Alzheimer’s disease Risk Factors
Genetics Factor
β-amyloid protein Accumulation
Alzheimer’s disease is caused by accumulation of β-amyloid protein. Amyloid Precursor Protein (APP) is cut by three different enzyme, alpha-secretase, beta-secretase, and gamma-secretase. These enzymes follow two pathways, non-amyloidogenic pathway (normal pathway) and Amyloidogenic pathway (harmful pathway)
In non-amyloidogenic pathway, about 90% of APP is cleaved by α-secretase. This pathway prevents formation of amyloid-beta peptides and considered safe.
In Amyloidogenic pathway, about 10% of APP is cleaved by β-secretase followed by γ-secretase. This produces amyloid-beta peptides, mainly: amyloid beta 40 (Aβ40) which is less harmful and amyloid beta 42 (Aβ42) which is more toxic and prone to aggregation. Aβ42 tends to stick together and form plaques in the brain, which damage neurons.
The accumulation of Aβ42 peptides is the early event in Alzheimer’s disease. These peptides aggregate to form amyloid plaques, leading to neuronal damage and cognitive decline.
Alzheimer’s Disease Symptoms: Early Warning Signs and Disease Progression
Alzheimer’s Disease and Protein Misfolding
Apolipoprotein E
The Apolipoprotein E (APOE) gene is located on Chromosome 19 and the main function of APOE is:
- To transport cholesterol and lipids in the blood
- Plays an important role in lipoprotein metabolism
- To involved in brain repair and neuronal maintenance
APOE gene is considered the most important genetic risk factor for late-onset Alzheimer’s disease (LOAD). APOE have three variants (isoforms), ε2, ε3, and ε4.
The most common genotype is ε3/ε3, which generally does not increase Alzheimer’s risk whereas, the ε4 allele significantly increases the risk of Alzheimer’s disease (AD).
About 40% of Alzheimer’s patients carry at least one ε4 allele. If there are two copies (ε4/ε4), risk of Alzheimer’s diseases increases. People with ε4/ε4 genotype may develop Alzheimer’s 10–15 years earlier than average.
Although APOE is strongly linked to Alzheimer’s disease, it is also associated with other neurological and systemic conditions, such as Multiple Sclerosis, Parkinson’s disease and other age-related macular degeneration.
It has also been linked to cardiovascular diseases, cerebrovascular disorders and human longevity.
Inheritance patterns of AD
Alzheimer’s disease (AD) can be inherited genetically and cause of autosomal dominant and autosomal recessive inheritance.
In autosomal dominant inheritance, a person needs only one mutated copy of a gene to develop the disease. If a parent carries the AD mutation, each child has a 50% chance of inheriting it. So, the mutation can pass directly from parent to child.
In autosomal recessive inheritance, a person must inherit two mutated copies of a gene (one from each parent). In this case, parents do not show symptoms of Alzheimer’s disease, but they are carriers of the defective gene.
Earlier belief about Early Onset of Alzheimer’s Disease (EOAD)
Scientists previously believed that all cases of EOAD were caused by dominant mutations (for example in genes like APP, PSEN1, and PSEN2). These mutations are highly penetrant, meaning that people who inherit them usually develop the disease.
However, population studies showed that this belief is not completely correct. Only about 10% of EOAD cases follow this dominant inheritance pattern. The remaining ~90% of cases cannot be explained by known dominant mutations. This means there may be due to other unknown genetic factors, recessive mutations and complex genetic interactions.
The study concluded that EOAD is strongly linked to genetic mutations. However, the researchers did not support the idea that EOAD is entirely caused by autosomal dominant inheritance.
Their findings suggested that only about 10% of EOAD cases are caused by dominant mutations. Most EOAD cases may follow autosomal recessive inheritance, meaning a person must inherit two mutated copies of a gene (one from each parent).
Environmental and behavioral factors
Smoking
Smoking also affects the brain and nervous system. Chronic smoking can lead to learning and memory problems, brain tissue shrinkage (brain atrophy) and reduced intellectual and executive functions. These changes can contribute to neurodegenerative diseases, including Alzheimer’s disease.
Research suggests that about 14% of Alzheimer’s cases worldwide are linked to lifetime smoking. Smokers may develop Alzheimer’s symptoms earlier. Smoking increases the risk of Alzheimer’s by about 70% and the risk increases with the number of cigarettes and years of smoking. However, this risk may actually be underestimated because of two biases:
1. Survival bias: Many smokers die earlier from smoking-related diseases, so they may not live long enough to develop Alzheimer’s and be included in studies.
2. Competing risk bias: Death due to smoking-related diseases may occur before Alzheimer’s develops.
Smoking damages the brain
Smoking cause Alzheimer’s disease through several biological processes:
1. Toxic chemicals in cigarette smoke– Cigarette smoke contains harmful substances such as phenolic compounds, nitrosamines, carbon monoxide and free radicals. These substances are toxic to brain cells.
2. Increased brain inflammation– Smoking increases pro-inflammatory cytokines in the brain. This leads to the production of more free radicals, which damage neurons.
3. Reduced antioxidant defences– Smoking lowers the levels of protective antioxidants in the brain, such as glutathione.
These combined effects cause high oxidative stress in the brain, which can lead to increased amyloid-beta (Aβ) production, increased tau protein phosphorylation. Both of these are key pathological features of Alzheimer’s disease.
Poor Sleep
Research shows a bidirectional relationship between sleep disturbances and Alzheimer’s disease means, poor sleep can increase the risk of Alzheimer’s disease and as Alzheimer’s progresses, sleep problems become worse. Disruption in sleep can also trigger brain inflammation.
Poor sleep can also worsen cognitive decline, especially memory and thinking abilities. Poor sleep cause:
Amyloid-beta accumulation– Several studies in humans and animal models show that sleep disturbances increase amyloid-beta (Aβ) levels that leads to AD. For example: People who sleep 6 hours or less per night tend to have higher Aβ accumulation in the brain, poorer cognitive performance, particularly memory.
Affect tau pathology- Sleep disturbances are not only related to Aβ plaques but also to tau protein abnormalities. Research shows that slow-wave activity during non-rapid eye movement sleep (NREM sleep) is inversely related to tau pathology.
Sleep: Stages, Importance, Disorders
Sleep is essential for brain waste clearance
The glymphatic system is a brain-clearing mechanism that removes waste products and abnormal proteins. It cleans the brain during sleep. The glymphatic system works best during sleep, especially during deep slow-wave sleep.
During sleep it removes amyloid-beta, tau proteins and other metabolic waste, but sleep disturbances impair this clearance system. As a result, Aβ and tau accumulate in the brain, increasing the risk of Alzheimer’s disease.
Chronic stress
Studies shows that long-term stress can damage cognitive functions such as memory, learning ability, decision-making and attention. Chronic stress cause changes in important region of brain such as
- Prefrontal cortex which is responsible for decision-making and executive function.
- Hippocampus which plays important role in memory formation.
The changes due to chronic stress cause neuronal atrophy (shrinkage of neurons), dendritic shortening and loss of synaptic spines (reduced neural connections) and reduced neurogenesis (less formation of new neurons). These structural changes ultimately lead to cognitive impairment.
In humans, chronic stress experienced during childhood, or during adulthood can impair cognitive abilities and increase the risk of psychological disorders. However, not everyone is affected the same way. Risk can vary depending on factors like sex, and genetic factors.
Research suggests that chronic stress and glucocorticoids play a dual role in Alzheimer’s disease development.
External glucocorticoids can increase the toxic effects of amyloid-beta (Aβ). This leads to greater tau phosphorylation and tau accumulation in neurons that leads to Alzheimer’s diseases.
Physical activity
Studies show that people who are physically active have a lower risk of cognitive decline and dementia, including Alzheimer’s disease.
Studies found that physical activity reduced the risk of overall dementia by about 28%. It reduced the risk of Alzheimer’s disease by about 45% compared to people who were physically inactive.
Physical activity triggers several beneficial biological processes in the brain, including neurogenesis (formation of new neurons), synaptogenesis (formation of new neural connections), angiogenesis (formation of new blood vessels).
Physical activity improve memory, learning ability and brain plasticity (the brain’s ability to adapt and reorganize).
The hippocampus, a brain region responsible for memory, normally shrinks with age. In healthy elderly individuals, hippocampal volume declines about 1–2% per year. However moderate aerobic exercise can reverse this shrinkage. A 1-year aerobic exercise program resulted in 2% increase in hippocampal volume, offsetting normal age-related decline.
People who exercise regularly throughout life also tend to have larger brain volumes; better executive function compared with physically inactive individuals.
Physical activity reduces amyloid-beta accumulation, regulate Aβ metabolism and reduce tau protein phosphorylation. It not only helps prevent the disease but can also improve symptoms in people who already have Alzheimer’s disease.
Current evidence suggests that regular physical activity can reduce the risk of developing Alzheimer’s disease, improve cognitive symptoms and slow the progression of the disease.
Alcohol consumption
Alcohol consumption is related to cognitive decline and Alzheimer’s disease (AD).
Moderate alcohol consumption
Some studies suggested that moderate alcohol intake may reduce the risk of AD. Moderate alcohol increase acetylcholine release in the hippocampus, improve learning and memory. It also may reduce cardiovascular risk factors such as platelets aggregation and serum lipid level in blood.
Some alcoholic drink specially wine, contain polyphenols such as quercetin, morin, tannins, and resveratrol. This polyphenol may inhibit amyloid aggregation, reduce oxidative stress, reduce inflammation and maintain protein homeostasis.
However, scientists still debate whether low alcohol intake truly protects against AD, because other factors may influence results, such as social interactions associated with drinking, and differences in alcohol metabolism.
Heavy alcohol consumption
Unlike moderate drinking, heavy alcohol consumption increases the risk of dementia and AD. Heavy alcohol use can impair cognitive and executive functions, cause loss of cholinergic neurons, and lead to hippocampal atrophy. These brain changes are also commonly seen in AD patients.
Effect of stopping alcohol
Some studies suggest that stopping alcohol after AD diagnosis may improve early cognitive symptoms, indicating that heavy drinking may worsen disease progression.
Obesity
Many studies have found that obesity during middle age increases the risk of developing Alzheimer’s disease or other forms of dementia later in life. Obesity measures by using BMI (Body Mass Index) and WHR (Waist-to-Hip Ratio).
Higher BMI or WHR in midlife is associated with more risk of dementia, even when other risk factors are considered.
Interestingly, researchers also observed that BMI often decreases several years before dementia diagnosis. People who later develop dementia often lose weight before symptoms appear. Because of this, studies sometimes show confusing results.
Various studies sometimes show confusing results between body weight and dementia risk.
The relationship between Body Mass Index and dementia happens due to two different processes:
Harmful effect of high BMI (long-term studies)- When researchers follow people for many years, they find that higher BMI (overweight or obesity) increases the risk of dementia and Alzheimer’s disease. This means midlife obesity can damage brain health over time.
Reverse causation effect (short-term studies)- In shorter studies, higher BMI sometimes appears protective, but this is misleading.
This happens because people often start losing weight before dementia symptoms appear. So when dementia is diagnosed, they already have lower BMI. This creates the false impression that higher BMI protects against dementia, when actually weight loss is an early sign of the disease.
Some studies showed that people with higher BMI in late life showed a slightly lower risk of AD. However, individuals with large BMI decrease from midlife to late life had a 20% higher risk of AD.
The “obesity paradox”
The “obesity paradox” means that in some studies, people with higher body weight seem to have a lower risk of dementia, but this may not be truly protective.
Researchers suggest that weight loss occurring before or during the clinical stage of dementia may happen because of increase energy expenditure and hypothalamus dysfunction.
1. Increased energy expenditure- People with dementia may burn more energy than normal, even without increased physical activity. This can lead to unintentional weight loss.
2. Hypothalamic dysfunction– The Hypothalamus controls appetite, metabolism, and body weight regulation. When dementia affects this brain region, it can cause reduced appetite, metabolic imbalance and weight loss
Poor Diet
Poor diet increases the risk of cognitive decline. Poor diet associated with cognitive impairment, and Alzheimer’s diseases development.
In addition, protein–calorie malnutrition in people who already have AD increases the risk of death.
Eating large amounts of refined carbohydrates or high-glycemic foods can increase amyloid-β (Aβ) accumulation in the brain, which is a key feature of AD. This harmful effect is stronger in people carrying the APOE ε4 gene, which already increases AD risk.
Western diet – A typical Western diet (high in processed foods, sugar, and unhealthy fats) can increase AD risk by increasing inflammation, altering metabolism, and reducing cerebral blood flow.
Mediterranean diet – In contrast, following a Mediterranean diet is associated with lower risk of Alzheimer’s disease. Mediterranean diet may help better cognitive performance, increased gray matter volume in the brain, lower risk of mild cognitive impairment (MCI) and reduced risk of progression from MCI to AD.
Studies using brain imaging techniques show that people who follow a Mediterranean-style diet have less amyloid plaque accumulation and better brain metabolism
Ketogenic diet – A ketogenic diet may also help reduce AD risk because it can reduce oxidative stress, reduce inflammation, improve brain energy metabolism and enhance attention, memory, and cognitive performance.
Consumption of omega-3 fatty acids lower the risk of Alzheimer’s disease and slower cognitive decline.
Social Isolation
Social isolation affects brain health. It negatively affects both mental and physical health.
Research shows that it can worsen cognitive function, speed up psychological aging and increase the risk of Alzheimer’s disease and other dementias.
The relationship between social isolation and AD is bidirectional. Social isolation may increase the risk of AD, but early symptoms of AD may also cause people to withdraw socially. For example, people experiencing early memory or thinking problems may avoid social interactions.
Social isolation is of two types, objective isolation and perceived isolation.
Objective isolation includes having few social contacts, limited social networks, and reduced participation in social activities.
Perceived isolation means feelings of loneliness, and feeling that social support is inadequate. Both forms are strongly linked to cognitive decline.
Social isolation may influence AD through psychological and neurobiological mechanisms. People with higher cognitive reserve are better able to cope with brain changes. However, social isolation reduces cognitive stimulation, which can lead to lower cognitive reserve and increased vulnerability to cognitive decline and Alzheimer’s disease.
Medical condition
Different medical conditions can increase the risk of developing Alzheimer’s disease (AD) or other forms of dementia. Medical Conditions Associated with Alzheimer’s Disease are cardiovascular disease (CVD), diabetes mellitus (DM), Depression, Parkinson’s disease, hypothyroidism, and chronic kidney disease.
1. Cardiovascular disease- Research shows a strong connection between CVD and dementia. Studies found that higher vascular risk is linked to decline in multiple cognitive functions. It also increases the progression toward Alzheimer’s disease.
People with CVD had about 30% higher risk of AD. Those with peripheral artery disease had about 140% higher risk of developing AD. This suggests that poor vascular health affects brain function and increases dementia risk.
2. Diabetes mellitus– Diabetes mellitus is another major risk factor. People with diabetes or prediabetes have higher chances of cognitive decline, dementia, and Alzheimer’s disease.
In Type 1 diabetes, high blood sugar increases dementia risk. Brain imaging studies show that diabetes may cause brain atrophy in regions such as thalamus, frontal cortex, and temporal cortex.
However, the direct link between Type 1 diabetes and early AD-related neurodegeneration is still unclear.
3. Depression– Depression is also strongly associated with dementia. It increases the risk of dementia by about 82%. It contributes to about 7.9% of Alzheimer’s disease cases worldwide. Depression occurring later in life particularly increases the risk of developing dementia.
4. Parkinson’s disease (PD)– Patients with Parkinson’s disease (PD) also have a higher risk of dementia. Dementia incidence ranges from 30 to 112 cases per 1,000 person-years in PD patients. Risk of dementia may be up to 6 times higher compared with people without PD.
Although dementia in PD and AD both involve memory impairment, the cognitive patterns differ, especially in attention and orientation tests.
5. Hypothyroidism– Some studies suggest that there is high prevalence of hypothyroidism in AD patients. Dementia risk increases by about 12% for every 6 months of elevated thyroid stimulating hormone (TSH) levels.
Women with high TSH levels had 115% higher risk of AD. However, other studies report no significant link, and some meta-analyses even suggest a lower risk after adjusting for vascular factors.
6. Chronic kidney disease- The relationship between chronic kidney disease (CKD) and Alzheimer’s disease is also unclear. Some findings show worse kidney function is associated with poorer cognitive performance. Faster decline in kidney function (measured by eGFR) increases dementia risk.
In one study shows that rapid eGFR decline was linked to more than 5-fold higher risk of vascular dementia. However, other studies found that CKD at baseline did not significantly increase Alzheimer’s disease risk. Thus, the evidence remains mixed and debated.
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