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According to new research, having two copies of the APOE4 gene variant may increase the risk of getting Alzheimer’s. The study also discovered that individuals with two copies of APOE4 are more likely to develop the disease earlier in life.

A recent study reveals that some Alzheimer’s cases have a direct hereditary origin [1].

No underlying cause for the majority of Alzheimer’s patients is currently known. Nonetheless, researchers have long understood that having an APOE4 gene variant in your family can increase your risk of being diagnosed. Individuals with two copies, which account for 2–5% of the population overall, are significantly more vulnerable [2].

Researchers have now proposed that possessing two copies of APOE4 may actually cause the condition rather than just increasing the likelihood of developing it.

A New Genetic Disorder

Researchers previously recognized two types of Alzheimer’s disease: familial and sporadic. The familial form results from genetic mutations, as the name implies. Typically, familial types are less common and develop early. Previously, medical practitioners believed less than 5% of cases, or around one in every fifty, were familial [3].

The new study suggests that 1 in 6 cases of Alzheimer’s would be due to the genetic type of the disease. This change occurred because scientists think they now have a better understanding of the role the APOE gene has in Alzheimer’s development. They believe they have discovered that a familial form of Alzheimer’s may be a separate disease rather than an offshoot.

Various forms of APOE that a person can have are:

• APOE2 protects against developing Alzheimer’s.
• APOE3 is considered neutral.
• APOE4 raises the risk of developing Alzheimer’s. Individuals who carry two copies of this gene are at a higher risk.

APOE4 was initially considered to be a risk factor. Scientists now believe that it is an inherited type of Alzheimer’s and a separate disease.

Details About the New Study

Researchers in the United States and Spain contrasted individuals with two copies of APOE4 to those with other forms of the APOE gene [1].

The researchers examined data from 10,000 participants in five clinical trials and data from about 3,297 brains kept at the National Alzheimer’s Coordinating Center. Examining the brains kept at the Coordinating Center, scientists discovered that 273 had two gene copies. About 240 of them had dementia.

Additionally, the researchers discovered that the condition manifested roughly ten years sooner in those with the APOE4 variant with an average onset age of 65. According to their results, those with this inherited form of Alzheimer’s developed the disease at a faster rate than those with other kinds of Alzheimer’s.

The researchers stated that possessing one copy of the gene raises the Alzheimer’s risk. However, having two copies increased the likelihood of developing beta-amyloid and tau buildup in the brain.

These findings led the researchers to hypothesize that individuals who have two copies of APOE4 have a genetic type of Alzheimer’s.

According to a previous study, approximately 30% to 35% of individuals with two copies of the APOE4 gene would get dementia or at least mild cognitive impairment [4].

However, APOE4 has a substantial association with cardiac disease. It is possible that individuals with two gene copies passed away from heart disease rather than dementia since they had died before the researchers started looking for dementia.

Researchers in the current study estimate that 15% of patients with Alzheimer’s disease carry two copies of APOE4. The APOE4 gene is present in two copies in about 2% of the general population, making it one of the most common hereditary disorders.

Future Implications of the Research

The new research highlights whether asymptomatic individuals should undergo genetic testing to know if they carry two copies of APOE4.

Most people who carry two APOE4 genes are those whose parents were both diagnosed with Alzheimer’s disease quite early on—probably in their 60s.

Genetic tests are not currently performed in clinical settings to diagnose or predict Alzheimer’s risk. Many specialists do not recommend it due to the complexity associated with analyzing the results.

According to the study’s authors, this type of testing could be beneficial, and doctors should recommend it to their patients.

Lecanemab is a drug used to treat Alzheimer’s disease by removing amyloid plaques from the brain. Knowing if an individual has two copies could be life-saving. However, people with two copies of APOE4 are more likely to have brain swelling from these medications and since this medicine can cause brain swelling, several treatment centers do not offer it.

June is Alzheimer’s and Brain Awareness Month. It aims to increase public awareness and motivate individuals to donate money or their time to support and research. Besides raising awareness about Alzheimer’s, it aims to provide opportunities to raise funds for research and support services for Alzheimer’s patients and their families. Donate to the Alzheimer’s Research Foundation to help us support the Alzheimer’s family caregivers and provide them with resources.
Donate now: https://www.alzra.org/donate-now/

References

1. Fortea, J., Pegueroles, J., Alcolea, D., Belbin, O., Dols-Icardo, O., Vaqué-Alcázar, L., Videla, L., Gispert, J.D., Suárez-Calvet, M., Johnson, S.C. and Sperling, R., 2024. APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nature Medicine, pp.1-8.
2. Alzheimer’s Disease Genetics Fact Sheet. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-genetics-fact-sheet. Accessed: 7th June, 2024.
3. Familial Alzheimer’s Disease. UCSF Weill Institute for Neurosciences. https://memory.ucsf.edu/genetics/familial-alzheimer-disease. Accessed: 7th June. 2024.
4. Qian, J., Wolters, F.J., Beiser, A., Haan, M., Ikram, M.A., Karlawish, J., Langbaum, J.B., Neuhaus, J.M., Reiman, E.M., Roberts, J.S. and Seshadri, S., 2017. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLoS medicine, 14(3), p.e1002254.
5. Alzheimer’s disease may be inherited more often than previously thought. Medical News Today. https://www.medicalnewstoday.com/articles/alzheimers-disease-may-be-inherited-more-often-than-previously-thought. Published Online: 7th May, 2024. Accessed: 7th June, 2024.
6. Study Identifies Genetic Variant as a Clear Cause of Alzheimer’s—Does This Mean You Should Get Tested? Health. https://www.health.com/genetics-causes-alzheimer-study-8648326. Published Online: 5th June, 2024. Accessed: 7th June, 2024.

There are various types of dementia. One of these is frontotemporal dementia, which impacts the brain regions critical for language, behavior, and personality.

Frontotemporal dementia (FTD), also known as frontotemporal degeneration, is a set of conditions characterized by progressive neuron loss in the brain’s frontal (the areas behind your forehead) or temporal (the regions behind your ears) lobes. It causes nerve cell destruction in these brain regions, resulting in loss of function, which can cause deterioration in behavior and personality and trouble producing or comprehending language.

FTD is one of the less prevalent kinds of dementia. In contrast to other forms of dementia, like Alzheimer’s disease and vascular dementia, FTD often affects persons between the ages of 45 and 65. It also tends to be identified earlier in life.

Protein accumulation in the frontal and temporal lobes of the brain leads to FTD. Since these regions of the brain control language and behavior, individuals with FTD frequently exhibit speech and behavior problems.

It is unknown what precisely causes FTD, but one in every eight people who have it has family members who have had it as well [1]. Therefore, experts assume there is a genetic element to it.

Types of Frontotemporal Dementia

There are the following two types of dementia.

Behavioral variant frontotemporal dementia (bvFTD)

It is the most common type of FTD. The symptoms of behavioral variant frontotemporal dementia (bvFTD), also known as behavior variant FTD, are notable behavioral and personality abnormalities that typically impact individuals in their 50s and 60s but can also appear in their 20s or 80s. The loss of nerve cells in the areas controlling behavior, judgment, empathy, and foresight, among other capacities, is particularly noticeable in bvFTD.

Primary progressive aphasia (PPA)

Primary progressive aphasia (PPA) is the second most common type of frontotemporal degeneration, affecting language skills like speaking, writing, and comprehension. PPA typically manifests in midlife, before the age of 65, though it can sometimes happen later in life. The two most distinct types of PPA have slightly different symptoms.

• In the semantic variant of PPA, the person loses their capacity to understand or articulate words in a spoken sentence.
• In the nonfluent/agrammatic variant of PPA, the individual’s speaking is hesitant or ungrammatical.

Some patients with FTD have a less frequent variation associated with mobility issues. Symptoms of this condition may resemble those of amyotrophic lateral sclerosis (ALS) or Parkinson’s disease.

Symptoms of Frontotemporal Dementia

FTD symptoms appear gradually and grow steadily, sometimes swiftly. They differ from person to person, depending on the brain regions involved. These are typical signs and symptoms [2]:

• Behavior and/or dramatic personality changes
• Socially inappropriate, impulsive, or repetitive behaviors
• Impaired judgment
• Apathy
• Lack of empathy
• Decreased self-awareness
• Loss of interest in normal daily activities
• Emotional withdrawal from others
• Loss of energy and motivation
• Inability to use or understand language
• Hesitation when speaking
• Less frequent speech
• Distractibility
• Trouble planning and organizing
• Frequent mood changes
• Agitation
• Increasing dependence

Some individuals experience physical symptoms such as tremors, muscle spasms or weakness, stiffness, poor coordination or balance, or trouble swallowing. While they are less frequent than behavioral and linguistic alterations, psychiatric symptoms like delusions or hallucinations can also happen.

Diagnosis of Frontotemporal Dementia

An expert evaluation by a specialist experienced with these conditions should diagnose behavioral variant frontotemporal dementia and PPA. The diagnosis is based on the patient’s symptoms and the findings of neurological examinations. Brain scans, such as magnetic resonance imaging (MRI) and glucose positron emission scans, are valuable supplementary testing. However, they must be interpreted alongside the patient’s medical history and neurological exam.

Causes & Risk Factors

About one-third of cases of frontotemporal degeneration are hereditary. Individuals with a family history of frontotemporal degeneration can now seek genetic counseling and testing. A family history of frontotemporal degeneration or a related condition is the only recognized risk factor [3].

Treatment

There are no known therapies for any of the frontotemporal subtypes. Some drugs can help with agitation, irritation, or depression. These treatments help patients enhance their quality of life.

Frontotemporal dementia progressively worsens over time, and the rate of decline varies from person to person. Most patients survive for eight to ten years after diagnosis; however, some people live much longer.

People with FTD often exhibit muscle weakness and coordination issues for many years, leaving them needing a wheelchair. These muscle problems may result in difficulties with chewing, swallowing, moving, and controlling the bladder and bowels. People with FTD eventually die as a result of physical changes that can cause skin, urinary system, or lung infections.

Stages of Frontotemporal Dementia

FTD progresses through seven stages. Not everyone will reach stage seven; some people advance more quickly, while others stay at one stage for years before moving on to the next [1]. The seven core stages of FTD are listed below.

1. Mild Cognitive Changes

Early-stage frontotemporal dementia is very inconspicuous in most cases. Many people and even those close to them do not recognize any specific signs that would raise concerns. Nevertheless, people may exhibit mild cognitive abnormalities such as strange actions or antisocial behavior at this early stage. They may also exhibit speech issues or trouble putting sentences together correctly. While memory problems are uncommon with FTD, they can occur.

Nonetheless, people with early-stage FTD frequently do not link certain behaviors and situations to a neurological disorder. A person’s quality of life is not significantly affected at this point.

2. Changes in Behavior and Sharpness

The second stage of FTD may only show slight changes because it is still relatively early in the disorder’s progression. Like many disorders that impact a person’s behaviors and subtle personality traits, most people are unlikely to attribute it to a health problem. Dementia, in all its forms, might be hard to identify in the early stages because it is normal for people to get forgetful, have trouble with phrases, or stammer when they get older.

However, individuals close to someone with FTD may detect variations in their behavior and general sharpness. For instance, some people occasionally struggle to find the appropriate words to say, while others lack the cognitive ability to change one word for another. If identified early on, these difficulties may be crucial for diagnosing FTD. Unusual or antisocial behavior can also start affecting the person’s social and career life.

3. Language Issues

The symptoms of frontotemporal dementia start to intensify more quickly and become more recognizable in the middle stages of the disease. Individuals with FTD may also develop more significant language variants at this point. It usually begins with forgetting more sophisticated terminology and less often used terms, which can influence the career of individuals who use more advanced language regularly. These symptoms are usually more noticeable to people around the affected individual. The affected person does not usually notice them themselves.

Language difficulties, combined with unusual actions, a lack of inhibition, and social tact, may indicate FTD at this stage. For some people, their home and professional lives start to deteriorate in the early and middle phases of FTD.

4. Implications on Quality of Life

Stage four of FTD causes symptoms that significantly impact the person’s quality of life and the way they interact with others. A person may find it more difficult to recall and utilize basic phrases, such as common terminology and the names of everyday items, as their language impairments worsen. Forgetting simple words is far more visible to other people than forgetting more complicated words.

This is the point at which some FTD patients start to exhibit typical dementia symptoms, like forgetfulness and trouble with daily activities. Although this is not always the case, the combination of memory impairments, behavioral variations, and linguistic difficulties make life exceedingly challenging. It is typical for an individual with FTD to be incapable of identifying and addressing their own problems.

5. Mood Swings and Personality Changes

FTD at stage five is regarded as one of the mid-to-later stages and may more substantially affect an individual’s quality of life. Additionally, as memory impairments can also exacerbate cognitive impairment, including language and problem-solving difficulties, it may start to exhibit a resemblance to typical Alzheimer’s symptoms. That’s why a person with FTD could have trouble doing daily chores and making decisions—particularly ones crucial to their well-being, like healthcare.

The symptoms at this stage might be wide-ranging. A person may generally experience mood swings and personality changes, but they will usually be more severe than the subtle behaviors they previously demonstrated. It can become nearly impossible to carry on conversations and use speech to carry out regular tasks and address problems. Hence, friends or family members are frequently needed to provide help and handle different tasks for patients with late-stage FTD.

Besides cognitive problems, FTD can lead to motor impairment, including stiffness and the inability to use specific body parts. An example is the capacity to swallow and drink fluids. Behavior and memory problems can sometimes lead to people acting strangely and doing things they are unaware of.

6. Memory Deterioration

People with FTD may resemble those suffering from Alzheimer’s dementia when they reach stage six of the illness. There is a prominent impact on behavior and language, and memory loss adds to the acute mental decline. Individuals may exhibit little emotional, physical, or verbal output.

Motor problems, such as imbalance and reflexes, can potentially be a symptom of late-stage frontotemporal dementia. Thus, falls and accidents are common, exacerbated by a decrease in aspiration and strange reactions to everyday situations. It can be difficult for a person with FTD to recover psychologically from a fall injury, which may require them to use wheelchairs and other devices permanently.

A person with late-stage FTD experiences a significant mental and physical decrease in day-to-day functioning. Daily duties, including eating, cleaning, dressing, and moving, often require assistance from another person. Later-stage dementia necessitates continuous care at home or placement in a specialized care facility for this reason.

7. Severe Cognitive Deterioration and Health Decline

Stage seven is the most advanced and final stage of FTD. Living alone is nearly impossible at this time, and patients suffer from severe cognitive deterioration. Since there is no cure for FTD, the person will continue to decline in a variety of ways. While this typically results in a continuous deterioration of the symptoms they have experienced throughout the seven stages of the condition, others may experience additional and more severe symptoms later on. For instance, if a person has always had problems with their speech and movement skills, later stages may now affect their memory and other mental aspects.

FTD by itself is not lethal; however, it can raise the chance of developing a very severe condition at stage seven. Pneumonia, the most frequent cause of death in patients with FTD, is a typical example. Additionally, FTD increases a person’s susceptibility to falls and accidents, which can result in fall-related injuries and fatalities, from which recovery is far more challenging.

References

1. What are the 7 stages of Frontotemporal Dementia? Dementech Neurosciences. https://dementech.com/2022/11/10/what-are-the-7-stages-of-frontotemporal-dementia/. Published Online: 10th November, 2022. Accessed: 7th May, 2024.
2. Frontotemporal Dementia. John Hopkins Medicine. https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/frontotemporal-dementia. Accessed: 7th May, 2024.
3. Frontotemporal Dementia. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/frontotemporal-dementia. Accessed: 7th May, 2024.
4. Understanding the Stages of Frontotemporal Dementia. Healthline. https://www.healthline.com/health/stages-of-frontotemporal-dementia. Published Online: 18th November, 2022. Accessed: 7th May, 2024.