Genes And Their Impact On Memory Loss

Introduction

“There are three signs of old age: loss of memory… I forgot the other two.” – Richard Bernard 'Red' Skelton (July 18, 1913 – September 17, 1997) an American comedy entertainer.

One often joke about getting older, and all the other elements that go with old age especially forgetting, but for some this may be a joke or one may joke about it because it’s a scary part of getting older, the fact is Alzheimer Disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and this is just to name a few are all very real and very scary neurodegenerative memory diseases, which people struggle with, daily. It’s a known fact that when an individual gets older they tend to struggle with memory loss, some even develop neurodegenerative memory disease, and with no known cure as yet, is there anything that might help prevent these diseases?

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Memory and aging

Alzheimer’s disease is still the most common of the chronic neurodegenerative memory disorders, with age being the main risk. (Deak, F., Kapoor, N., Prodan, C., & Hershey, L. A. (2016) p. 523). According to the article Memory loss: Five new things, they have discovered the following; Firstly, that there are new genes that both causes and protects against AD, and also furthermore that the protective gene variant may lead to new treatments for AD. Secondly, both Amyloid PET and MRI are helpful tools for identifying patients with mild cognitive impairment (MCI) who may develop AD at a later stage. Thirdly, patients with mild traumatic brain injuries (TBI’s) appear to have a greater risk for AD and chronic traumatic encephalopathy(CTE). These 2 conditions can overlap in older individuals who have at least 1 APOE e4 genotype. Fourthly, lifestyle factors appear to delay the expression of the late-life AD genotype in older adults, for example, daily physical activity can reduce the incidence rate of AD and vascular dementia, even after adjusting for the APOE e4 genotype. Lastly, Donepezil is useful in treating mild to moderate AD and DLB; it can help prevent nursing home placement in patients with moderate to severe AD. Memantine is useful in managing the cognitive and behavioral symptoms of AD and DLB. (Deak et al., 2016, p. 526)

An important finding regarding memory loss and aging

An important finding regarding memory loss and aging is the new gene that both causes and protects against AD. “Researchers suspect that many more genes that haven't been identified yet affect the risk of AD. Such information may prove vital in the development of new ways to treat, or even prevent, AD in the future.” (“Alzheimer’s genes: Are you at risk?” 2019) If one thinks about other illnesses like cancer, for instance, there is a lot of information going around telling individuals to get regular screenings and check-up, saying that the sooner one can pick up a cancerous cell and treat it the better chance they will have to survive, but what about AD? Certainly, it would be much better to find out early on that you might have a risk for AD than to wait until you’re old and stuck in a nursing home not knowing where you are.

Genes control the function of every cell in your body. There are risk genes and deterministic genes. Risk genes increase the likelihood of developing a certain disease and deterministic genes, guarantee that you will develop a certain disease.

The Apolipoprotein E (APOE)

The most common gene at this stage relating to AD is the Apolipoprotein E (APOE) gene. This gene provides instruction for the making of proteins (called Apolipoprotein E). “This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke.” (“APOE gene,” 2020).

There are three slightly different versions (alleles) of the APOE gene namely the e2, e3, and e4. APOE e2 is the least common and reduces the risk for AD. APOE e3 is the most common and found in more than half of the general population and doesn’t seem to affect the risk of AD. APOE e4 is a little more common and increases the risk for AD. Individuals with two copies of the allele are at even greater risk for AD than individuals with only one copy. “Inside the brain, APOE helps to clear beta-amyloid, a component of plaques. APOE e2 appears to perform this function more effectively than APOE e4, with APOE e3 in the middle.” (Dacks, 2016)

The APOE e4 allele affects an individual’s risk to obtain AD but it is not the cause. It is not yet known how the APOE e4 allele is related to the risk of AD, but researchers have found that this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. (“APOE gene,” 2020) 2

Death of nerve cells (neurons) caused by a build-up of amyloid plaques is one of the progressive signs and symptoms of this disorder and this may be seen as why the APOE e4 allele increases one’s risk for AD, but not everyone that has this allele will develop the disease and likewise not everyone with AD have this allele.

Treatments regarding the APOE genes

Some drugs in development (called 'structure correctors') may change the physical structure of the APOE e4 protein so that it behaves more like the APOE e2 protein. Another approach is gene therapy, which attempts to insert APOE e2 genes into the brains of people with APOE e4 genes.

Gene mutation and its effect on Alzheimer’s disease

Brain-derived neurotrophic factor (BDNF)

“A gene mutation may accelerate the loss of memory and thinking skills in people who are at risk for Alzheimer's disease, according to a study published in the May 3, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The gene mutation is called the BDNF Val66Met” (“Gene mutation may speed up memory loss in Alzheimer’s disease,” 2017). The BDNF Val66Met is part of a group of proteins called neurotrophins. Neurotrophins help with the growing of nerve cells and help them to specialize, and survive. 'We found that people with Alzheimer's risk who have this BDNF gene mutation called the Met allele may have a more rapid decline of memory and thinking skills,' said study author Ozioma Okonkwo, Ph.D., of the University of Wisconsin School of Medicine in Madison, Wisc. 'Because this gene can be detected before the symptoms of Alzheimer's start, and because this presymptomatic phase is thought to be a critical period for treatments that could delay or prevent the disease, it could be a great target for early treatments.' (“Gene mutation may speed up memory loss in Alzheimer’s disease,” 2017)

Amyloid precursor protein (APP), Presenilin 1 (PSEN1), Presenilin 2 (PSEN2)

Three genes have been identified in which mutations cause early-onset AD. If you inherit one of these mutated genes from either parent, you will probably have AD symptoms before age 65. The genes are Amyloid precursor protein (APP), Presenilin 1 (PSEN1), Presenilin 2 (PSEN2). Mutations of these genes cause the production of excessive amounts of a toxic protein fragment called amyloid-beta peptide. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of AD. (“Alzheimer’s genes: Are you at risk?” 2019) 3

Other late-onset genes

As research on the genetics of AD progresses, researchers are uncovering links between late-onset Alzheimer's and a number of other genes. These genes include; ABCA7, The exact role of ABCA7 isn't clear as yet but researchers suspect it may have something to do with the gene's role in how the body uses cholesterol. CLU, This gene helps regulate the clearance of amyloid-beta from the brain. An imbalance in the production and clearance of amyloid-beta is central to the development of AD. CR1, A deficiency of the protein this gene produces may contribute to chronic inflammation in the brain. Inflammation is another possible factor in the development of AD. PICALM, This gene is linked to the process by which brain nerve cells (neurons) communicate with each other. Smooth communication between neurons is important for proper neuron function and memory formation. PLD3, Scientists don't know much about the role of PLD3 in the brain. But it's recently been linked to a significantly increased risk of Alzheimer's disease. TREM2, This gene is involved in the regulation of the brain's response to inflammation. Rare variants in this gene are associated with an increased risk of AD. SORL1, some variations of SORL1 on chromosome 11 appear to be associated with Alzheimer's disease.

Klotho gene variant (KL-VS)

“Everyone carries the klotho gene. Klotho is a complex hormone produced in both the kidney and the brain,” (Chan, 2020) “Klotho is a membrane-bound or soluble antiaging protein, whose protective activity is essential for a proper function of many organs.” (Olejnik, Franczak, Krzywonos-Zawadzka, Kałużna-Oleksy, & Bil-Lula, 2018, p. 1). a Gene variant of two amino acid substitutions in human KL, F352V (V) and C370S(S), segregate together to form the KL-VS variant. (George, 2020)

Researchers found that carrying one copy of KL-VS increases circulating klotho, in other words, KL-VS heterozygosity is associated with longer life and cognitive resilience both in mice and in humans. This variant slowed the progression of AD symptoms and it lowered the beta-amyloid plaques in the brains of APOE e4 carriers who had not yet progressed to dementia. A single copy of the KL-VS variant reduced AD risk in APOE e4-positive older adults. On the other hand carrying two copies of KL-VS decreases the hormone. The klotho gene variant may open new doors for drug designs in the treating of AD, and may even hold the key for a longer and healthier life.

APOE3 Christchurch (APOE3ch)

The APOE3ch is a rare gene variant, which may offer protection against AD. Individuals with a rare genetic mutation of PSEN1 E280A have a 99.9% chance of developing early-onset autosomal dominant AD. The 76-year-old Colombian woman, from Medellín, who carried this PSEN1 E280A mutated gene, also carried two copies of the APOE3 Christchurch (APOE3ch) mutation. According to researcher she could be the first known candidate for a gene that has the potential to be used in the development of treatment to halt the progression of the disease. (Gallagher, 2019) Two copies of APOE3ch might protect the brain because the variation reduced the ability of the APOE protein to bind a type of sugar found on the surface of brain cells called heparan sulphate proteoglycans (HSPGs). This binding is thought to help tau tangles develop. These findings suggest that therapies to reduce the binding of APOE and HSPG may be a potential way to treat or prevent Alzheimer’s disease. (“Gene variation may protect against Alzheimer’s disease,” 2019) “Sometimes close analysis of a single case can lead to discovery that could have broad implications for the field,” says NIA Director Dr. Richard J. Hodes.

Aging is still one of the greatest risk factors for AD

Each year there are more and more studies showing that certain genetics contain risk factors for individuals to obtain AD, but age is still the strongest risk factor regarding this disease. During aging, our body undergoes various changes such as accumulation of DNA damage, neuroinflammation, loss of proteostasis, decreased neurogenesis, and the development of metabolic abnormalities, these changes have been shown to lead to decreased homeostasis, synaptic dysfunction, and cognitive impairment. These age-associated changes, in combination with genetic risk factors, may accelerate the progression of AD. Cognitive decline occurs with age even in the absence of AD, although this age-associated change appears subtle when compared to the changes accompanying AD pathology.

Conclusion

Aging remains one of the strongest risk factors for AD, given that the risk of disease onset significantly increases with age. Even if people have potential genetic risk factors for AD, they will rarely develop the disease before 65 years of age. With all the research towards neurodegenerative memory disorders like AD and the new findings regarding genes, that may cause or protect against AD, the main goal will always be to try and help for early treatment and the prevention of nursing home placement and to hopefully find a cure among one of these genes (mutation).

References

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