AAM - Genetics of Alzheimer's

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Alzheimer's disease (AD) is a progressive neurodegenerative condition that is also the most common cause of dementia in the elderly. In most cases, it leads to severe functional deterioration and loss of independence.

Link between genetics and alzheimer

Image Credit: David Carillet/Shutterstock.com


Age is the most important risk factor now known for AD. The prevalence of this condition increases with age, from <3 per 1,000 person-years in the years between 65 and 69 years, to 56 per 1,000 person-years above the age of 90 years.

A tenth of people over the age of 70 have cognitive impairment in the form of memory loss, and it is estimated that about half of them will have AD. This percentage increases to somewhere between one in four and one in two above 85 years. Most of these patients will live less than a decade with dementia.

AD can be of early-onset or late-onset (EOAD and LOAD, respectively). The latter is much more common, beginning over 60 (some say 65) years. EOAD is the cause of 1% to 6% of all cases.

In both these types, some people have a family history of AD. About 60% of EOAD patients have multiple family members with AD, of which more than one in ten show autosomal dominant inheritance over three or more generations. In some cases, families with late-onset disease have shown early-onset AD (EOAD) cases.


The beta-amyloid protein implicated in AD's pathogenesis is a 42 amino acid peptide (Aβ42). It is one of several fragments created from the amyloid precursor protein (APP), such as Aβ40, after cleavage by secretases.

APP is a type-I integral-membrane protein found in several tissues but highly expressed in neural synapses. Though its function remains unknown, it is likely to regulate the formation and impulse traffic through synapses.

Two enzymes, the α-secretase, which catalyzes normal or non-neurotoxic cleavage of the APP, and the β-secretase, which carries out neurotoxic cleavage, facilitate the first step. The second step is the cleavage of this product by γ-secretase to produce beta-amyloid (Aβ).

Genetic Variants of AD

A few autosomal dominant families have shown mutations in single genes. For instance, one family in Colombia had over a thousand members with a single mutation that causes EOAD. This led to the identification of the APOE gene as a risk factor.

Autosomal Dominant AD – Associated Genes

Multiple genes have been associated with autosomal dominant AD but are responsible for less than one percent of cases.

"A large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes." Lars Bertram

The APP gene is on chromosome 21q, the same one implicated in Down syndrome via trisomy. Down syndrome patients develop early AD in their forties, with amyloid deposits being visible.

Over 30 missense mutations have been found close to the Aβ peptide sequence in APP, mostly affecting the secretase cleavage sites or transmembrane domains on exons 16 and 17. These mutations, such as the Swedish and London mutations, are responsible for 10-15% of early-onset familial AD (EOFAD), mostly within specific families, with AD presenting by the mid-forties.

EOFAD mutations mostly cause an altered proportion of Aβ42 levels compared to other Aβ isoforms.

PSEN Mutations

Another type of AD involves approximately 180 PSEN1 missense mutations in about 400 families. These affect the gene at position 14q24.2 that encodes a major part of the complex required for the γ-secretase cleavage of APP. These account for 18% to 50% of autosomal dominant EOFAD.

PSEN1 mutations seem to promote Aβ42 formation over that of Aβ40, thus resulting in lower levels of γ-secretase activity. This oligomer-forming peptide may thus be an early biomarker of AD in the preclinical stage. However, these mutations are associated with the most severe AD forms, being seen in every generation and at early ages, even at 30 years in some cases.

Features of PSEN1-associated AD include not just dementia but parkinsonism. Some families with such mutations also show limb spasticity and seizures.

PSEN2 mutations on chromosome 1 have also been identified but are rarely the cause of EOFAD and cause AD of later-onset relative to PSEN1. Like PSEN1 mutations, these show alternative splicing and are part of the secretase cleavage complex. They appear to cause greater phenotypic variability among patients in affected families, perhaps because environmental factors play a greater modifying role.

Effects of EOFAD Mutations

Currently, 24 APP mutations, 185 PSEN1, and 13 PSEN2 mutations have been reported. All of these cause an increase in the ratio of Aβ42:Aβ40, and one boosts the levels of multiple types of amyloid, including Aβ, thus causing Aβ aggregation. Aβ42 is more likely to form oligomers and eventually amyloid fibrils compared to Aβ40.

Neurofibrillary tangles due to tau protein hyperphosphorylation are also common in the brains of AD patients. This microtubule-associated protein forms insoluble aggregates after phosphorylation.

Sporadic AD

More than 90% of AD are sporadic LOAD cases, apparently resulting from interactions between multiple genes and environmental factors. The immediate relatives of patients with late-onset disease do not show a Mendelian pattern of inheritance.

No single gene has yet been identified that can be blamed for this condition. Several apolipoprotein E (APOE) gene variants on chromosome 19q13.2 have been associated with sporadic LOAD. Still, other interacting risk factors are undoubtedly involved since the risk allele APOEε4 is found in many people who live to be 90 or more.

This gene is key to cholesterol and triglyceride metabolism and distribution in the human body, and the APOE ε4 allele is linked to higher blood cholesterol levels. The three APOE ε4 alleles (ε2, ε3, and ε4) are thought to cause amyloid aggregation and tau hyperphosphorylation potentially.

This gene is the single most important risk factor for LOAD, but its APOE ε4 allele is neither essential nor sufficient to cause AD. Rather, it reduces the age of onset of AD in a dose-dependent manner.

In the brain, apoE is required to remove bad fats from the circulation for their breakdown. However, when bound to lipid in the brain, apoE attaches itself to amyloid-beta aggregates, depending on the specific isoform, which promotes Aβ removal.

Individuals with APOE ε4 show higher levels of amyloid and tangles, with more mitochondrial damage. The number of copies of this allele is proportional to the risk of AD in the above-65 individual with a positive family history of the condition.

With one APOE4 gene, the risk of AD is 3-4 times higher relative to those with two APOE3 genes. A single APOE2 gene reduces the risk, conversely, relative to two APOE3 genes.

Conversely, the APOE 3/3 profile increases the risk of AD development by the age of 90 years threefold or more than a single APOE ε4 allele, suggesting the crucial role of other factors than APOE alone. The risk among family members of an individual homozygous for APOE ε4 (which is uncommon) is 44% by the age of 93, again demonstrating that half the people carrying one or more copies of this allele are spared AD.

The ε4/ε4 genotype carries the greatest risk for AD among those with a positive family history. It is found in about one percent of Caucasians, vs one in five people in communities with familial LOAD, Blacks and Caribbean Hispanics.

About 40% of those with LOAD lack even one ε4 copy of the apoE gene, while those with one copy have a lower risk of AD by the age of 87. With LOAD, first-degree relatives have a lifetime risk of one in four to one in five of AD, compared to one in ten in the rest of the population.

Women have a 45% chance of AD by the age of 73 with this ε4/ε4 genotype, but only one in four men. Other genes in the vicinity have been proposed to cause a higher AD risk, but this is considered less likely than the involvement of APOE itself.

The genetics of Alzheimer's disease and frontotemporal dementia - Prof Stuart Pickering-Brown

GWAS Testing

Overall, 15 genes show GWAS significance, but the disease-enhancing or causing variants are known for only four: APP, PSEN1, and PSEN2 for EOFAD, and the APOE for LOAD.

Many other genes show technically significant associations with increased AD risk, of which ten show the strongest links. These include SORL1 (sortilin-related receptor), ACE (angiotensin-converting enzyme 1), and Interleukin 8 (IL8).

Using the genome-wide association study (GWAS), as many as one million genetic markers (single nucleotide polymorphisms, SNPs) have been tested for AD risk, yielding ATXN1 (ataxin 1) and CD33 (siglec 3), among others. AD scientist Tanzi identified APOE and CD33 as the only genes that showed GWAS significance among families and case-control series. Both protective and high-risk single nucleotide changes have been reported.


Further Reading

Last Updated: Sep 9, 2021

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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