Neurodegenerative diseases represent a group of disorders characterized by the progressive structural and functional degeneration of the central and peripheral nervous systems. They affect millions of people worldwide, especially the elderly population.
What are the symptoms of neurodegenerative disease?
The symptoms of neurodegenerative diseases vary, with some predominantly leading to problems with movement (ataxias, e.g. Parkinson‘s), while others mainly cause problems with mental functioning (dementia, e.g. Alzheimer‘s). Most neurodegenerative disorders develop at later life stages and lead to increased disability over time. They can affect many aspects of a person’s life, such as bladder and bowel function, blood pressure, breathing, heart function, memory and cognitive abilities, mobility and balance, mood, sleep, speech and swallowing.
What causes neurodegenerative diseases?
Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose their function over time and ultimately die. Treatments may help relieve some of the physical or mental symptoms. However, there is currently no way to slow disease progression or cures. The risk of being affected by a neurodegenerative disease increases significantly with age.
The combination of genetics and environmental factors contributes to the risk of developing a neurodegenerative disease. Therefore, it is difficult to predict who will develop the disease. A person’s genetics might make them more susceptible to a certain neurodegenerative disease. But whether, when, and how severely the person is affected depends on environmental exposures throughout life.
What are the most common neurodegenerative diseases?
Alzheimer’s disease and Parkinson’s disease are the most common neurodegenerative diseases, followed by Amyotrophic lateral sclerosis, Huntington’s disease, and Creutzfeldt-Jakob disease.
Alzheimer’s disease (AD) is the most common cause of dementia accounting for 60-80% of cases. Dementia is a general term for memory loss and loss of other behavioral and cognitive abilities.
Genetic factors are known to be involved in all forms of AD. Variants in PSEN1, PSEN2 and APP lead to the autosomal dominant inherited early form of AD (disease onset <60 years). In families with affected individuals in at least three generations, ~60% of cases are caused by variants in the PSEN1 gene and ~20% by variants in the APP gene. Variants in the PSEN2 gene cause <5% of cases.
Symptoms can range from mild to severe, up to the inability to do activities of daily living. The most common type of AD affect people who are 65 and older (late-onset). Rarely, AD can develop in people <60 years (young-onset). Symptoms of young-onset AD develop between 30-60 years. The hallmark pathologies of AD are the accumulation of the protein beta-amyloid (plaques) in the brain and twisted strands of the protein tau (tangles) inside neurons.
Types of genetic testing for Alzheimer’s
Recommended for patients who:
- Have dementia and want to know if it is caused by Alzheimer’s
- Have been diagnosed with Alzheimer’s and want to confirm the diagnosis
- Developed Alzheimer’s at an earlier age (<60 years)
Recommended for relatives of Alzheimer’s patients who:
- Want to determine their carrier status (diagnostic testing detected variant in patient)
- Have a strong family history of dementia suggesting a variant for inherited Alzheimer’s
Please note: To date, no treatment is available that can prevent or slow the progression of Alzheimer’s. A positive result has implications for the patient and their relatives, who may or may not want to know the result. Additionally, it cannot predict symptom onset. A negative result is quite common even with a very strong family history. This does not rule out the possibility of a genetic explanation for dementia. An inconclusive result may cause anxiety and uncertainty.
Parkinson’s disease (PD) affects predominately dopaminergic neurons in the brain area called substantia nigra, leading to low levels or missing dopamine in the brain and eventually resulting in neuronal impairment.
In about 5%–10% of patients with PD, pathogenic variants in DJ1, GBA, LRRK2, PINK1, PRKN, SNCA or VPS35 genes can be found. Late-onset PD (age >50 years) is associated with autosomal dominant variants in the LRRK2 or GBA genes, whereas young-onset PD (age <40 years) is caused by variants in the PRKN, PINK1, and DJ1 genes following an autosomal recessive inheritance.
Motor symptoms include tremor, bradykinesia, limb rigidity, gait and balance problems. Non-motor symptoms may include depression, constipation, sleep disturbances, loss of sense of smell and cognitive impairment. The disease is progressive and symptoms can vary for each patient.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a common neuromuscular disease that belongs to the group of motor neuron diseases. ALS is caused by degeneration of motor neurons leading to gradual muscle weakness and atrophy.
The majority of ALS cases occur sporadically with no associated risk factors and no family history. However, 5-10% of all ALS cases are familial. Variants in the C9ORF72 gene account for about 25-40% of all familial cases and a small percentage of sporadic cases. Another 12-20% of familial ALS result from variants in the SOD1 gene.
Early symptoms can be subtle and may include muscle weakness or stiffness. As the disease progresses, problems with moving, swallowing, speaking or forming words, and breathing may occur. Eventually, the ability to initiate and control voluntary muscle movements is lost. Most ALS patients die from respiratory failure, usually within 3-5 years after symptom onset. However, about 10% of patients survive >10 years.
Huntington’s disease (HD) is an inherited neurological disorder characterized by involuntary movements, severe emotional disturbance and cognitive decline.
HD is caused by a CAG repeat expansion in the HTT gene. In the normal HTT gene, this sequence is repeated between 11-29 times. In the mutant gene, the repeat occurs ≥40 times. As a result, huntingtin protein clumps in the brain leading to neuronal loss, especially in the basal ganglia and cortex. HD is inherited in an autosomal dominant pattern.
Symptoms develop between 30-50 years, but may also occur as early as age 2 or as late as 80. The main characteristic of HD is uncontrolled movement. Additionally, a decline in thinking and reasoning skills, including memory, concentration, judgment, and ability to plan and organize can be observed. Patients may develop mood changes like depression, anxiety, irritability, and anger.
Creutzfeldt-Jakob disease (CJD) is a rare, degenerative brain disorder and the most common prion disease (or transmissible spongiform encephalopathies).
CJD is caused by the buildup of abnormal prion proteins in the brain. At least 85% of CJD cases are sporadic and about 5-10% of cases are hereditary. Infectious prions can occur due to variants in the PRNP gene. Variants in PRNP in sperm or egg cells are transmitted to the offspring. In the sporadic form, errors are more likely to occur with aging, which explains the general advanced age at onset of CJD and other prion diseases.
Symptoms usually occur at age 60, and about 70% of patients die within one year. CJD is characterized by rapidly progressive dementia. Initially, patients may experience memory impairment, behavioral changes, lack of coordination and visual disturbances. As the illness progresses, patient’s mental impairment becomes severe and involuntary muscle movements, blindness, weakness of extremities, and coma may occur. Pneumonia and other infections often occur which can lead to death.
 Alcalay RN et al. Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists. Genet Med,574–580 (2020). https://www.nature.com/articles/s41436-019-0684-x
 Cook L et al. Genetic Testing for Parkinson Disease: Are We Ready? Neurol Clin Pract. 2021 Feb;11(1):69-77. doi: 10.1212/CPJ.0000000000000831. https://cp.neurology.org/content/11/1/69
 Deuschl G et al. The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017. Lancet Public Health. 2020 Oct;5(10):e551-e567. doi: 10.1016/S2468-2667(20)30190-0. https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(20)30190-0/fulltext
 GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480. doi: 10.1016/S1474-4422(18)30499-X. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30499-X/fulltext
 Gitler AD et al. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017;10(5):499-502. doi:10.1242/dmm.030205 https://journals.biologists.com/dmm/article/10/5/499/2428/
 Huntington’s Disease Society of America. Overview of Huntington’s disease. Retrieved 19 April 2022 from https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/
 ALS Association. Who Gets ALS? Retrieved 19 April 2022 from https://www.als.org/understanding-als/who-gets-als
 Alzheimer’s Association. Alzheimer’s and Dementia. Retrieved 19 April 2022 from https://www.alz.org/alzheimer_s_dementia
 Alzheimer’s Association. What is Alzheimer’s Disease? Retrieved 19 April 2022 from https://www.alz.org/alzheimers-dementia/what-is-alzheimers
 Alzheimer’s Association. Huntington’s Disease. Retrieved 19 April 2022 from https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/huntington-s-disease
 Alzheimer’s Society. Genetic testing for dementia. Retrieved 19 April 2022 from https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/types-genetic-testing
 Alzheimer’s Society. Is dementia hereditary? Retrieved 19 April 2022 from https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/is-dementia-hereditary
 Alzheimer’s Society. Alzheimer’s Society’s view on genetic testing. Retrieved 19 April 2022 from https://www.alzheimers.org.uk/about-us/policy-and-influencing/what-we-think/genetic-testing
 Centers for Disease Control and Prevention. Prion Diseases. Retrieved 19 April 2022 from https://www.cdc.gov/prions/index.html
 European Parkinson’s Disease Association. Parkinson’s genetic testing. Retrieved 19 April 2022 from https://www.epda.eu.com/about-parkinsons/diagnosis/genetic-testing/
 National Human Genome Research Institute. About Huntington’s Disease. Retrieved 19 April 2022 from https://www.genome.gov/Genetic-Disorders/Huntingtons-Disease
 Muscular Dystrophy Association. Spinal Muscular Atrophy. Retrieved 19 April 2022 from https://www.mda.org/disease/spinal-muscular-atrophy/types
 National Institute on Aging. Alzheimer’s Disease Fact Sheet. Retrieved 19 April 2022 from https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet
 National Institute on Aging. Genetic Testing for Alzheimer’s Disease. Retrieved 19 April 2022 from https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet#four
 National Institute of Neurological Disorders and Stroke. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet. Retrieved 19 April 2022 from https://www.ninds.nih.gov/amyotrophic-lateral-sclerosis-als-fact-sheet
 National Institute of Neurological Disorders and Stroke. Spinal Muscular Atrophy Fact Sheet. Retrieved 19 April 2022 from https://www.ninds.nih.gov/spinal-muscular-atrophy-fact-sheet
 National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob Disease Fact Sheet. Retrieved 19 April 2022 from https://www.ninds.nih.gov/creutzfeldt-jakob-disease-fact-sheet
 Parkinson’s Foundation. FAQs: Genetics & Parkinson’s. Retrieved 19 April 2022 from https://www.parkinson.org/understanding-parkinsons/causes/genetics/faqs
 Parkinson’s Foundation. What Is Parkinson’s?. Retrieved 19 April 2022 from https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons