Genetic Risk Factors for Alzheimer’s Disease
Linlu Dai
Marianopolis College, 4873 Westmount Ave, Westmount, Quebec H3Y 1X9, Canada
Keywords: Alzheimer's Disease, Genetic Risk Factors, APOE Ε4.
Abstract: Amyloid-Beta plaques and neurofibrillary tangles are the main causes of Alzheimer's disease (AD), a brain
condition that results in memory loss and cognitive impairment. Both environmental and genetic factors
contribute to it. While the APOE ε4 gene increases the risk of late-onset AD, rare mutations in PSEN1,
PSEN2, and APP cause early-onset AD. Other genes, including TREM2, CLU, and PICALM, have been
linked to AD by genome-wide association studies (GWAS). Genetic risk is assessed using Polygenic Risk
Scores (PRS). However, environmental and lifestyle variables also play a significant role in the development
of illness.
1 INTRODUCTION
Alzheimer's disease (AD) represents a significant
neurodegenerative condition, recognized as the
predominant cause of dementia globally.
Neurodegenerative diseases present a big problem for
modern medicine and are rising as a more significant
health problem around the world. Memory, cognitive
processes, and the ability to do daily tasks worsen
over time, significantly affecting how people act.
Over time, Alzheimer's disease affects people to lose
their sense of who they are and greatly increases their
independence. This dependence causes much pain for
people involved, including the individual in question
who has the disease, their family and workers.
Alzheimer's disease is the most prevalent type of
dementia globally, and its origins are linked to
complex factors (Malik, Nasir, 2021). The
prevalence of Alzheimer's disease rapidly increases
largely due to the aging global population of today.
This trend poses a major challenge for healthcare
services and society overall. Even with many studies
conducted, the precise origins of Alzheimer's disease
are still not fully understood (Fu, Mago, Schiff,
Krysowaty, 2024).
1.1 Overview of Alzheimer’s Disease
The progressive degradation of brain neurons is the
hallmark of Alzheimer's disease (AD), which is
essentially a neurodegenerative illness. The death of
neurons harms brain communication networks, which
leads to several cognitive and functional problems.
AD is caused by two main types of abnormal protein
buildups: amyloid plaques and neurofibrillary
tangles. The clinical signs of AD show up slowly at
first and get worse over time. Memory problems are
often the first and most obvious signs, especially
when remembering new information. This could be
linked to issues with executive processes like making
plans, solving problems, and making choices. As the
disease worsens, more and more areas of cognition
are affected. These include language (having trouble
remembering words and understanding what people
are saying), visual-spatial skills (being disoriented
and having trouble navigating space), and mental
symptoms (e.g. agitation, depression, anxiety,
hallucinations) and behavioral. The severity of these
symptoms makes it very hard for a person to do daily
tasks, making them more dependent on others for
help. In the end, the disease causes people to lose
their independence, become severely disabled, and,
in many cases, die. The disease's misleading
symptoms often delay identification, making it harder
to start treatment at the right time when it would be
most helpful (Sottejeau, Bretteville, Cantrelle, 2015).
1.2 Importance of Genetic Risk Factors
Research has revealed both uncommon and prevalent
genetic variables linked to Alzheimer's disease (AD).
Human genes contain mutations such as PSEN1,
PSEN2, and APP, which are associated with familial
early-stage versions of the disease. Conversely,
prevalent genetic variants, especially the APOE ε4
allele, are strongly associated with an elevated risk of
134
Dai, L.
Genetic Risk Factors for Alzheimer’s Disease.
DOI: 10.5220/0014436700004933
Paper published under CC license (CC BY-NC-ND 4.0)
In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 134-143
ISBN: 978-989-758-789-4
Proceedings Copyright © 2026 by SCITEPRESS – Science and Technology Publications, Lda.

late-onset Alzheimer's disease (AD), the most
frequent variant (Santos, Ferreira, 2020). Recent
genetic research has identified numerous more genes,
including TREM2, CLU, and PICALM, that
contribute to the likelihood of acquiring Alzheimer’s
disease (AD) and offer significant insights into the
condition's course. However, environmental, lifestyle
and genetics are not the only explanations that are
associated with the disease. There are genetic
research studies, including large-scale studies and
family-based approaches, that have deepened the
understanding of how AD is inherited over time. A
notable finding can be summarized: employing
polygenic risk scores (PRS), which integrate data
from various genetic variants, aids in assessing an
individual's overall genetic risk for AD. This review
studies AD's molecular and genetic field which
shows key genetic risk factors and discusses how
genes and the environment interact to influence the
disease. It also examines the potential of PRS in
predicting risk and guiding prevention efforts so the
medical field can have access to better diagnostics,
targeted treatments, and strategies to prevent or delay
of AD (Chouraki, Seshari, 2018).
1.3 Epidemiology of Alzheimer’s
Disease
The epidemiological data on AD shows a troubling
case. Alzheimer's disease leads to brain damage,
which is the primary reason for dementia, making up
60–80% of all cases. As people age, this issue occurs
more frequently, presenting a significant challenge
for the global aging population. Once a person
reaches 65 years of age, the likelihood of developing
Alzheimer's disease tends to increase twofold
approximately every five years. Alzheimer's disease
that begins before the age of 65 is uncommon, but it
is possible. Many individuals around the globe are
presently impacted by Alzheimer’s, and this figure is
anticipated to increase significantly in the coming
decades. The epidemiological data on AD indicates a
troubling scenario. Alzheimer's disease is the primary
cause of brain damage leading to dementia,
representing 60–80% of all cases. As people age, this
occurrence becomes much more frequent, presenting
a significant issue for the global population that is
aging. Once a person reaches 65 years of age, the
likelihood of developing Alzheimer's disease
typically increases twofold every five years.
Alzheimer's disease that begins before the age of 65
is uncommon, but it is possible. Many individuals
around the globe are presently impacted by
Alzheimer’s, and this figure is anticipated to increase
significantly in the coming decades. The rising
number of cases is a big problem for healthcare
systems, which need to spend a lot of money on
testing tools, specialized care facilities, and programs
to help caregivers. Alzheimer's disease has also a big
impact on the economy. It has direct costs like
hospital stays, medications, and doctor visits. It also
has secondary costs like lost work time and the value
of unpaid caregiving by family members. Moreover,
the disease affects some groups more than others.
Different amounts of risk are caused by things like
genetics, race, ethnicity, socioeconomic status, and
way of life. Understanding these differences is
important for coming up with targeted prevention and
response strategies that meet the specific needs of
different groups. Epidemiological research offers
important information on a number of risk factors.
Age, a family history of the illness, certain genetic
characteristics, heart disease (including diabetes,
high blood pressure, and high cholesterol),
inadequate exercise, poor nutrition, and brain traumas
are some of these (MD Medicine).
2 MECHANISMS
2.1 Pathophysiology of Alzheimer’s
Disease
A combination of mutations leads to Alzheimer's
disease, which is inherited within families and
involves shared risk variants. Amyloid-beta plaques
and neurofibrillary tangles are key signs of
Alzheimer's disease (AD). Amyloid-beta plaques are
deposits formed by misfolded amyloid-beta peptides,
while neurofibrillary tangles consist of deposits of
hyperphosphorylated tau protein in neurons. This
issue leads to an increase in neurodegeneration,
synaptic dysfunction, and cognitive loss. Changes in
the APP, PSEN1, and PSEN2 genes are the main
cause of early-onset familial Alzheimer's disease
(EOFAD), since they have a direct impact on the
synthesis and accumulation of amyloid-beta.
However, APOE-ε4 is the most important genetic
risk factor for late-onset Alzheimer's disease
(LOAD), which is more common and impacted by a
number of genetic variables. Two helpful
techniques in Alzheimer's research include familial
linkage analysis and genome-wide association
studies (GWAS) (Zhou, Yang, Wu, 2023).
Genetic Risk Factors for Alzheimer’s Disease
135

2.1.1 Amyloid-Beta Plaque
The amyloid-beta (Aβ) protein, which is present
outside of cells, builds up to form amyloid plaques.
Amyloid precursor protein (APP), a bigger protein, is
the source of the smaller protein known as Aβ.
Amyloid precursor protein (APP) processing is
disrupted in Alzheimer's disease, which causes
amyloid-beta (Aβ) to accumulate in the brain and
eventually form plaques. These plaques obstruct
neuronal transmission, which causes inflammation
and, eventually, the failure and death of the neurons.
When these plaques build up, they usually start in
memory-related parts of the brain, such the
hippocampus, and then move to other parts of the
brain, eventually affecting the whole brain.
(DeFelipe, Furcila, 2018).
2.1.2 Neurofibrillary Tangles
Neurofibrillary tangles are considered an alternative
main cause of disease. They are found inside neurons
and mostly contain the protein tau. Tau keeps
microtubules stable in a healthy brain. Microtubules
are important for moving nutrients and other
important things inside neurons. In Alzheimer's
disease, tau changes strangely by breaking away from
microtubules and forming clumps. These tangles
block the transport route within neurons which leads
to neuronal dysfunction and, eventually, cell death.
There is a clear pattern to how knots form. They start
in the entorhinal cortex, that is closely connected to
the hippocampus and then spread to other brain parts.
The aggravation shows how cognitive decline
impacts over time (Medeiros, Vargas, 2011).
2.2 Genetic Foundations
Alzheimer's disease (AD) is also affected by a
combination of genetic and environmental aspects.
Most Alzheimer's cases come from genetic factors
that influence an individual's likelihood of
developing the disease as well as the advancement of
its symptoms. Studies have revealed that various
genetic components linked to AD, such as hereditary
patterns and particular genes, increase vulnerability
to developing the disease (National Institute on
Aging).
2.2.1 Heredity and Family History
Having a family history of Alzheimer's disease (AD)
is a significant risk factor for the illness. According
to research, those with a first-degree relative who has
Alzheimer's disease are two to three times more likely
to have the illness themselves than people without a
family history. When more family members are
involved, the chance increases. Early-onset familial
Alzheimer's disease (EOFAD) and late-onset
sporadic Alzheimer's disease (LOAD) are the two
primary forms of Alzheimer's disease based on how
they are inherited. Less than 5% of all AD cases are
EOFAD, which is inherited in an autosomal dominant
fashion, which means that only one parent possessing
the gene may pass on the characteristic. Usually, a
diagnosis is made before the age of 65. The
majority of AD cases, on the other hand, are caused
by LOAD, which has a more complex genetic profile
that includes many risk genes as well as the
interaction of environmental and genetic variables.
(California University).
2.2.2 Genetic Susceptibility Genes
Genetics play a significant role in determining an
individual's chances of developing Alzheimer's
disease (AD). Recent studies have found additional
important genetic factors, such as CLU, BIN1,
SORL1, and ABCA7. These genes play a role in
different biological processes that help in the
development of the disease, including amyloid-beta
metabolism, synaptic function, and the inflammatory
response. The APOE ε4 allele is an important genetic
factor linked to late-onset Alzheimer's disease.
People with one or more copies of this allele have a
much higher chance of getting the disease. However,
the relationship between this gene and the increase of
Alzheimer is still unclear. Other genes appear to be
linked to Alzheimer's. For instance, the CLU gene
plays a role in removing amyloid-beta from the brain,
while the BIN1 gene is associated with tau tangles.
These genes illustrate the complexity of the genetics
involved in Alzheimer’s disease. (Sims, Lee, 2014).
Additionally, genes and outside factors, like lifestyle
and environment, make it more complicated to
understand why some people are at higher risk for
Alzheimer’s. Researchers continue to study this
disease to find more genes that might increase the risk
and to see how these genes work with environmental
factors (Huang, Zhang, 2021).
2.3 Genetic Research Methods
Recent progress in genetic research has improved the
capacity to pinpoint genetic risk factors linked to
Alzheimer's Disease (AD). Genome-Wide
Association Studies (GWAS) and Family Linkage
Analysis are important techniques that help advance
research on Alzheimer's disease.
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2.3.1 Genome-Wide Association Studies
(GWAS)
Among these, GWAS shows itself as a powerful
technique for finding genetic variations linked to
complex diseases like AD (Zhang, Li, 2006). This
method involves examining the genomes of many
individuals, comparing those diagnosed with AD to a
healthy group, and identifying specific genetic
variations called single nucleotide polymorphisms
(SNPs) that are more prevalent in individuals with the
disease. However, even though GWAS has provided
significant insights, it does have limitations. GWAS
approach primarily recognizes common genetic
variants, which may not have significant individual
effects, and often misses rare mutations as well as
important gene-environment relations. Furthermore,
the results of GWAS studies need functional
validation to prove their causal roles in the
development of AD (Jansen, Savage, 2020). As of
now, GWAS has found more than 50 genetic sites
linked to Alzheimer's disease. This research has
discovered key signs, including APOE, CLU, BIN1,
SORL1, and ABCA7 which represent important roles
in amyloid-beta metabolism, immune response, and
tau pathology (Kunkle, Grenier-Boley, 2019).
Moreover, the approach called Polygenic Risk Scores
(PRS) enables researchers to assess a person's total
genetic risk for Alzheimer's by considering various
genetic risk factors (Rmanan, Kim, Holohan, 2012).
Moreover, analysis that use data from GWAS show
significant biological processes related to
Alzheimer's disease. The processes include
endosomal transport, inflammation, and lipid
metabolism, which are crucial for understanding the
mechanisms to the disease (Dai, Li, Xue, 2022).
2.3.2 Family Linkage Analysis
Family linkage analysis is a method used to find
genetic factors related to Alzheimer's disease (AD),
particularly in families where several members are
impacted. This method consists of examining
families with several individuals diagnosed with AD
to be able to trace the heritage of specific genetic
characteristics in the genes that has been passed
down. By taking this approach, researchers are able
to identify particular areas of the genome that might
board genes associated with the disease (O’Brien,
Wong, 2017). When researching early-onset
Alzheimer's disease (EOFAD), a rare genetic type of
the disease that usually appears before the age of 65,
this method works particularly well. Mutations in
certain genes, such as APP, PSEN1, and PSEN2,
which contribute to the production and accumulation
of amyloid-beta, a significant protein connected to
the disease, are commonly linked to EOFAD (Jack,
Holtzman, 2017). Family linkage analysis reveals
genetic markers that might not be evident in irregular
instances, in contrast to the more frequently studied
late-onset Alzheimer's disease (LOAD). Researchers
have discovered several important risk genes that
affect amyloid-beta metabolism, tau pathology, and
synaptic function by identifying specific genetic
regions through linkage analysis (Alzheimer’s
Association, 2023).
3 IMPACT AND RISK
DISCUSSION
3.1 Major Genetic Risk Genes
Alzheimer's disease is a condition influenced by both
genetic and environmental. APOE ε4 allele is a key
genetic risk factor, also known as mutations in the
PSEN1 and PSEN2 genes. These factors play a
significant role in the possibility of developing the
disease, which could affect the process such as the
production and clearance of amyloid-beta, neuronal
health, and cognitive decline. Although genetic
testing can indicate people who may have a higher
risk for Alzheimer's, the interaction between genetic
factors and environmental influences complicates the
ability to predict and prevent the disease (Mayo
Clinic)
3.1.1 APOE Gene and Its Isoforms
The APOE (Apolipoprotein E) gene is the most
significant genetic risk factor for Alzheimer's disease
(AD), especially the most common kind, late-onset
Alzheimer's. APOE helps transport lipids like
cholesterol to brain cells and is crucial for the
removal of amyloid-beta, a protein that may build up
and form plaques in the brain (National Institute of
Aging, 2021). The three primary variations of APOE
are ε2, ε3, and ε4. Because it raises the risk of
Alzheimer's, the ε4 variation is one to watch out for.
Individuals who have one copy of the ε4 mutation are
at high risk, but those who have two copies
(homozygous for ε4) are much more likely to get the
disease. More amyloid plaques, which can impair
brain function and cause cell death, are associated
with APOE ε4. However, the precise mechanism by
which the APOE ε4 variation increases the risk of
Alzheimer's disease is still being investigated. This
variation is believed to affect the brain's ability to
Genetic Risk Factors for Alzheimer’s Disease
137

eliminate amyloid-beta more difficult. It may also
contribute to inflammatory reactions in the brain,
which could exacerbate the illness. Furthermore,
Alzheimer's disease is not always the result of
harboring the APOE ε4 variation. Numerous other
genetic and environmental variables also have a
substantial impact on the disease's progression
(Miglio, Vanzulli, 2021). The APOE gene's ε2
variant may provide some protection against
Alzheimer's disease by lowering the risk of the
condition. Nonetheless, the ε3 variant is the most
common and is thought to be neutral (Gong, Zhang,
Zeng, 2020).
3.1.2 PSEN1 and PSEN2 Genes
Other mutations that specifically affect early-onset
Alzheimer's disease (EOFAD) exist in addition to the
APOE gene. Usually affecting those under 65, the
mutations constitute a rare form of the disease. The
PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2)
genes are the primary sites of these alterations. The
synthesis of proteins essential for breaking down
amyloid precursor protein (APP) into smaller
fragments like amyloid-beta depends on the PSEN1
and PSEN2 genes (Sanchez, Kaciroti, 2017). This
mechanism breaks down when PSEN1 and PSEN2
mutations occur, which ultimately results in an excess
of amyloid-beta, particularly the dangerous type
known as Aβ42. This poisonous form has the ability
to aggregate and create plaques, which obstruct brain
cell-to-cell contact and result in cell death.
Alzheimer's disease-related cognitive impairment
can be explained by this process (Bertram, Tanzi,
2016). The most frequent cause of EOFAD is
mutations in the PSEN1 gene, which frequently
exhibit a "autosomal dominant inheritance pattern".
In other words, they can develop the disease simply
by inheriting one mutated copy from a parent.
Mutations in the PSEN2 gene can also cause EOFAD,
but they are much less common and don’t always lead
to the disease in everyone who carries them
(Alzheimer’s Research UK, 2024). The role of the
PSEN1 and PSEN2 mutations shows how important
amyloid-beta production is for the development of
Alzheimer’s. While there is a strong link between
PSEN1 mutations and early-onset Alzheimer's,
having these mutations alone does not mean a person
will develop the disease, as other genetic,
environmental, and lifestyle factors also affect
whether the disease will occur (Alzheimer’s gov,
2022).
3.2 Secondary Genetic Risk Genes
Other genetic variables can raise an individual's risk
of getting Alzheimer's disease (AD), in addition to
important genetic factors such as alterations in the
APOE, PSEN1, and PSEN2 genes. These secondary
genes might not have as strong an effect as the main
risk genes, but they still play an important role in
understanding how Alzheimer's works. Other key
factor genes include TREM2, CLU, PICALM, and
others identified in studies like Genome-Wide
Association Studies (GWAS) (Gatz, Reynolds,
2006).
3.2.1 TREM2 Gene
Due to its association with Alzheimer's disease,
particularly the late-onset variant (LOAD), the
TREM2 (Triggering Receptor Expressed on Myeloid
Cells 2) gene has gained significant attention in
recent studies. TREM2 is essential for the brain's
immunological response and is mostly located in
microglia, the immune cells that make up the brain. It
has been demonstrated that some mutations in the
TREM2 gene, particularly the R47H variant, increase
the risk of Alzheimer's disease. TREM2 aids in the
removal of toxic compounds such as amyloid-beta
plaques by brain cells known as microglia. This
cleansing mechanism malfunctions when TREM2
mutations occur, resulting in an accumulation of
amyloid-beta and increased inflammation, both of
which can worsen brain injury. This highlights the
role inflammation plays in Alzheimer's disease
development (Guerreiro, Wojtas, 2013). TREM2
mutations are extremely uncommon and account for
a very small percentage of Alzheimer's cases, despite
the fact that the R47H mutation significantly raises
the chance of developing Alzheimer's (Wang, Cella,
2015).
3.2.2 CLU, PICALM, and Other Genes
Another significant genetic risk factor for
Alzheimer's disease is the Clusterin (CLU) gene. It
generates a protein that aids in the brain's amyloid-
beta removal. Changes in the CLU gene can lead to
problems with clearing amyloid-beta that causes it to
build up. CLU is thought to help with the amyloid-
beta clumping and manage inflammation and cell
survival. Studies indicate that individuals with
specific variants of the CLU gene face an increased
chance of developing Alzheimer's that makes it a
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significant risk factor in the genetic research
surrounding the disease (Zhao, Wu, Li, 2019).
Helping to eliminate amyloid-beta from the brain
is one of clusterin's primary functions. The
breakdown of another protein, amyloid precursor
protein (APP), results in the production of amyloid-
beta. Amyloid-beta accumulates and creates plaques
that damage brain cells if it is not efficiently removed.
In order to prevent amyloid-beta from becoming
poisonous, clusterin attaches to it and facilitates its
removal from the brain. If CLU doesn’t work
properly, it can lead to plaque buildup, a common
feature of Alzheimer’s disease. Some studies also
suggest that clusterin may affect how quickly
amyloid-beta forms into plaques (Wojtas, Kang,
2017).
Studies have revealed a strong correlation
between late-onset Alzheimer's disease and a
particular variant of the CLU gene (rs11136000). The
T form of this gene variant reduces inflammation in
the brain and improves amyloid-beta reduction,
which lowers the risk for AD. Conversely, the
variant's C form is linked to an increased risk of AD,
presumably as a result of its decreased ability to
remove amyloid-beta. When paired with other
genetic and environmental factors, these genetic
variants can raise the risk of Alzheimer's disease, but
they do not alone cause it (Ling, Simpson, 2012).
CLU and another gene called APOE play similar
roles. Both genes help manage fat transport and
cholesterol in the brain, which are considered vital for
healthy brain function and communication between
nerve cells. Clusterin works with APOE to transport
fat by helping to keep brain cells healthy. Problems
with fat transport can impact amyloid-beta processing
and make brain cells more vulnerable to damage. For
people with the APOE ε4 variant, certain CLU
variations can increase or decrease their risk for AD
by impacting how amyloid beta is handled
(Montagne, Nation, 2020).
The PICALM (Phosphatidylinositol Binding
Clathrin Assembly Protein) gene makes a protein that
is essential for a process that helps cells take up
amyloid-beta and perform other functions. PICALM
has been linked to how effectively amyloid beta is
cleared from the brain, and certain variants of this
gene also increase the risk of Alzheimer's. Studies
suggest that PICALM may affect tau pathology,
which is related to the development of amyloid-beta.
Additionally, some versions of PICALM may play a
role in how much amyloid-beta builds up in the brain,
which suggests it could be important in the early
stages of Alzheimer's. However, like TREM2, the
risk from PICALM variants isn't as strong as that
from primary risk genes like APOE (Zhao, Wang,
Zhou, 2022)
3.3 Gene-Environment Interaction
3.3.1 Interaction between Environmental
Factors and Genetic Susceptibility
Stress, physical exercise, exposure to toxic
substances, and our diet can all alter how our genes
affect our risk of Alzheimer's. Due to differences in
their genes and the ways in which they are expressed,
various persons are at different genetic risk. For
instance, one of the main genetic risk factors for late-
onset Alzheimer's disease is the APOE ε4 allele. But
not everyone who carries this gene will develop the
illness, demonstrating the importance of
environmental factors as well. Research has shown
that lifestyle choices can either make the effects of
APOE ε4 worse or better. For instance, people with
the APOE ε4 gene who exercise regularly, eat
healthily, and have active social lives might have a
lower risk of cognitive decline compared to those
who are inactive. Additionally, exposure to air
pollution and heavy metals has been linked to a
higher risk of Alzheimer's, especially for those who
are already at genetic risk (Lourida, Hannon, 2021).
3.3.2 Influence of Lifestyle
A person’s lifestyle (what they eat, how much they
move, whether they smoke or drink alcohol, and how
engaged their mind is) plays a significant role in how
genetic risks for Alzheimer's can impact them. One
well-known example is the Mediterranean diet, a way
of eating rich in fruits, vegetables, healthy fats, and
whole grains. This diet has been shown to help
protect against memory decline and Alzheimer's,
especially in people who may be genetically at risk.
The foods in this diet can fight damage in the brain
that leads to Alzheimer's (Shannon, Stephan, Granic,
2023). Even for people who are genetically
predisposed to Alzheimer's, maintaining an active
lifestyle can lower the risk of the disease. Exercise
helps support new brain cell growth and lowers
harmful substances in the brain, which provides
protection against the disease. Also, keeping the mind
active through learning and social interactions can
lower the risk of dementia which indicates that
mental challenges may help counterbalance genetic
risks for Alzheimer's. [41] Epigenetic changes, which
can affect how genes behave without changing the
Genetic Risk Factors for Alzheimer’s Disease
139

DNA itself, are another way lifestyle factors can
influence Alzheimer’s risk. Changes in gene
expression brought on by factors like nutrition, stress,
and exposure to toxins may be inherited by offspring.
For example, long-term stress and lack of good sleep
have been linked to changes in genes that are
involved in brain health, which could speed up
Alzheimer's development in those who are already
genetically vulnerable (Rodriguez, Delgado, 2023).
3.4 Polygenic Risk Scores (PRS)
Polygenic risk scores (PRS) are a way to measure
how likely someone is to develop Alzheimer's disease
(AD) based on their genes. Instead of looking at just
one gene, like the APOE ε4 allele, PRS considers
many different genetic variations found throughout
the genome. This method gives a broader view of a
person's genetic risk and helps sort individuals into
different risk levels for Alzheimer's (Tan, Bonham,
2023).
3.4.1 Calculation and Significance of PRS
PRS is calculated by adding up the effects of different
risk genes in a person's DNA.
𝑃𝑅𝑆 =
∑
𝛽

× 𝑋




(1)
In this formula:
- 𝛽

shows how much each risk gene affects the
chance of getting Alzheimer's.
- 𝑋

shows how many copies of that risk gene a
person has (either 0, 1, or 2).
PRS is mainly useful because it gives a
personalized estimate of a person's risk for
Alzheimer's disease. Research shows that people with
higher PRS scores are more likely to develop
Alzheimer's, even if they don’t have the well-known
risk gene (APOE ε4). PRS can help identify at-risk
individuals early, which allows them to make
lifestyle changes, get preventative care, or be treated
more attentively.
3.4.2 Application of PRS in Prediction and
Prevention
PRC scores look at many different genes because
some diseases are not caused by just one gene but by
many that each contribute a little bit to a person’s risk.
PRS merges the effects of these genes to show how
likely it is that someone will develop a certain
condition. The higher the score, the greater the risk.
This information can help doctors and patients make
informed decisions about their health (National
Human Genome Research Institute)
One of the main uses of PRS is to predict health
risks. For example, researchers have discovered
genetic markers linked to diseases like Alzheimer’s.
By calculating a PRS, doctors can identify people
who may be at higher risk even before they show any
symptoms. This early detection is crucial because it
lets individuals and healthcare providers take action
early to manage the risk (Lewis, Vassos, 2021).
Specific and personalized prevention methods can
be applied after identifying individuals at risk
through PRS depending on each individual who has
attained AD. This might include lifestyle changes like
eating healthier, exercising regularly, or getting more
mental stimulation. For instance, someone who is
found to have a high genetic risk for heart disease
may be encouraged to follow a heart-healthy diet or
increase physical activity to reduce their risk. In some
cases, people with a high genetic risk of certain
cancers may need more frequent medical check-ups
or screenings. Healthcare providers can help improve
health outcomes by applying prevention methods to
the individual's genetic risk (Torkamani, Wineinger,
2022).
4 CONCLUSION
4.1 Summary of Main Findings
Alzheimer's disease (AD) is a complex brain disorder
affected by several different factors, including genes,
the environment, and lifestyle choices. This paper
looked at critical genetic factors that contribute to AD
such as APOE ε4 gene and other mutations linked to
early-onset familial AD in genes such as PSEN1,
PSEN2, and APP. There are also other genetic factors
like TREM2, CLU, and PICALM, that offer
understandings to how the disease works, especially
when it is subject of regarding how the brain clears
harmful proteins, manages inflammation, and
processes fats. The way genes and the environment
like diet, exercise, and exposure to toxins interact
makes understanding AD even more challenging.
New tools called Polygenic Risk Scores (PRS) can
help assess risk more precisely by looking at multiple
genetic variations at once. PRS can help in early
detection, personalized treatments, and targeted
prevention strategies. It can suggest interventions,
such as lifestyle adjustments and preventive
strategies, that could help delay the onset and
progression of the disease when healthcare providers
can effectively identify individuals with a greater
genetic inclination.
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4.2 Clinical and Public Health
Implications
Understanding genetic risk factors for Alzheimer’s
disease (AD) is necessary for healthcare and public
health. Testing for genetic risks in people who are at
high risk can help with earlier diagnoses and better
treatments. Public health campaigns that encourage
brain-healthy habits, like eating the Mediterranean
diet, staying physically active, and keeping the mind
engaged, can help reduce the number of AD cases in
the community. Personalized medicine that considers
genetic risk can make prevention and treatment even
more effective, which can potentially lead to better
results for patients and less impact on society from
AD.
4.3 Future Research Directions and
Unresolved Questions
Despite advances in genetic research, many questions
remain unanswered about Alzheimer's disease (AD).
Future studies that explore how genetics and
environmental factors work together to affect the risk
of developing AD will push the current healthcare
knowledge even further as it is important to improve
the accuracy of Polygenic Risk Scores (PRS) for
different populations, as genetic risks can vary by
ethnicity as well. Additionally, by understanding how
changes in gene activity, known as epigenetics, give
more spotlight to Alzheimer's Disease research, could
help develop new treatments. As we gain more
insights into the genetics of AD, prevention strategies
and innovative treatments become vital when
managing this neurodegenerative disease.
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