Genetics of dementia
Open accessAbstract
25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling.
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People with one copy of the APOE-e4 form have about three times the risk of developing Alzheimer's compared with those with two copies of the e3 form, while those with two copies of the e4 form have an estimated eight- to 12-fold risk.
“Those who inherit one copy of the e4 form have about three times the risk of developing Alzheimer's compared with those with two copies of the e3 form, while those who inherit two copies of the e4 form have an estimated eight-to 12-fold risk.[73][74][75]”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [73]
In “Advice for the other families,” the paper reports threefold risk for ApoE E3/E4 and eightfold risk for E4/E4, each compared with E3/E3. It supports the one-copy estimate and the lower end of the two-copy range, but does not give a 12-fold estimate. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPeople who have or had a parent or sibling with Alzheimer's are more likely to develop the disease than those without a first-degree relative with Alzheimer's.
“However, individuals who have or had a parent or sibling (first-degree relative) with Alzheimer's are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer's.66,73”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [73]
In “Advice for the other families” (page unavailable), the paper says that people with a first-degree relative with Alzheimer’s disease have roughly 2.5 times the lifetime risk of dementia. It does not specifically report an increased risk of developing Alzheimer’s disease, as the citing sentence claims. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIndividuals who have or had a first-degree relative with Alzheimer's dementia are more likely to develop Alzheimer's than those who do not have a first-degree relative with Alzheimer's dementia.
“However, individuals who have or had a parent or sibling (first‐degree relative) with Alzheimer's dementia are more likely to develop Alzheimer's than those who do not have a first‐degree relative with Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [81]
In “Advice for the other families” (page not provided), the review says that having a first-degree relative with Alzheimer’s disease is associated with roughly 2.5 times the lifetime risk of dementia. It reports risk of dementia generally, not specifically the risk of developing Alzheimer’s disease as the citing sentence states. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe main genetic risk factor in sporadic Alzheimer's disease is the APOE gene.
“the main genetic risk factor in SAD is the APOE gene [91,92,93,94].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [92]
Having the e4 form of APOE increases one's risk of developing Alzheimer's dementia compared with having the e3 or e2 forms but does not guarantee that an individual will develop Alzheimer's dementia.
“Having the e4 form of APOE increases one's risk of developing Alzheimer's dementia compared with having the e3 or e2 forms but does not guarantee that an individual will develop Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [81]
APOE-e4 has the strongest impact on risk of late-onset Alzheimer's dementia among the many genes that increase risk.
“Of the many genes that increase risk, APOE‐e4 has the strongest impact on risk of late‐onset Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [81]
The risk of developing Alzheimer's dementia increases with inheriting one copy of the e4 form and increases further still with inheriting two copies of the e4 form, compared with inheriting only copies of the e2 or e3 forms.
“In general, the risk of developing Alzheimer's dementia increases with inheriting one copy of the e4 form and increases further still with inheriting two copies of the e4 form, compared with inheriting only copies of the e2 or e3 forms.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [81]
APOE-ε4 alleles are associated with accelerated Aβ-deposition and earlier onset and higher risk of developing AD symptoms.
“APOE-ε4 alleles are associated with accelerated Aß-deposition and earlier onset and higher risk of developing AD symptoms.21,23”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [21]
Familial autosomal dominant AD is rare (<1%), usually manifests in early-onset AD (onset age <65 years; <4% of AD), and is caused by mutations in presenilin 1, amyloid precursor protein, or presenilin 2.
“Familial autosomal dominant AD is rare (<1%), usually manifests in early-onset AD (onset age <65 years; <4% of AD), and is caused by mutations in presenilin 1, amyloid precursor protein, or presenilin 2. 21”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [21]
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References 144 · Cited by 342
- Authors
- Loy, C. T., Schofield, P. R., Turner, A. M., & Kwok, J. B.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Sydney Children's Hospital (AU)
- Corresponding author
- Kwok, John BJ
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 383
- Issue
- 9919
- Pages
- 828-840
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2000445641
- Cited by
- 342
- References
- 144
- Citations by year
- 2026: 12 · 2025: 31 · 2024: 37 · 2023: 32 · 2022: 26 · 2021: 28 · 2020: 35 · 2019: 35 · 2018: 24 · 2017: 19 · 2016: 20 · 2015: 22 · 2014: 19 · 2013: 1 · 2012: 1
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- NHMRC Project (510218)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- dementia genetics, familial dementia, Alzheimer's disease, frontotemporal dementia, genetic testing, genetic counseling, APP gene, presenilin 1, presenilin 2, MAPT, gene regulatory networks, C9orf72, autosomal dominant inheritance, family history (medicine)
- MeSH terms
- Aged, Alzheimer Disease, Dementia, Genetic Counseling, Genetic Testing, Humans, Genetic Linkage, Middle Aged, Mutation, Pedigree, Phenotype, Genetic Variation
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