Alzheimer’s disease is one of the most common conditions associated with memory and cognition impairment in the elderly.
Alzheimer’s disease (AD) is a degenerative disorder that affects person’s cognition, memory, and behavior (and therefore is described as dementia). This illness is caused by brain degeneration and abnormal protein deposition in the brain cells. AD progresses for decades as the brain structures are gradually affected (sustain atrophy). Of note, Alzheimer’s disease is the most common cause of dementia and typically manifests in adults older than 65 years. Unfortunately, AD is uncurable but there are options available to prevent further cognitive impairment as well as provide support to ensure the normal daily life of the affected person and their family.
Although the exact cause of the disease remains unknown multiple genes were found to be associated with AD as the disorder often runs in the families. Despite the fact that there is a strong link between the family history of the disease and the risk of the disease development, those who do not have ill relatives still may have AD.
In this article, we will review different genes implicated in the disease and see how AD is inherited.
The genetic heritability of Alzheimer’s disease
The disorder is considered to have a mixed origin – the development of the disease is predisposed by genetic factors which are then influenced by environmental and lifestyle exposures. In a small percentage of individuals amongst all the affected a specific single genetic mutation is found – in this case we talk about a familial AD which tends to begin at a younger age and affects people anywhere from 30 to 65 years. This early-onset AD comprises up to 5% of all AD cases.
Single genes AD
Single genes causing Alzheimer’s are known to cause one type of early-onset Alzheimer’s disease, these genes are inherited as an autosomal dominant pattern, meaning that a child born from an ill mother/father who carries a mutation has a 50% risk of inheriting the defective gene and eventually will develop AD.
The genes involved in AD include the following:
- APP (amyloid precursor protein) gene located on chromosome 21 which encodes the synthesis of the protein responsible for the development of the nerve cells, formation of links between these cells, and repair of the brain cells;
- PSEN-1 (presenilin-1) gene located on chromosome 14 is necessary for the APP processing via the γ-secretase complex;
- PSEN-2 (presenilin-2) gene located on chromosome 1 also plays a key role in APP processing;
Susceptibility genes and increased risks
On the other hand, there are also several susceptibility genes that increase the person’s risk of developing AD but do not directly cause the disease. These are usually present in the majority of individuals who have AD. Although almost all affected individuals have relatives with AD it is not the same as familial Alzheimer’s described in the previous paragraph.
Apolipoprotein E (APOE) gene located on chromosome 19 was found to be related to the risk of developing Alzheimer’s. There are several different forms (alleles) of this gene, of which APOE4 is considered to bear AD risk – approximately 14% of the general population are carriers of APOE4. In contrast, about 8% of the population have APOE2 which may even reduce the risk and be protective against AD when in fact APOE3 (present in 78% of the population) seems to be neutral regarding the Alzheimer’s disease risk. APOE4 gene may predispose to the buildup of amyloid in the brain tissue – these deposits seem to be responsible for memory and cognition impairment. Every person has two copies of the APOE gene – those who have two copies of the mutant (APOE4) gene increase Alzheimer’s risk by 10-15 times, whereas carrying one mutant gene with one normal variant would double or triple the risk in comparison to a healthy person who has two APOE3 genes. On the other hand, as it was mentioned previously, APOE2 may even be protective, therefore, Alzheimer’s risk is reduced in APOE2 carriers by 40%.
Some other genes (up to 20 genes) were also investigated to be related to AD:
- ABCA7 (ATP binding cassette, subfamily A member 7);
- BIN1 (Bridging Integrator 1);
- CD2AP (CD-2-associated protein);
- CLU (allele C of the clusterin);
- CR1 (complement receptor 1);
- EPHA1 (EPH Receptor A1);
- MS4A4A/MS4A4E/MS4A6E (Membrane Spanning 4-Domains);
- PICALM (Phosphatidylinositol Binding Clathrin Assembly Protein);
- PLD3 (Phospholipase D Family Member 3);
- TREM2 (Triggering Receptor Expressed On Myeloid Cells 2);
- SORL1 (Sortilin-related receptor, L);
Down syndrome and Alzheimer’s
Since the APP gene is located on chromosome 21, those who have Down syndrome have 3 copies of the APP gene and are at risk of developing Alzheimer’s disease. It is considered that about 25% of people who have Down syndrome will develop Alzheimer’s disease-like symptoms after the age of 35.
Individuals who have a first-degree relative with dementia have an increased risk of developing Alzheimer’s disease, the same applies to families in which several siblings have a disease. The risk is significantly higher if the disease starts at a young age. It should be noted that still in the majority of cases Alzheimer’s disease genes are only leading to increased susceptibility to developing dementia but the ultimate results depends on the environment and lifestyle exposures such as smoking, alcohol intake, and exercise.
Genetic tests are available to identify one’s risks. Sometimes genetic testing can even predict the development of the disease with high certainty as the rare autosomal dominant mutations almost 100% result in early-onset AD.
Genetic tests are helpful to identify whether a person is genetically predisposed to develop Alzheimer’s disease at some point and whether further investigations to exclude the disorder are needed.
How to prevent Alzheimer’s disease
As the exact cause of Alzheimer’s disease is not known there are no interventions to prevent it. Still, it is suggested that lifestyle modifications can decrease the risk of getting the disease. These modifications include: