascade in which harmful factors overcome the brain’s defenses [1].

This diseases cascade isn’t activated overnight. Small and silent changes in Alzheimer’s disease occur 20 years before people experience the first symptoms [2].

It’s probably at this stage – or before – that the battle between your brain’s defenses and stressors reaches its peak. It is at this point that you have the greatest chance of changing the outcome.

The exact underlying cause of Alzheimer’s is still unclear. However, there is probably no single cause of Alzheimer’s. Just as there is no single cause of high blood pressure, diabetes, or depression [3].

As with all diseases, various factors add up. One damaging factor can be neutralized with a stronger protective factor – or it can be worsened with another stressor.

The latest research suggests that a combination of genetic factors, infections, gut flora imbalances, and aging all play a role. Together, they lead to brain inflammation, oxidative stress, beta-amyloid buildup, and neurotransmitter imbalances. The end result is brain cell loss and dementia.

A Disease of the Modern Lifestyle

Though Alzheimer’s is commonly diagnosed in people over 65 years old, many people nowadays start to experience signs of cognitive decline at a much younger age.

For this reason, Alzheimer’s is now being reframed as a disease of the modern, sedentary, unhealthy lifestyle–much like obesity and type 2 diabetes [4].

1) Beta-amyloid Plaques Block Brain Communication

The Hallmark of Alzheimer’s?

Beta-amyloid protein deposits have been regarded as the hallmark of Alzheimer’s disease for decades. They were first discovered as highly-concentrated plaques in Alzheimer’s patients [5, 6].

However, beta-amyloid proteins are not only bad – they only become toxic once they create large deposits. At normal levels, these proteins perform beneficial functions, like fighting infections in the brain [5, 6].

Healthy brains can break down and clear beta-amyloid proteins before they cause damage. But in Alzheimer’s disease patients, the removal process doesn’t work as well as it should. This ultimately leads to a buildup of beta-amyloid proteins, which clump together and form plaques [7].

Plaque deposits form between brain cells, fading and weakening communication clefts or synapses between the cells. When synapses are lost, neurons become disconnected and eventually die. Plaque deposits can also kill neurons by other means, such as by increasing inflammation and oxidative damage [8].

Gaps in the Theory

However, this theory doesn’t completely hold up. Scientists recently discovered that it suffers from the following major problems [9]:

  • Many elderly people without dementia have amyloid deposits
  • Some Alzheimer’s patients have few amyloid deposits but significant dementia
  • Animal studies reveal that these plaques don’t always kill brain cells or cause dementia
  • Drugs that reduce beta-amyloid deposits have generally failed to improve dementia in clinical trials

Beta-amyloid deposits could simply be a feature of aging rather than of Alzheimer’s disease.

Failed Drugs

Drugs that remove beta-amyloid were able to drop plaque levels to normal – but they didn’t improve mental function. So far, all drugs targeting molecules that produce amyloid-beta (aducanumab, verubecestat, etc.) have failed [10, 11, 12].

Studies investigating these drugs had small sample sizes, and roughly a quarter of the subjects dropped out due to side effects. New results are expected to be released in 2019 [11].

More selective drugs (Amytrap, PMN310) are also currently being developed, but none have yet been proven to work [13, 14].

New findings will soon confirm or end the amyloid hypothesis.

Though beta-amyloid plaques may contribute to memory loss in Alzheimer’s, other hypotheses are starting to gain traction.

2) Tau Neurofibrillary Tangles Kill Brain Cells

Tau proteins are the second hallmark of Alzheimer’s disease. These proteins form hair-like knots called neurofibrillary tangles inside neurons. Tau proteins are a normal component of brain cells, but they cause damage when they become overactive [15].

In healthy neurons, tau proteins support structures called microtubules, which help transport nutrients into cells. In the brains of Alzheimer’s patients, overactive tau proteins join into disordered threads that block the transport of nutrients, eventually killing brain cells [2].

Tau tangles are hair-like clumps that kill brain cells by blocking nutrient transport.

3) Acetylcholine Deficiency Worsens Memory

Acetylcholine is the most important neurotransmitter for cognition. Your rest-and-digest system uses acetylcholine to coordinate cholinergic activity. In turn, acetylcholine enhances learning, memory, relaxation, and digestion [16, 17].

Loss of neurons and their connections reduces cholinergic activity, which impairs cognitive function [18].

In Alzheimer’s disease, cholinergic neurons gradually die off. Enzymes that create acetylcholine – such as acetylcholinesterase – also become slower and less functional [19, 20].

Beta-amyloid plaques and tau tangles contribute to acetylcholine deficiency in people with Alzheimer’s. Beta-amyloid blocks connections between neurons, while tau tangles deprive neurons of nutrients. These disconnected and starved neurons start dying, gradually shrinking the brain [21, 22].

Increasing the activity of acetylcholine in the brain reduces the beta-amyloid burden, protects the brain, and improves cognition [23, 24].

Acetylcholine deficiency in Alzheimer’s disease worsens cognitive function, learning, and memory.

4) Inflammation Damages the Brain

Inflammation in the brain contributes to Alzheimer’s disease as much as beta-amyloid plaques and neurofibrillary tangles do [25].

Microglia are the immune cells of the brain. In healthy people, microglia remove invaders and cellular waste while maintaining synapses. In Alzheimer’s disease, microglia become overactive and release toxic, inflammatory compounds that destroy synapses and harm brain cells [25, 26].

In mice with Alzheimer’s disease, microglia close to built-up plaques become larger and more dense. At the same time, microglia in other parts of the brain shrink and become inactive. These changes lead to neurotransmitter imbalances and disrupt connectivity in the whole brain [27].

Aging, infections, obesity, type 2 diabetes, and traumatic brain injury all contribute to microglia overactivation and an excessive inflammatory response [25, 28].

Neuroinflammation due to overactive microglial cells leads to loss of synapses and neurons in AD.

5) Infections May Trigger the Disease

A theory that has been gained traction lately, is that Alzheimer’s disease can be caused by infections. Viruses, bacteria, fungi, and parasites can all be the trigger. These microorganisms can invade the brain and increase chronic inflammation, free radicals, beta-amyloid, and tau proteins [29, 30, 31].

The following pathogens have been associated with Alzheimer’s [31, 32]:

Viruses

  • Human herpesvirus 1 (HHV-1), (HSV-1)
  • Human herpesvirus 2 (HHV-2), (HSV-2)
  • Cytomegalovirus (CMV), (HHV-3)
  • Epstein-Barr virus (EBV), (HHV-4)
  • Varicella-zoster virus (VZV), (HHV-5)
  • Human herpesvirus 6 (HHV-6)
  • Hepatitis C virus (HCV)

Bacteria

Fungi & Parasites

Herpesvirus and Alzheimer’s

According to an observational study of more than 30k people in Taiwan, those carrying the herpes virus HSV-1 (also known as HHV-1) had an almost 3-fold increased risk of developing dementia. On the other hand, people taking antivirals such as acyclovir had an astounding 90% reduced risk [33].

Additionally, people carrying the ApoE4 gene variant are more vulnerable to the effects of HSV. Carriers of ApoE4 experience more frequent reactivation of the virus and suffer from more pronounced inflammation and cell damage [34].

In the lab, beta-amyloid and tau proteins build up in HSV-1 infected cells. Plus, DNA of the herpes virus found in beta-amyloid deposits [34].

What’s more, a recent mouse study revealed that the herpes virus kills brain cells each time it reactivates. Infected mice had beta-amyloid and tau deposits and brain inflammation (increased microglia, IL-1b, and IL-6) [35].

Viruses Can Alter the Genetic Code

A recent study found that these viruses can interact with a person’s genes, changing the expression of their genetic code. They identified the following genes and viruses [36].

  • Genes: AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8, and SNCA
  • Viruses: hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), and human papillomavirus (HPV)
Infections, in particular herpes viruses, may cause Alzheimer’s disease. Certain gene variants can make you more vulnerable to infection-triggered brain damage.

6) Imbalanced Gut Bacteria Worsen Brain Inflammation

Recent research suggests that the microbiome plays a large role in Alzheimer’s development. The idea is that dementia and Alzheimer’s begin in the gut, where an imbalanced flora leads to the whole-body inflammation that reaches the brain via the gut-brain axis [37].

Microbiome imbalances can also increase intestinal permeability, causing leaky gut. Microbes and their waste products can then sneak into the bloodstream through the damaged gut lining. The same can happen to the blood-brain barrier (causing “leaky brain”), especially in older people [37].

Waste products that make their way into the blood include beta-amyloid and lipopolysaccharides (LPS). If the blood-brain barrier is also compromised, these waste products pass from the blood straight into the brain. The brain is extremely sensitive to these toxins, which trigger inflammation and activates microglia [37].

A vicious cycle starts to unfold.

The influx of microbes and their toxins keep the microglia in a constantly activated state. This results in chronic neuroinflammation, which eventually kills brain cells and causes memory loss [37].

Microbiome imbalances can damage the gut and blood-brain barrier, allowing inflammatory toxins from the gut to sneak into the blood and brain.

Alzheimer’s Disease Risk Factors

1) Age

Aging is the single greatest risk factor for developing late-onset Alzheimer’s disease: 3% of 65-74-year-olds, 17% of 75- to 84-year-olds, and 32% of those over 85 years old develop Alzheimer’s [2].

2) Genetics

Besides aging, the most significant risk factor for developing late-onset Alzheimer’s disease is having the E4 variant (allele) of the apolipoprotein E (ApoE4) gene. Having two copies of the ApoE4 gene increases the risk of AD 12-fold while having one copy increases it 4-fold [38].

Having a first-degree relative (parent or sibling) with Alzheimer’s adds to the risk, even if you don’t carry the ApoE4 variant. In other words, hereditary factors other than the ApoE gene influence a person’s risk of developing Alzheimer’s [2].

3) Sedentary Lifestyle

A review study involving more than 160k people found that physical exercise cuts the risk of developing Alzheimer’s disease in half. This means that if you don’t exercise, your risk of developing Alzheimer’s is twice as high [4].

4) Smoking

Smoking increases the risk of Alzheimer’s disease more than 100%, an observational study of more than 20k people found. Smoking during midlife (40-55 years old) is particularly damaging to the brain [39].

5) Obesity

Being obese or overweight, especially during midlife, is a significant risk factor for developing Alzheimer’s disease. An observational study of 6,500 people revealed that being obese, particularly around the belly, was linked with higher rates of dementia 3 decades later. This was true even in people without diabetes or heart disease [40].

According to another review of over 60k people, being overweight or obese (measured by BMI) in midlife was linked with dementia and Alzheimer’s disease. Interestingly, being underweight was also associated with an increased risk, while a normal body weight was not [41].

An excess of leptin, the satiety hormone released by fat cells, may also cause brain damage. The more fat you have, the more leptin you release. Leptin curbs hunger and causes weight loss, but it also makes the brain’s glutamate receptors (NMDA) more sensitive. Glutamate toxicity is involved in Alzheimer’s, and more sensitive receptors can worsen the damage [42].

Being overweight or obese during midlife significantly increases your risk of developing Alzheimer’s disease later in life.

6) Stroke

Strokes can happen due to blood clots or a blood vessel ruptures in the brain. Unfortunately, both stroke and Alzheimer’s become more common in older people. A review study found that stroke significantly increases the risk of Alzheimer’s. Likewise, Alzheimer’s increases the risk of stroke [43].

7) Head Trauma

A systematic review of studies involving more than 2 million people revealed that head injury increases the risk of Alzheimer’s disease by 50% and the risk of any type of dementia by more than 60% [44].

Your choice of profession may also influence your risk of head injury and AD. People who experience recurrent head injuries due to their profession, such as football players, are four times more likely to develop a neurodegenerative disorder [45].

8) Poor Sleep

When we are awake, waste products such as beta-amyloid proteins naturally accumulate in the brain. During sleep, the brain clears these waste products [46].

If you don’t get enough high-quality sleep, waste products can build up and damage your brain cells. In the long run, this can lead to cognitive impairment and dementia, including Alzheimer’s [46].

A review of studies including nearly 250k people revealed that those with sleep disturbances had an increased risk of developing dementia [47].

In both humans and animals, sleep deprivation or disturbance is linked with increased beta-amyloid and tau protein in the brain. What’s worse, as more of these waste products build up, they disrupt the sleep-wake cycle and fragment sleep. This creates a vicious cycle: poor sleep worsens Alzheimer’s, and Alzheimer’s worsens sleep [48, 49, 50].

Not getting enough high-quality sleep greatly increases your risk of Alzheimer’s disease.

9) Diabetes & Insulin Resistance

According to several review studies, type 2 diabetes at least doubles the risk of developing Alzheimer’s disease. In fact, Alzheimer’s and diabetes have so many similarities that researchers have termed Alzheimer’s “type 3 diabetes” [38, 51].

People with type 2 diabetes have insulin resistance: insulin is high but tissues don’t respond to it. Insulin resistance has been observed in the brains of Alzheimer’s disease patients. What’s more, high insulin in the brain increases inflammation and beta-amyloid production [38].

Another process goes haywire in both type 2 diabetes and Alzheimer’s: autophagy. Autophagy is how cells recycle and reuse their damaged components. It clears cellular junk and makes good use of it [52].

When autophagy becomes impaired, the immune system can no longer clear beta-amyloid deposits [52].

Having type 2 diabetes and insulin resistance increases your risk of developing Alzheimer’s and worsens brain damage.

10) Chronic Stress

Chronic stress contributes to the development and progression of Alzheimer’s disease. Mice studies show that corticotropin-releasing hormone (CRH), released from the pituitary gland as part of the stress response, stimulates the production of beta-amyloid proteins [53, 54].

The stress hormone cortisol is equally harmful. In mice studies, cortisol stimulates the accumulation of both beta-amyloid and tau proteins [55, 54].

11) Low Testosterone

The male hormone testosterone normally decreases with age. Treating neurons with testosterone decreases beta-amyloid production, according to a cell study. This raises the possibility that testosterone supplementation in elderly men may protect against Alzheimer’s [56].

What’s more, low testosterone levels worsen cognitive function in elderly men. A review study showed that low testosterone is linked with an increased risk of Alzheimer’s disease in older men [57].

Interestingly, low testosterone has also been linked with increased levels of inflammation (IL-1, IL-6, and TNF-alpha) [58].

Low testosterone increases the risk of Alzheimer’s disease and is linked with increased inflammation.

12) Low Vitamin D

A review study revealed that Alzheimer’s disease patients have lower levels of vitamin D, compared to healthy people. Another review including nearly 10k people found that blood levels of vitamin D less than 50 nmol/L were associated with a higher risk of AD and dementia [59, 60].

Moreover, cell studies have shown that vitamin D reduces inflammation and stimulates the clearance of beta-amyloid deposits in the brain [61, 62].

13) Aluminum

Aluminum is toxic to neurons, and high levels of aluminum in drinking water may increase the risk of Alzheimer’s disease. In a study of 2k people, cognitive decline and dementia were more common in people with a higher aluminum intake. Conversely, an increase in silica intake was associated with a reduced risk of dementia [63, 64].

Additionally, aluminum may contribute to the progression of Alzheimer’s because it reduces the brain’s ability to remove beta-amyloid deposits [65].

Alzheimer’s Disease Genes

Early-onset

Early-onset Alzheimer’s disease accounts for 1-6% of cases and symptoms normally set in from age 30 until 65. Mutations of 3 genes are responsible for this type of AD, including amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) [66].

Those who inherit mutations in either the APP or PSEN1 genes are sure to develop Alzheimer’s disease. Those who inherit a mutation in the PSEN2 gene have a 95 percent chance of developing the disease. However, the vast majority of patients have the late-onset type, where symptoms begin around age 65 or older [2].

Late-onset

The main gene associated with developing late-onset Alzheimer’s disease is the apolipoprotein E (ApoE) gene. The ApoE gene functions as a cholesterol transporter, assists in injury repair and maintains proper clearance of beta-amyloid proteins in the brain [67].

ApoE2 is a rare variant of the ApoE gene that reduces the risk of Alzheimer’s disease. ApoE2 has a strong neuroprotective effect with efficient removal of beta-amyloid protein in the brain [67].

ApoE3 is the most common variant of the ApoE gene and does not have any positive or negative influence on Alzheimer’s disease risk [67].

ApoE4 is less efficient in clearing beta-amyloid protein, and is linked with higher levels of inflammation, compared to the ApoE2 and ApoE3 variants. Having two copies of the ApoE4 gene increases the risk of Alzheimer’s disease 12-fold while having one copy increases it 4-fold [67].

In an autopsy study of 603 people, 40% of those carrying the ApoE4 variant had developed beta-amyloid plaques at the age of 50-59 years, compared to only 8% of those with other variants [68].

The genes responsible for early-onset Alzheimer’s are APP, PSEN1 and PSEN2, while the main gene variant associated with late-onset Alzheimer’s is ApoE4.

Want More Targeted Ways to Lower Your Alzheimer’s Risk?

We recommend SelfDecode’s comprehensive guide on the ApoE gene, with recommendations about how to lower risk if you have the risk-associated ApoE ε4 variant.

If you’re interested in natural and targeted ways of improving your cognitive function, we recommend checking out SelfDecode’s Limitless Mind DNA Protocol. It gives genetic-based diet, lifestyle and supplement tips that can help improve your cognitive function. The recommendations are personalized based on your genes.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thanks for your support!

What Else Can You Do Now?

Head over to our posts about Alzheimer’s disease prevention and natural treatment options. The sooner you start implementing brain-healthy practices in your life, the better.

Takeaway

There is no single cause of Alzheimer’s disease. A combination of genetic factors, infections, gut flora imbalances, and aging all play a role. Together, they lead to brain inflammation, oxidative stress, beta-amyloid buildup, and neurotransmitter imbalances. The end result is brain cell loss and dementia.

The known risk factors for developing Alzheimer’s disease – such as obesity, a sedentary lifestyle, poor sleep, and chronic stress – all have one thing in common: excess inflammation.

The APOE4 variant especially increases the chance of late-life Alzheimer’s. But even if you have the “bad” gene variant, you won’t necessarily get Alzheimer’s disease. There are various steps you can take to naturally reduce your risk.

About the Author

Jimmy Julajak, MSc

MS (Psychology)

Jimmy got his MSc from the University of Copenhagen.

Jimmy is a psychologist and researcher. He is particularly interested in the workings of the brain and strategies for improving brain health. He believes that people shouldn't hand over the responsibility for their health only to their doctors. His aim is to empower each person with easy-to-understand, science-based health knowledge.

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