The ravages of age touch us all — some more lightly than others. Geneticist Henne Holstege wanted to study people with a particular superpower: those resistant to neurodegeneration, despite their age or their genes putting them at high risk.
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At first, she struggled to get funders interested. “For five years, all my grants were rejected,” she recalls. “Each time was a cup of poison.”
But she persevered, convinced that these super-agers could help scientists to understand why a privileged few people manage to avoid conditions such as neurodegeneration, which ail so many in older age.
She finally launched her project in 2013, and ever since, Holstege and others in her field have uncovered a rash of gene variants that seem to protect against dementias.
Researchers are increasingly convinced that understanding resilience to dementia is just as interesting as the more familiar genetics of high risk.
The brain, it seems, has its own defence mechanisms against the toxic proteins that cause Alzheimer’s — mechanisms that scientists now hope to exploit.
They think that protective gene variants will help to illuminate how the disease emerges and worsens — and potentially how to treat it. Of particular interest is a group of variants that affect the workings of the ApoE protein (apolipoprotein E), which carries fat molecules essential for cellular function. Some forms of this protein are long-known contributors to the risk of Alzheimer’s. But some recently discovered and rare variants seem to confer resistance.
“Nature has already done the experiment for us: certain gene variants protect us from Alzheimer’s and they do so safely,” says neuroscientist Guojun Bu from the Hong Kong University of Science and Technology. “Learning how they do this could guide us to new therapies.”
Impervious to plaques
The relentless course of Alzheimer’s disease follows a decades-long progression that is kick-started when amyloid-β proteins in the brain clump into plaques. It concludes with loss of synapses and death of brain cells.
Except when it doesn’t. Just occasionally, people whose brains are full of plaques don’t follow the usual route. They stay free of dementia for most or all of their long lives. A few people don’t even build plaques, even though some might carry gene variants conferring a high Alzheimer’s risk.
In the brain of a person with Alzheimer’s disease (right), amyloid-β proteins clump into plaques, as shown in a magnetic-resonance-imaging scan.Credit: Mark & Mary Stevens Neuroimaging & Informatics Inst./SPL
In the normal course of disease, the amyloid-β proteins in plaques activate immune cells in the brain known as microglia, which try to clear them. But if active for too long, the microglia become inflammatory and start to damage neurons. This, along with other cellular stresses, promotes the build-up and spread of a different, deadlier type of protein, called tau, which forms long, thin tangles. These tangles correlate with the development and severity of dementia symptoms.
Although lifestyle and environmental factors can affect the likelihood of developing the disease, the most powerful influence is genetics.
The exact mechanistic details of how plaques lead to symptoms are still unclear. Gene variants that either accelerate or slow disease could affect many pathways. One such pathway might relate directly to clearance of toxic amyloids or spreading of tau, but could also be acting indirectly, by affecting energy systems in brain cells, for example. “That’s why it is important to identify these variants and discover their exact mechanisms,” says Holstege, who is at Amsterdam University Medical Centre.
Searching the genome
The search for gene mutations that contribute to the risk of Alzheimer’s goes back decades. A small number of Alzheimer’s cases are strongly hereditary, involving mutations in genes that result in a higher proportion of stickier, toxic forms of amyloid-β proteins. Just one copy of any of these mutated genes almost inevitably leads to disease development early in adult life, most often when someone is in their 40s or 50s.
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However, familial early-onset Alzheimer’s accounts for fewer than 1% of all cases; most cases affect people over 65. The APOE gene is the most important genetic determinant of the late-onset form of disease. The protein it encodes, ApoE, is central to lipid transport between cells and around the body. If it does its job properly, it can help to prevent amyloid build-up and clear it from the brain; it can also influence tau pathology, partly through effects on microglia.
Three main alleles of the gene exist, which generate a spectrum of risk. The alleles differ from each other in only one or two nucleotide positions. APOE3 is the most common variant. APOE4 dials the risk up and is the greatest genetic risk factor known. “The particular nucleotide substitution makes the protein it encodes more likely to aggregate and less likely to do its day job of transporting lipids,” says Bu. APOE2 dials the risk down: two copies can delay onset of Alzheimer’s by a decade. Only about 1% of the population has two copies of APOE2.
But however notable the effects of APOE alleles, the vast majority of late-onset Alzheimer cases result from the combined effects of many, often rare, gene variants — some increasing and others reducing disease risk — as well as short stretches of DNA that influence how much each gene is expressed.
Scientists have so far identified only part of the genetic contribution to Alzheimer’s risk. They think that the missing genetics — including numerous but rare variants — might hold some of the most biologically informative clues about resilience.
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The usual way to search for variants is in genome-wide association studies (GWAS), in which scientists analyse millions of spots on the genome for differences between groups — for example, those with disease or at high risk of disease, compared with those who are disease-free or cognitively resilient. These spots are called single nucleotide polymorphisms (SNPs). A SNP can act as a flag for a stretch of DNA that looks different in high-risk individuals than in those who are cognitively resilient.
To search for extremely rare resilience genes, you need sequences from huge numbers of people and sensitive identification techniques. Both have improved in the past decade or so. Hundreds of thousands of genomes from people with and without Alzheimer’s are available from sources such as UK Biobank. “The more people you look at, the more likely you are to spot very rare occurrences,” says Michael Greicius, a geneticist at Stanford University in California.
New cohorts are being put together all the time, and those that include people of Asian, African and other ancestry show significant differences in Alzheimer’s risk genetics compared with predominantly European-ancestry cohorts1.
Greicius’s team has found a rare protective variant known as W276C in a population of people with Native American ancestry, which has not been seen in the other cohorts2. “There’s an incredible amount of power in ancestrally diverse data sets that we miss completely when we myopically focus on European ancestry,” he says.
Not-so-sticky proteins
Once candidate resilience variants have been identified in human genetic studies, scientists begin the lengthy task of working out whether — and how — they might affect disease biology. They mutate these genes in mice or cell cultures and also look for cells or biological pathways that have been affected in donated brain tissue.
A dozen or so rare gene variants have now been verified in this way as likely contributors to Alzheimer’s resilience, although the strength of evidence varies greatly between them. APOE itself has produced some of the clearest examples. Three extremely rare variants of APOE3 have been found in people who seem to escape Alzheimer’s, and one variant of APOE4 seems to neutralize the risk usually carried by that form. All of them are gold dust for scientists. “These rare variants hold the key to understanding how the common risk variants do what they do,” says biochemist Rosie Jackson at the University of Dundee, UK.
The changes to the protein might be tiny, but the consequences are huge. They all affect how the ApoE protein binds to molecules.
ApoE is shaped a bit like a hairpin (see ‘Protective protein’). One arm has surfaces that attract and carry lipids. Once a lipid is bound, the protein opens up and reshapes itself around it. The other arm binds to receptors on cells, allowing those cells to ingest ApoE and use its lipid cargo. These receptors can also take up tau and contribute to its spread between cells.
Sources: T. Kanekiyo et al. Neuron 81, 740–754 (2014); H.-J. Moon et al. Front. Mol. Neurosci. 17, 1399965 (2024).
There are three rare variants found in the APOE3 allele. One is known as the Christchurch variant (after the city in New Zealand in which it was discovered) and it affects the receptor-binding region of the ApoE protein. It is thought to bind ApoE less strongly to receptors, making tau less likely to spread.
The other two rare APOE3 variants influence the lipid-binding section, probably making the protein less sticky and less likely to clump and form plaques.
