Genetic Testing in the fight against Alzheimer’s

Alzheimer’s disease is a neurodegenerative disease responsible for most cases of dementia. Neurodegenerative diseases cause memory loss, behavioral disturbances, and general cognitive decline.

Alzheimers Disease

Alzheimer's Disease. Image Credit: Juan Gaertner/

Early-onset Alzheimer’s disease is almost entirely influenced by genetics, whilst late-onset Alzheimer’s disease has much less genetic influence, with the biggest risk factor being age. Genetic testing has long played a part in the prediction of early-onset Alzheimer’s disease, but the development of next-generation sequencing technology provides much greater insight into potential risk factors.

There are two distinct types of Alzheimer’s disease (AD); late-onset AD, the more common of the two, occurs later in life and has a more heterogeneous presentation. Late-onset AD is difficult to predict, as it occurs as a combination of genetic and environmental factors, alongside the natural degenerative process of aging. In contrast, early-onset AD typically presents earlier, and many cases of early-onset AD can be attributed to mutations in particular genes involved in the metabolism of amyloid-beta, the protein that forms the plaques in the brain that characterize AD.

Genetics of early-onset Alzheimer’s disease

Early-onset AD typically presents before the age of 65. It is much rarer than late-onset, accounting only for up to 6% of cases. Early-onset AD typically shows an autosomal dominant inheritance pattern with mutations in one of three main genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Mutations in PSEN1 account for 80% of cases of early-onset AD, whilst APP mutations account for around 15% and PSEN2 mutations are much rarer, accounting for around 5% of cases.

Genetics of late-onset Alzheimer’s disease

Late-onset AD, also known as sporadic AD, accounts for over 90% of cases of AD. It typically presents later, with symptoms showing after the age of 65. Sporadic AD does not share the same genetic inheritance as early-onset AD, as development is thought to be a combination of genetic factors, environmental factors, and aging. Despite this, one particular gene has been demonstrated to be associated with sporadic AD, apolipoprotein E (APOE).

APOE has four common alleles, of which ε4 is known as a risk or susceptibility allele. This means that people who have the ε4 allele have a higher risk of developing sporadic AD than the general population. This risk is around four times as high for those with one copy of the allele, and around fifteen times as high for those with two copies of the allele.

The risk is also higher in women than men, meaning that a woman with two ε4 alleles has an approximate 45% chance of developing AD by the age of 73. Although there is a strong association, ε4 is not sufficient alone to cause AD, nor is it necessary. Other risk alleles have been studied, but none as extensively as the APOE gene.

Genetic testing for Alzheimer’s disease

Genetic testing is not sufficient for an AD diagnosis, which requires the presence of neurophysiological features, however, those with affected family members can undergo genetic testing. For early-onset AD, Sanger sequencing can be used to sequentially test the three main genes in order of likelihood (PSEN1, APP, then PSEN2).

For late-onset AD genetic testing is not recommended, as the presence of the risk allele does not necessarily result in disease so can cause unnecessary psychological harm. Despite not being sufficient for a diagnosis, genetic testing can still be helpful in that it may identify the causal factor, which may inform the person and their family to how the disease may progress if the person is eligible for clinical trials, and perhaps in the future, which treatments would be most effective.

The study of AD has long involved genetic testing, with the genes PSEN1, PSEN2, and APP all being identified through early linkage studies. Historically, genetic testing has been very specific and targeted to one gene, though advancements in sequencing technologies and the development of next-generation sequencing mean that now massively parallel testing can take place, looking at many different genes at the same time, or even the whole genome.

Genome-wide association studies (GWAS) have been key in recent years for identifying potential candidates for risk alleles. Many susceptibility loci which may confer a small increase in risk have been identified in this way, although those identified still do not apply to many cases. It is believed that some of these cases are caused by very rare mutations that have been difficult to identify but may have a large effect. As a result of this, some effort is being focused on whole genome and whole exome sequencing to identify these variants that may previously have been missed.


Early-onset Alzheimer’s disease is almost completely genetic, with mutations in three known genes. This makes genetic testing straightforward for predictive purposes, and also provides key information about the mechanism through which the disease develops. Knowledge of the genetic basis of the disease provides important information that can inform the development of potential treatments, that can be targeted to those faulty genes.

Conversely, the genetic component of late-onset Alzheimer’s disease is less well understood. Whilst one important risk allele has been identified, there may be many others that remain undiscovered. Genome-wide association studies and next-generation sequencing technologies have paved the way in identifying new variants that may be involved, but, likely, there are still rare variants that will only be identified with increased genetic testing.


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Further Reading

Last Updated: Apr 12, 2021

Morgan Rustidge

Written by

Morgan Rustidge

Morgan completed her BSc in Genetics at the University of Sheffield in 2019, fuelled initially by an interest in genetic diseases. As part of her undergraduate degree, she also studied aspects of Microbiology, Molecular Biology, and Biochemistry.


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