Alzheimer's disease and genetics

Definition:Alzheimer’s disease is a progressive neurodegenerative disorder that causes a gradual, irreversible loss of memory, language, visual-spatial perceptions, and judgment. The Alzheimer’s Association reports that approximately 6.5 million Americans had the disease in 2022, a number that is expected to increase to as high as 12.7 million by 2050 if means of preventing or effectively treating it are not discovered. The annual costs of caring for persons with Alzheimer’s disease and costs to businesses for lost productivity from American caregivers totaled $321 billion in 2022, according to the Alzheimer’s Association. The number of persons with Alzheimer’s disease and the associated economic burden is expected to rise dramatically as the baby boomer generation ages.

Risk Factors

Individual features and environmental influences may either cause a disease or increase the risk of developing that disease. Aging is a well-established risk factor for Alzheimer’s disease, and the rate of Alzheimer’s disease increases two- to threefold every five years after age sixty-five. According to the Alzheimer's Association in 2022, 6.5 million Americans age 65 or older had Alzheimer’s disease, with 73 percent being age 75 or older, and two-thirds being women. Hispanics, especially those of Caribbean descent, and African Americans are respectively 1.5 and 2 times more likely to develop Alzheimer's disease than Caucasians are.

Alzheimer’s disease is a complex disorder, and many scientists believe that a combination of variations in some genes, possibly acting in conjunction with external factors, may increase the risk. Several genetic factors are known to cause Alzheimer’s disease, but they are extremely rare and account for a very small minority of cases. Persons with early-onset Alzheimer’s disease (which develops before the age of sixty) who also have multiple family members with Alzheimer’s disease from at least three generations are considered to have familial early-onset Alzheimer’s disease, which is very rare (fewer than 5 percent of all persons with the disease, according to the Alzheimer's Association). Familial early-onset Alzheimer’s disease is caused by mutations in the gene for amyloid precursor protein (APP) gene and the presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Down syndrome (Trisomy 21) is another genetically determined cause of Alzheimer’s disease. Persons with Down syndrome have evidence of amyloid pathology at an early age, and about half of those who live to their fifties or sixties will develop Alzheimer’s disease, accounting for fewer than 1 percent of all cases, according to the Genetics Home Reference.

Risk factors for the much more common late-onset Alzheimer’s disease (occurring after age sixty-five) are less clear-cut. Some scientists hypothesize that late-onset Alzheimer’s disease is caused by amyloid plaque accumulation in the brain or by enhanced degradation of the tau protein leading to development of neurofibrillary tangles. To date, no single factor has been identified that definitely causes late-onset Alzheimer’s disease. The risk of this form is increased (but not caused) by the presence of susceptibility genes. Persons without susceptibility genes can develop Alzheimer’s disease, however, just as individuals who carry a susceptibility gene may never develop the disease. The most thoroughly studied susceptibility gene for Alzheimer’s disease is apolipioprotein E (APOE) ɛ4. Individuals who carry one or more APOE ɛ4 alleles are at increased risk compared with noncarriers. Environmental factors that may increase the chance of Alzheimer’s disease include diabetes mellitus, hypercholesterolemia, hypertension, depression, stroke, traumatic brain injury, and a lower level of education.

Etiology and Genetics

The hallmark lesions in the brains of persons with Alzheimer’s disease are extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Accumulation of the amyloid-beta (A-beta) peptide in the brain triggers a series of events that culminate in the development of Alzheimer’s disease. The A-beta peptide is a sticky substance that forms clumps (or aggregates) called “amyloid plaques” that surround nerve cells. Amyloid plaques concentrate in the hippocampus and other brain regions that control memory and cognition. A-beta is produced by a series of steps that convert APP to neurotoxic forms of A-beta. APP is broken down by the beta-secretase and gamma-secretase enzymes, which results in the formation of toxic A-beta peptides that aggregate and form plaque. Another enzyme, alpha-secretase, is believed to protect against A-beta production. Accumulation of A-beta, either by overproduction or reduced clearance from the brain or both, leads to inflammation, poorly functioning nerve cells, hyperphosphorylation of tau proteins (causing formation of neurofibrillary tangles and destruction of nerve cell structure). Together, these pathological events result in death of nerve cells in the brain, decreased function of the neurotransmitters (chemical messengers in the brain), loss of gray matter, dementia, and death.

The rare, familial early-onset Alzheimer’s disease is caused by mutations in the APP, PSEN1, and PSEN2 genes. Genes that encode for APP regulate the production of beta-secretase, and genes encoding for presenilin 1 and presenilin 2 control production of gamma-secretase. Mutations in the PSEN1 gene are the most common cause of Alzheimer’s disease in persons with familial early-onset disease, occurring in 30 to 70 percent of cases, according to neurologist Thomas D. Bird. Gene mutations controlling for the production of APP are less common (10 to 15 percent of cases), and PSEN2 mutations are extremely rare.

Mutations in the APOE gene represent the most common genetic risk factor for late-onset Alzheimer’s disease. There are at least three forms of APOE alleles: ɛ2, ɛ3, and ɛ4. Scientists believe that APOE may interrupt the normal breakdown of APP and alter A-beta production. The APOE ɛ2allele, which is rare and develops later in life, may protect individuals against Alzheimer’s disease. The APOE ɛ3 allele is believed to play a neutral role in Alzheimer’s disease risk. The APOE ɛ4 allele occurs in approximately 25 percent of all individuals. Persons who carry the APOE ɛ4 allele have a threefold increased risk of developing Alzheimer’s disease compared with noncarriers, while individuals with two copies of the APOE ɛ4 allele are ten times more likely to develop Alzheimer’s disease than noncarriers, according to the National Human Genome Research Institute.

Numerous other candidate genes found on chromosomes 2, 7, 9, 10, 11, 12, 15, and 19 are under investigation as well. SORL1 and GRB-associated binding protein 2 (GAB2) are among other susceptibility genes that may increase the risk of developing Alzheimer’s disease. The SORL1 gene found on chromosome 11 encodes for normal APP breakdown and generation of A-beta. Single nucleotide polymorphisms (SNPs) that have been identified on the SORL1 gene are related to Alzheimer’s disease, but the risk relationship is not yet completely understood. GAB2 is a susceptibility gene that increases the risk of Alzheimer’s disease for individuals who also carry the APOE gene. A 2013 genome-wide association study meta-analysis by J. C. Lambert, et al. indicated the candidate genes CASS4, CELF1, FERMT2, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, NME8, PTK2B, SLC24A4, SORL1, and ZCWPW1 as potential risk factors.

The National Institute on Aging (NIA) and other branches of the National Institutes of Health (NIH) sponsor studies designed to identify genes associated with late-onset Alzheimer’s disease.

Symptoms

Early symptoms of Alzheimer’s disease are difficult to discern. Mild cognitive impairment, which is characterized by subtle memory loss, impaired language skills, or other minor deficits in mental function that are noticed by friends and family but are not so severe as to impair the individual’s ability to perform basic activities of daily living, is believed to precede Alzheimer’s disease. In persons who will eventually develop the disease, the symptoms of mild cognitive impairment become progressively more severe and are eventually manifest as loss of higher brain activities, inability to speak, failure to understand the spoken and written word, and inability to perform even the simplest activities of daily living. Agitation, aggression, nighttime wandering (sundowning), and other behavioral disturbances often accompany advanced Alzheimer’s disease and may result in institutionalization. Survival following a diagnosis of Alzheimer’s disease has been reported to range from eight to ten years, but as the Genetics Home Reference notes, patients may live for as long as twenty-five years or as little as a year after being diagnosed.

Screening and Diagnosis

In 1906, a German physician, Dr. Alois Alzheimer, reported on the rapid mental decline and death of his patient, Frau August D, and at autopsy described plaques and neurofibrillary tangles in her brain. Today, observation of plaques and tangles at autopsy remains the only way to definitively diagnose Alzheimer’s disease. A presumptive diagnosis of Alzheimer’s disease is based on clinical observation of symptoms and progressive deterioration.

Early diagnosis of Alzheimer’s disease is essential to ensure that treatable causes of memory loss and cognitive impairment and other diseases, such as depression, drug interactions, nutritional deficiencies, or endocrine disorders are ruled out. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) multiphase study sponsored by the National Human Genome Research Institute (NHGRI) is investigating the impact of genetic testing and disclosure of APOE gene status to the adult children and siblings of persons with Alzheimer’s disease. Findings from the REVEAL study will help inform patients’ and clinicians’ decisions about genetic counseling and guide actions taken after learning about this status.

Treatment and Therapy

Despite a huge research effort, disease-modifying therapies that prevent, slow, or halt disease progression have yet to be identified. Cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA) receptor antagonist are widely used to treat cognitive problems. These drugs slow the rate of symptom development for some patients, but they do not significantly impact disease progression. Other drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), cholesterol-lowering statins, ginkgo biloba, estrogen, and vitamin E have not been shown to be effective. Treatments that interfere with tau pathology, prevent clumping of A-beta, or boost the immune response to A-beta are being actively studied in clinical trials.

For associated problems, such as emotional and behavioral changes, caregiver support is the firstline treatment approach. Medications such as antidepressant, anxiolytic, or antipsychotic drugs may be given for psychiatric symptoms. Similarly, adopting proper sleep hygiene practices is recommended for sleep problems before pharmacological treatments are considered.

The NIA Alzheimer’s Disease Prevention Initiative seeks to accelerate the rate of new drug discovery and development. The Alzheimer’s Association is a national organization that provides patient advocacy and funding for research of potential new therapies.

Prevention and Outcomes

Genetic counseling is useful for those rare persons with familial early-onset Alzheimer’s disease, but there is no consensus among experts about the benefits of testing other individuals. Due to the passage of the 2008 Genetic Information Nondiscrimination Act, employers and insurers cannot discriminated against individuals on the basis of genetic test results. Issues of patient confidentiality, medical record security, and potential psychological distress remain germane to genetic testing for Alzheimer’s disease, however.

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