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 what scientists think might be the 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 how research suggests that the modern lifestyle, your environment, and genetic factors might contribute to it.
The Brain’s Silent Battle
One fact is clear: Alzheimer’s disease is a result of gradual brain cell loss. Researchers explain that brain degeneration specific to the disease happens through a complex cascade in which harmful factors overcome the brain’s defenses [1].
Studies emphasize that 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].
According to one hypothesis, it’s probably at this stage – or before – that the battle between your brain’s defenses and stressors reaches its peak. Some scientists argue that it is at this point that people may have the greatest chance of changing the outcome. This is still an experimental stance, and more research is needed to verify it.
According to the National Center for Complementary and Alternative Medicine (NCCIH) [3]:
“Currently, there is no strong evidence that any complementary health approach or diet can prevent cognitive impairment.”
Various Factors Add Up
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 [4].
Scientists think that the disease is caused by a combination of factors over time. As with all diseases, various factors add up. Theoretically speaking, 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, lifestyle and environmental influences, infections, gut flora imbalances, and aging all play a role. Together, they are thought to lead to brain inflammation, oxidative stress, beta-amyloid buildup, and neurotransmitter imbalances. The end result is brain cell loss and dementia.
The Modern Lifestyle Hypothesis
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 by some scientists as a disease of the modern, sedentary, unhealthy lifestyle – much like obesity and type 2 diabetes. This stance is still experimental, however [5].
Nonetheless, based on this theory, scientists speculate that the type of lifestyle someone leads can have a large impact on brain health.
No clinical evidence backs up this hypothesis, though.
On the other hand, there’s evidence that type 2 diabetes and heart disease are strongly linked to the development of Alzheimer’s disease. These chronic diseases can be prevented by eating a healthy diet and exercising. By lowering your risk of one chronic disease, you might also lower your risk of many others – killing two birds with one stone [6, 7, 8, 9].
When to See a Doctor
If you are experiencing cognitive issues – including those of poor memory, forgetfulness, or personality changes – it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.
Major memory and behavior changes – such as forgetting recent events or conversations, misplacing your possessions, getting lost in familiar places, having trouble finding the right words to describe something, and low mood or apathy – are all reasons to see a doctor.
Many conditions, some of which are treatable, can result in poor memory or other symptoms of cognitive impairment or dementia.
Your doctor should diagnose and treat the condition causing your symptoms.
Likewise, if you are concerned about the symptoms of someone close to you, talk to them about scheduling a doctor’s appointment and going there together.
Many people with cognitive decline are not fully aware of their own memory and behavior, and the support of loved ones can be indispensable.
Research on Potential Alzheimer’s Disease Causes
Since the exact cause of Alzheimer’s disease is unknown, all the factors and processes outlined below are experimental and their contribution to disease development uncertain. The aim of this section is to outline research findings for informational purposes only.
1) Beta-amyloid Plaques May 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 [10, 11].
However, beta-amyloid proteins are not only “bad” – scientists hypothesize that they only become toxic once they create large deposits. At normal levels, these proteins seem to perform beneficial functions, like fighting infections in the brain [10, 11].
Research suggests that healthy brains can break down and clear beta-amyloid proteins before they cause damage [12].
Researchers suggest that, in Alzheimer’s disease patients, the removal process doesn’t work as well as it should. This appears to ultimately lead to a buildup of beta-amyloid proteins, which clump together and form plaques [12].
According to preliminary research, plaque deposits form between brain cells, fading and weakening communication clefts or synapses between the cells [13].
When synapses are lost, neurons become disconnected and eventually die. Plaque deposits might also kill neurons by other means, such as by increasing inflammation and oxidative damage – but this is also uncertain [13].
Gaps in the Theory
This theory doesn’t completely hold up. Scientists recently discovered that it suffers from the following major problems [14]:
- 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. Further research is needed to understand the impact of these deposits on Alzheimer’s disease and cognitive function.
Failed Drugs
Drugs that remove beta-amyloid were able to drop plaque levels to normal in several clinical trials – but they didn’t improve mental function. So far, all drugs targeting molecules that produce amyloid-beta (aducanumab, verubecestat, etc.) have failed [15, 16, 17].
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 [16].
More selective drugs (Amytrap, PMN310) are also currently being developed, but none have yet been proven to work [18, 19].
New findings will soon confirm or end the amyloid hypothesis.
2) Tau Neurofibrillary Tangles May Kill Brain Cells
Tau proteins are considered the second hallmark of Alzheimer’s disease. These proteins form hair-like knots called neurofibrillary tangles inside neurons. Scientists point out that tau proteins are a normal component of brain cells, but they seem to cause damage when they become overactive [20].
Research suggests that, in healthy neurons, tau proteins support structures called microtubules that help transport nutrients into cells. In the brains of Alzheimer’s patients, overactive tau proteins are hypothesized to join into disordered threads that block the transport of nutrients, eventually killing brain cells [2].
Although plausible, this theory requires further human research to be verified.
3) Acetylcholine Deficiency Might Worsen Memory
Acetylcholine is often described as the most important neurotransmitter for cognition. Your rest-and-digest system uses acetylcholine to coordinate cholinergic activity. In turn, acetylcholine supports learning, memory, relaxation, and digestion [21, 22].
Research reveals that a loss of neurons and their connections reduces cholinergic activity, which impairs cognitive function [23].
In Alzheimer’s disease, cholinergic neurons gradually die off. Enzymes that create acetylcholine – such as acetylcholinesterase – also become slower and less functional [24, 25].
Studies suggest that beta-amyloid plaques and tau tangles contribute to acetylcholine deficiency in people with Alzheimer’s [26, 27].
According to this theory, beta-amyloid blocks connections between neurons, while tau tangles deprive neurons of nutrients. Scientists say that these disconnected and starved neurons start dying, which seems to gradually “shrink” the brain [26, 27].
It’s theorized that increasing the activity of acetylcholine in the brain may reduce beta-amyloid burden, protect the brain, and improve cognition [28, 29].
Alzheimer’s medications help initially reduce symptoms of memory loss and other cognitive problems. Two classes of drugs are typically prescribed:
Cholinesterase inhibitors are thought to work precisely by increasing acetylcholine activity, while memantine acts on other neurotransmitters.
4) Inflammation May Damage the Brain
Scientists hypothesize that inflammation in the brain (neuroinflammation) may contribute to Alzheimer’s disease as much as beta-amyloid plaques and neurofibrillary tangles do. Human studies haven’t confirmed this theory yet, though [30].
Microglia are the immune cells of the brain. In healthy people, microglia remove invaders and cellular waste while maintaining synapses. Research suggests that, in Alzheimer’s disease, microglia may become overactive. As a result, they are thought to release toxic, inflammatory compounds that destroy synapses and harm brain cells [30, 31].
In mice with Alzheimer’s disease, microglia close to built-up plaques become larger and denser. 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 in animal experiments, but human data are lacking [32].
Limited evidence suggests that aging, infections, obesity, type 2 diabetes, and traumatic brain injury may all contribute to microglia overactivation and an excessive inflammatory response [30, 33].
5) Infections Hypothesized to Trigger the Disease
A theory that has been gained traction lately is that Alzheimer’s disease may be caused by infections. However, the link between infections and Alzheimer’s is still controversial and largely unconfirmed.
Various viruses, bacteria, fungi, and parasites have been suggested as potential triggers. These microorganisms are hypothesized to invade the brain and increase chronic inflammation, free radicals, beta-amyloid, and tau proteins [34, 35, 36].
The following pathogens have been associated with Alzheimer’s [36, 37]:
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
- Chlamydia pneumoniae
- Helicobacter pylori
- Borrelia burgdorferi (Lyme)
- Treponema pallidum
- Porphyromonas gingivalis
- Fusobacterium nucleatum
- Prevotella intermedia and other oral bacteria
Fungi & Parasites
- Candida albicans
- Toxoplasma gondii
Herpesvirus and Alzheimer’s
According to an observational study of more than 30k people in Taiwan, participants carrying the herpes simplex virus (HSV) had an almost 3-fold risk of developing dementia. The study also found that those taking antivirals such as acyclovir had a 90% reduced risk compared to those who did not [38].
This study has several limitations and its findings have not yet been replicated.
Other lines of evidence now point to the fact that people carrying the ApoE4 gene variant seem to be much more vulnerable to the effects of HSV. Carriers of ApoE4 experience more frequent reactivations of the virus, and suffer higher levels of inflammation and cell damage [39].
Scientists are also investigating whether the accumulation of beta-amyloid and tau proteins occurs in HSV infected cells in test tubes and whether HSV DNA is found in beta-amyloid deposits [39].
Having several trajectories of intriguing findings in mind, the NIH recently announced that it is funding high-priority research to better determine the relationship between microbial infections and Alzheimer’s disease [40].
Can Viruses Alter the Genetic Code?
A recent study investigated whether these viruses can interact with a person’s genes and change the expression of their genetic code. They identified the following genes and viruses for further research [41]:
- 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)
Their impact is still unknown.
6) Imbalanced Gut Bacteria May Worsen Brain Inflammation
Recent experimental research suggested that the microbiome may play a large role in Alzheimer’s development, but this hasn’t been confirmed in human studies.
The idea is that dementia and Alzheimer’s might begin in the gut, where an imbalanced flora is hypothesized to lead to the whole-body inflammation that might reach the brain via the gut-brain axis. This hypothesis is mostly theoretical and has yet to be properly researched [42].
Some scientists say that microbiome imbalances may also increase intestinal permeability, causing “leaky gut.” According to this theory, microbes and their waste products might then sneak into the bloodstream through the damaged gut lining [42].
The same is hypothesized to happen to the blood-brain barrier (causing “leaky brain“), especially in older people. This stance is controversial and unproven, though [42].
It further claims that 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 are theorized to pass from the blood straight into the brain. Since the brain is extremely sensitive to these toxins, they are thought to trigger inflammation and activates microglia [42].
If we follow this experimental theory through, a vicious cycle starts to unfold.
The influx of microbes and their toxins are said to keep the microglia in a constantly activated state. This allegedly results in chronic neuroinflammation, which is thought to eventually kill brain cells and cause memory loss [42].
But remember, this theory is pretty much as experimental as science can get. Research has a long way to go to confirm or disprove it.
Proposed Alzheimer’s Disease Risk Factors
The main idea is that living a healthy lifestyle, eating nutritious foods, getting quality sleep, and engaging in exercise is critical for maintaining a healthy brain – and sharp memory – as we age [6, 7, 8, 9].
Remember, the exact cause of Alzheimer’s disease is unknown. In line with this, many of the factors listed below are thought to add up. Some are hypothesized to zero out faced with potentially protective factors. But overall, the exact impact of each factor is often uncertain. This is especially true for factors labeled as “possible contributors.”
Some of the factors listed below were included based on studies that dealt with associations only, which means that a cause-and-effect relationship hasn’t been established.
For example, just because obesity has been linked with Alzheimer’s disease doesn’t mean that Alzheimer’s disease is caused by obesity. Obesity is known to be detrimental to overall health, but data are lacking to causation claims when it comes to Alzheimer’s specifically.
Some risk factors are highly experimental and unproven. These have been classified under the “insufficient evidence” section.
Likely Contributors:
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. Some estimates suggest that having two copies of the ApoE4 gene increases the risk of AD 12-fold while having one copy increases it 4-fold [43].
Scientists explain that having a first-degree relative (parent or sibling) with Alzheimer’s may add to the risk, even in people who don’t carry the ApoE4 variant. In other words, hereditary factors other than the ApoE gene seem to influence a person’s risk of developing Alzheimer’s [2].
Possible Contributors:
3) Smoking
Smoking has been linked with an increased risk of Alzheimer’s disease of more than 100%, an observational study of more than 20k people found. Smoking during midlife (40-55 years old) was described as particularly damaging to the brain [44].
4) Obesity
Being obese or overweight, especially during midlife, is a potential 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 [45].
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 [46].
An excess of leptin, the satiety hormone released by fat cells, is hypothesized to cause brain damage. This remains unproven, though.
The more fat you have, the more leptin you release. Scientists think that leptin may curb hunger and contribute to weight loss, but this is uncertain. Studies are investigating whether it also makes the brain’s glutamate receptors (NMDA) more sensitive. Glutamate toxicity is involved in Alzheimer’s, and more sensitive receptors might theoretically worsen the damage [47].
5) 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 if a person doesn’t exercise, their risk of developing Alzheimer’s might be twice as high [5].
6) 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% [48].
Your choice of profession may also influence your risk of head injury and Alzheimer’s. Research suggests that people who experience recurrent head injuries due to their profession, such as football players, are four times more likely to develop a neurodegenerative disorder [49].
7) 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 suggested that stroke may significantly increase the risk of Alzheimer’s. Likewise, Alzheimer’s increased the risk of stroke. More research on this link is needed [50].
8) Poor Sleep
Scientists say that, when we are awake, waste products such as beta-amyloid proteins naturally accumulate in the brain. During sleep, the brain clears these waste products. But when sleep is diminished or disturbed, the waste products can accumulate and cause damage to neurons. In the long run, this can lead to cognitive impairment and dementia, including Alzheimer’s disease [51].
While plausible, this theory has yet to be confirmed in large and properly-designed human studies. Nonetheless, getting quality sleep on a regular basis undoubtedly supports brain health and general wellness.
One review of observational studies including nearly 250k people revealed that those with sleep disturbances had an increased risk of developing dementia [52].
Studies in both humans and animals have shown that 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 might create a vicious cycle in which poor sleep worsens Alzheimer’s, and Alzheimer’s worsens sleep [53, 54, 55].
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 some researchers have termed Alzheimer’s “type 3 diabetes” [43, 56].
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 is hypothesized to increase inflammation and beta-amyloid production [43].
Some researchers believe that another process may go 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 [57].
According to this theory, when autophagy becomes impaired, the immune system can no longer clear beta-amyloid deposits. The impact of autophagy on Alzheimer’s is still highly uncertain, though, since solid evidence is lacking to support this link [57].
10) Chronic Stress
Limited evidence suggests that chronic stress may contribute to the development and progression of Alzheimer’s disease. It also likely contributes to many chronic diseases, including heart disease, and worsens mental health in the long run [58].
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 [59, 60].
The stress hormone cortisol might be equally harmful, according to animal experiments. In mice studies, cortisol stimulates the accumulation of both beta-amyloid and tau proteins [61, 60].
Further human studies are needed.
Insufficient Evidence for:
The following risk factors have only been investigated in low-quality human studies; there is currently insufficient evidence to support their contribution to Alzheimer’s disease.
11) Low Testosterone
The male hormone testosterone normally decreases with age. Scientists are investigating whether testosterone decreases beta-amyloid production in neuron cultures. They hypothesize that testosterone replacement therapy in elderly men with low testosterone might protect against Alzheimer’s, but far more research is needed to explore this possibility [62].
In some low-quality human studies, low testosterone levels were linked with worse 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, but large-scale data are lacking [63].
Interestingly, low testosterone has also been linked with increased levels of inflammation (IL-1, IL-6, and TNF-alpha) in animals [64].
12) Low Vitamin D
Not getting enough sun or having low vitamin D levels have been researched as possible contributors to Alzheimer’s disease, but no solid evidence is available [65, 66].
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 [65, 66].
A trial of 52 people suggested that vitamin D reduced beta-amyloid deposits and improved cognitive function, but only in those with a mild cognitive impairment which precedes Alzheimer’s disease. Patients with early Alzheimer’s disease did not experience improvement [67].
Scientists are also using cell studies to explore if vitamin D stimulates immune cells to break down beta-amyloid deposits in the brain. At the same time, vitamin D is hypothesized to protect healthy brain cells against damage from beta-amyloid proteins, but this remains clinically unverified [68, 69].
13) Aluminum
Aluminum is toxic to neurons in excess, but poisoning is extremely rare in the United States.
High levels of aluminum in drinking water have been suggested to 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 [70, 71].
Some scientists consider that aluminum may contribute to the progression of Alzheimer’s by reducing the brain’s ability to remove beta-amyloid deposits, but this hasn’t been proven [72].
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) [73].
Research suggests that 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 [74].
ApoE2 is a rare variant of the ApoE gene that has been linked with a reduced risk of Alzheimer’s disease. ApoE2 is hypothesized to have a neuroprotective effect by efficiently removing beta-amyloid protein in the brain, but its exact mechanism is still an open question [74].
ApoE3 is the most common variant of the ApoE gene and does not appear to have any positive or negative influence on Alzheimer’s disease risk [74].
ApoE4 is described as less efficient in clearing beta-amyloid protein. It has been linked with higher levels of inflammation, compared to the ApoE2 and ApoE3 variants. According to most studies, having two copies of the ApoE4 gene increases the risk of Alzheimer’s disease 12-fold while having one copy increases it 4-fold [74].
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 [75].
Takeaway
There is no single cause of Alzheimer’s disease.
Scientists believe that a combination of genetic factors, lifestyle and environmental influences, infections, gut flora imbalances, and aging all play a role. Together, they are hypothesized to lead to brain inflammation, oxidative stress, beta-amyloid buildup, and neurotransmitter imbalances.
We’re hopeful that future research will soon shed more light on potential Alzheimer’s disease causes. As of now, there is no strong evidence that trying to eliminate risk factors with any complementary health approach or diet can prevent the disease.
