Genetics of Alzheimer’s Disease: The Genes Playing Behind Memory Loss

Introduction:

Alzheimer’s disease is one of the common neurodegenerative disorders which affects elderly persons and is irreversible. About 90 percent of sporadic (the disease occurs due to mutation and is not inherited) patients have a late onset of this disease, which is around 60 to 65 years of age and the gene which is associated with this is apolipoprotein E (APOE) gene, which is also a risk factor, whereas in autosomal dominant Alzheimer’s disease the responsible genes are APP (Amyloid protein precursor), PSEN1 (presenilin-1), and PSEN2 (presenilin-2). They present with short-term memory loss, confusion, and disturbance in their behavior.

What Is Alzheimer's Disease?

Alzheimer’s disease is a type of brain disorder, which slowly causes memory loss, and destroys thinking skills including simple tasks. The genes which are responsible for this disease are APP, PSEN1, and PSEN2 and the strongest risk factor which is associated with this is the APOE e4 allele. There are two types, which are:

• Early-Onset or Familial Alzheimer’s Disease: This accounts for one to six percent of cases and occurs between 30 to 65 years of age. They have a family history of this disease, it is an inherited autosomal dominant disorder in which mutation in the amyloid beta gene occurs and fragments of AB42 protein get accumulated throughout the brain. Plaques in the frontal lobe and hippocampus are related to loss of memory and learning ability.

• Late-Onset Alzheimer’s Disease: It is the most common form and occurs between 60 to 65 years of age. It may or may not run in the family.

What Are the Clinical Symptoms of Alzheimer’s Disease?

The clinical symptoms of Alzheimer’s disease include:

• Dementia, which slowly progresses and becomes severe.

• Impairment in reasoning, language, decision-making, and executing functions.

• Difficulty at household activities or work.

• Change in the mood.

• Delusions and hallucinations (false sense of objects involving smell, taste, sound, sight, and touch) may be present but are not common.

• Neurological symptoms such as seizures (uncontrolled activity of the brain causing uncontrolled muscle movements or behavior), hypertonia (muscle spasm), myoclonus (sudden jerking or twitching of muscle), incontinence, and mutism (inability to talk).

• Malnutrition, pneumonia (infection of the lungs), and inanition (loss of energy) can cause life-threatening situations.

How Is Alzheimer’s Disease Diagnosed?

The diagnosis of Alzheimer's disease includes:

• Diagnosis is based on clinical symptoms, neuropsychological tests, and neurological examination.

• The diagnosis of dementia requires two or more criteria which involve loss of memory, language, orientation, calculation, and judgment.

• The diagnosis of dementia should exclude chronic drug intoxication, depression, thyroid disease, chronic central nervous system infection, and vitamin deficiencies.

• The diagnosis should exclude, Parkinson's disease (a brain disorder that causes uncontrollable movements), diffuse Lewy body disease (neurodegenerative disorders with symptoms such as dementia, parkinsonism, and hallucination), Creutzfeldt-Jakob disease (brain disorder which causes dementia), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, a disorder of blood vessels), which is done using neurological test and thorough clinical examination.

• Definitive diagnosis involves histopathological features such as amyloid (amyloid-β) plaques and neurofibrillary tangles. The most common form of amyloid-ß (it is obtained from amyloid precursor protein (APP) and further undergoes cleavage by gamma-secretase) is Aβ40, which has 40 amino acids and Aβ42 is also found but in less quantity. The neurofibrillary tangles contain hyperphosphorylated tau, which has more severity than the amyloid plaques.

What Are the Genes That Are Associated With Alzheimer’s Disease?

The genes that are associated with Autosomal Dominant Alzheimer’s disease are:

Amyloid Precursor Protein (APP)

• It is a type-I integral-membrane protein that is present in synapses of neurons (a point where the neurons connect and communicate with other neurons).

• It is synthesized in the endoplasmic reticulum (an organelle in the cell, which helps in protein synthesis).

• APP undergoes proteolysis by α-secretase and β-secretase to form amyloid-α peptide and amyloid-β peptide, these fragments are further cut by γ-secretase to form Aβ peptide. Therefore mutations in the APP gene cause an increased amount of Aß peptide.

• About 32 missense mutations (change in the single DNA base, which changes the amino acid sequence) have been identified in the APP gene.

• 10 to 15 percent of mutations occur in familial Alzheimer's disease and these types of mutations are not seen in sporadic Alzheimer's disease.

• Patients who have this gene have an onset around 50 to 60 years of age.

Presenilin 1 (PSEN1)

• This gene encodes for polytopic membrane protein and is present on the AD3 locus on chromosome 14.

• These cause cleavage of APP by γ-secretase.

• Mutations in this gene can cause early-onset familial Alzheimer's disease. These mutations increase the Aβ40 and Aβ42 levels.

• Missense mutations in this gene account for 18 to 50 percent of autosomal in autosomal dominant EOFAD.

• Defects in PSEN1 result in a more severe form and early onset of disease around 30 years of age.

• Clinical features of the PSEN1 gene are progressive dementia and parkinsonism, spasticity (muscle stiffness), and seizures.

Presenilin 2 (PSEN2)

• It is located on chromosome 1, like PSEN1 it causes cleavage of amyloid-β peptide but is less produced than PSEN1, and mutations in these genes can increase the levels of Aβ40 and Aβ42.

• Mutations are rare in this gene and about 14 mutations have been found.

• Defects in this gene can cause a late-onset of disease around 45 to 88 years of age.

The gene that is associated with sporadic Alzheimer’s disease is:

Apolipoprotein E (APOE) Gene

• This gene is located on chromosome 19q13.2, it is associated with sporadic late-onset and familial late-onset Alzheimer's disease.

• APOE polymorphism is due to adaptive changes in diet.

• There are three alleles ε2, ε3, and ε4 and among them, APOE ε4 genotype is identified as a risk factor for Alzheimer's disease, down’s syndrome (a genetic disorder which has an extra chromosome), head trauma, and stroke.

• APOE plays an important part in the metabolism and distribution of cholesterol and triglycerides.

• Persons who carry APOE ε4 have higher neurofibrillary tangles and deposition of amyloid plaques.

• After the age of 65, the risk increases with the increase in the number of ε4 alleles present.

Conclusion:

Alzheimer’s disease is an irreversible neurodegenerative disorder. There is no cure for this disease but the progression can be slowed down. The familial form of Alzheimer’s disease is due to autosomal dominant inheritance related to APP, PSEN1, and PSEN2 genes. Whereas the sporadic form of Alzheimer’s disease is due to the APOE gene.