Dementia touches the lives of millions worldwide. The collection of symptoms includes impaired memory, thinking, and daily functioning. While factors like lifestyle and environment are significant contributors, genetics can also shape a person’s risk.
To understand how genes may contribute to Dementia, it's important to start with what genes are: pieces of deoxyribonucleic acid (DNA). This potent molecule provides instructions for building and maintaining our bodies. We inherit this DNA from both parents.
Differences, or mutations, in specific genes, can disrupt their normal function, sometimes leading to harmful effects on the brain and body, including changes in brain tissue that can lead to Dementia.
However, as Dr. Anindita Deb, a board-certified neurologist and associate professor of Neurology & Neurosurgery at UMass Chan Medical School in Worcester, Massachusetts, explains, genes aren’t destiny. "People often think that if they have a specific gene, they will definitely develop Dementia, but it’s rarely that straightforward,” she says. “It's the interaction between genetics and environment that determines someone’s risk.”
Is Dementia Genetic?
In general, for almost every one of the leading pathologies of Dementia—Alzheimer’s, Vascular Dementia, Lewy Body Dementia (LBD), and Frontotemporal Dementia (FTD)—there is evidence of a genetic link for a small percentage of those affected.
However, in most people living with Dementia, there isn’t a known inherited cause.
Any of the major forms of Dementia can be sporadic (they occur randomly and aren’t linked to family history) or familial (cases are inherited and run in families due to specific genetic mutations).
"There are certain genes that can predispose a person to the development of early or younger-onset Alzheimer's Dementia, which generally runs in families," says Dr. Deb. While finding these genetic links has been groundbreaking information for many of the significant forms of Dementia, including Alzheimer's, many genetic links remain unknown.
Dr. Deb emphasizes that genetic predispositions, whether for Alzheimer’s disease-related Dementia or other types of Dementia, don’t guarantee that someone will develop the condition. "Genes alone can’t predict when symptoms will start, how severe they will be, or even if someone will develop Dementia at all. It’s the interaction between genetics and environmental factors that plays a crucial role."
Dementia Genetic Factors
Here’s a breakdown of the specific genes that impact the various types of Dementia.
Alzheimer’s Disease
Alzheimer’s disease is a common cause of Dementia, according to the Centers for Disease Control and Prevention. There are two main types of Alzheimer’s disease: young-onset, which typically appears before age 65, and late-onset, which occurs later in life. Less than 10% of Alzheimer’s disease is inherited, according to researchers in the journal Nature.
While some patients living with young-onset (sometimes also called "early-onset familial Alzheimer’s disease," (EOFAD)) develop the condition from a single genetic mutation passed down in their family, in most cases, inherited EOFAD is tied to an interaction between multiple genes, plus lifestyle and environmental factors.
Genetic mutations in the APP, PSEN1, and PSEN2 genes, alone or in combination, are considered genetic drivers in the risk of developing this young-onset form of Dementia. These mutations disrupt how the brain processes amyloid precursor protein. Typically, the protein is broken down and cleared away, but mutations cause it to build into sticky clumps, known as amyloid plaques. These plaques clog the brain, disrupting cell communication and eventually injuring and killing them.
However, for late-onset Alzheimer’s, the APOE gene, specifically the APOE ε4 variant of this gene, raises the risk of late-onset Alzheimer’s.
Vascular Dementia
Vascular Dementia is an umbrella term for cognitive decline caused by cerebrovascular disease or impaired blood flow to the brain. This form of Dementia may occur following a diagnosed stroke (post-stroke Dementia) or without a history of noticeable stroke but with signs of silent cerebrovascular damage on brain imaging.
While other diseases (like hypertension or diabetes) and environmental and lifestyle factors play a large role in stroke or cerebrovascular disease risk, genetics may also play a role.
One key genetic condition, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is caused by mutations in the NOTCH3 gene. These mutations damage small blood vessels in the brain, increasing the risk of stroke and the possibility of cognitive decline. Other conditions passed down from parents related to Vascular Dementia, such as cerebral amyloid angiopathy (CAA), are linked to genetic mutations, too.
Understanding these and other genetic connections to vascular disease could help to identify people at risk and lead to better tools for prevention and intervention.
Lewy Body Dementia
Lewy Body Dementia (LBD) is categorized into two subtypes: Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD). While both share the same types of brain changes, their symptoms and how they progress differ based on when cognitive decline and motor symptoms begin.
LBD occurs when clumps of a protein called alpha-synuclein accumulate in the brain, disrupting the function of brain cells. These protein clumps, known as Lewy bodies, are the hallmark of both subtypes. Mutations in the SNCA gene, which encodes the alpha-synuclein protein, and the GBA gene have been linked to an increased risk of developing both forms of LBD. The GBA mutation, in particular, may explain why DLB often overlaps with Parkinson’s disease symptoms.
Those living with Parkinson’s disease often exhibit signs of LDB. “Around 30% of people living with Parkinson’s disease have Dementia [at time of diagnosis], but not all patients will experience it,” says Dr. Deb, who also serves as co-chief of the Movement Disorders Division at UMass Chan Medical School. "While many Parkinson’s patients have cognitive impairment, especially in executive functioning, it doesn’t always progress to Dementia." Yet, throughout a lifetime, up to 80% to 90% of people living with Parkinson’s disease eventually develop Dementia by the age of 90, according to researchers in Brain Pathology.
Researchers have also confirmed a steady link to LBD with specific changes in the APOE gene, and two other new gene discoveries have recently been tied to LBD: B1N1 and TMEM175.
Frontotemporal Dementia
Frontotemporal Dementia (FTD) primarily affects the brain’s frontal and temporal lobes, which control personality, language, and behavior. It has several subtypes, including behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA)—all of which are associated with degenerative tissue changes in areas of the brain that support decision-making, behavioral control, emotion, and language.
Up to two in every 10 people living with FTD have a genetic cause, according to the UCSF Memory and Aging Center.
Specific genetic mutations in the MAPT, GRN, or C9orf72 genes are strongly linked to inherited forms of FTD, with C9orf72 being the most common. When FTD is genetic, just one of these genes is affected.
Some mutations are linked to certain FTD subtypes. For instance, MAPT mutations most often present as bvFTD. GRN mutations may result in mixed PPA or nonfluent variant PPA. Finally, C9orf72 mutations are linked to bvFTD with unique tendencies for particular symptoms, such as hallucinations or delusions.
Hope for the Future
As research advances, scientists continue to uncover the complex genetic factors that contribute to the various types of Dementia. This knowledge is opening doors to targeted therapies and more personalized prevention strategies and offering hope for a brighter future for those impacted by Dementia.
Authors' opinions are not necessarily those of the Dementia Society, Inc. We do not endorse nor guarantee products, comments, suggestions, links, or other forms of the content contained within blog posts that have been provided to us with permission, paid or otherwise. Dementia Society does not provide medical advice. Please consult your doctor. www.DementiaSociety.org
Author Bio: Courtney W. Chan is a Boston-based freelance medical writer.
References:
● Interview with Dr. Anindita Deb, MD, Board-Certified Neurologist (Movement Disorder Specialist), Co-Chief of the Division of Movement Disorders, and Associate Professor of Neurology and Neurosurgery at the University of Massachusetts Chan Medical School.
● Centers for Disease Control and Prevention. What Is Dementia? 2024. https://www.cdc.gov/alzheimers-dementia/about/.
● Longitudinal Clinical, Cognitive, and Biomarker Profiles in Dominantly Inherited Versus Sporadic Early-onset Alzheimer’s Disease. Brain Communications. 2023. https://academic.oup.com/braincomms/article/5/6/fcad280/7321528.
● Diagnosis and Management of Dementia with Lewy Bodies: Fourth Report of the DLB Consortium. Neurology. 2017. https://pmc.ncbi.nlm.nih.gov/articles/PMC5496518/.
● Genetics of Vascular Dementia – Review from the ICVD Working Group. BMC Medicine. 2017. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0813-9.
● Nature. 1987: Finding the first Alzheimer’s gene. 2024. https://www.nature.com/articles/d41586-024-02884-7.
● UCSF Memory and Aging Center. Familial Alzheimer’s Disease. https://memory.ucsf.edu/genetics/familial-alzheimer-disease.
● UCSF Memory and Aging Center. Familial FTD. https://memory.ucsf.edu/genetics/familial-ftd.
● The Epidemiology of Dementia Associated with Parkinson's Disease. Brain Pathology, 2010. https://pmc.ncbi.nlm.nih.gov/articles/PMC8094858/.
● Frontotemporal Dementia: A Clinical Review. Seminars in Neurology. 2019. https://doi.org/10.1055/s-0039-1683379.
● Cedars-Sinai. Dementia with Lewy Bodies (DLB). https://www.cedars-sinai.org/health-library/diseases-and-conditions/d/dementia-with-lewy-bodies-dlb.html.
● National Institutes of Health. Genetic study of Lewy body dementia supports ties to Alzheimer’s and Parkinson’s diseases. 2021. https://www.nih.gov/news-events/news-releases/genetic-study-lewy-body-dementia-supports-ties-alzheimers-parkinsons-diseases.
● National Institute on Aging. Alzheimer’s Disease Genetics Fact Sheet. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-genetics-fact-sheet.
● Harvard Health Publishing. Alzheimer’s in the Family: What You Need to Know. https://www.health.harvard.edu/mind-and-mood/alzheimers-in-the-family.
● National Institute of Neurological Disorders and Stroke (NINDS). Lewy Body Dementia. https://www.ninds.nih.gov/health-information/disorders/lewy-body-dementia.
● MedlinePlus. 2 Types of Lewy Body Dementia. 2019. https://magazine.medlineplus.gov/article/2-types-of-lewy-body-dementia.
● Investigation of the genetic aetiology of Lewy body diseases with and without dementia. Brain Communications. 2024. https://academic.oup.com/braincomms/article/6/4/fcae190/7685922.
● Cerebral Amyloid Angiopathy: The Vascular Pathology and Complications. Journal of Neuropathology & Experimental Neurology. 1986. https://doi.org/10.1097/00005072-198601000-00007.
● Cedars-Sinai Medical Center. Autoimmune Diseases in ALS Patients Linked to Genetic Mutation. https://www.cedars-sinai.org/newsroom/autoimmune-diseases-in-als-patients-linked-to-genetic-mutation/.
● Amyloid precursor protein processing and Alzheimer's disease. Annual Review of Neuroscience. 2011. https://pmc.ncbi.nlm.nih.gov/articles/PMC3174086/.
● UCSF Memory and Aging Center. Frontotemporal Dementia. https://memory.ucsf.edu/frontotemporal-dementia.
● An update on genetic frontotemporal dementia. Journal of Neurology. 2019. https://pmc.ncbi.nlm.nih.gov/articles/PMC6647117/.
Comentarios