Hereditary Alzheimer’s: could rare genes hold the clue to a cure? 

While Alzheimer’s disease and other dementias are not necessarily an inevitable and natural part of ageing, the biggest risk factor for most people in the development of Alzheimer’s disease has long been known to be advanced age. Studies estimate that if a person reaches the age of 90, the likelihood of developing Alzheimer’s increases to between 30%-50%.

Hereditary disposition towards the development of Alzheimer’s is a concern for many with family members who have lived with the disease, but the Alzheimer’s Society makes it clear that for the vast majority of those living with Alzheimer’s, age is the most important risk factor, with genetic susceptibility being of lesser significance.

However, a very small subset of people – less than 1% of those with Alzheimer’s worldwide – do have a genetic disposition towards development of the disease, thanks to three specific mutations in their chromosomes, passed down from their parents. This incredibly rare form of Alzheimer’s is called Dominantly Inherited Alzheimer’s Disease (DIAD). Unfortunately, those who inherit one of these three genetic mutations also develop the disease much earlier in life – often in their 30s or 40s, and sometimes even earlier.

The almost identical pathological nature of DIAD is one reason why those living with it are so important to current wider Alzheimer’s research. Knowing someone is almost certain to develop the disease means the full impact can be studied far in advance of a patient showing symptoms, and without conflicting data from other age-related illnesses.

The Dominantly Inherited Alzheimer Network (DIAN), based out of Washington University School of Medicine in St. Louis in the US, was established in 2008 with the aim of finding solutions to treat or prevent both DIAD, and the wider disease.

“DIAD occurs because of mutations that are identified in three different chromosomes, and these mutations can be passed on in an autosomal dominant fashion, meaning if someone carries one of these mutations, each one of their offspring has a 50/50 chance of inheriting the mutation,” explains DIAN principal researcher and neurologist Dr Eric McDade. 

“Unfortunately with these mutations, if you get it you almost invariably develop the disease. Because of that, it allows us to identify within families that have these mutations a very predictable lineage of who has the disease and who will end up with it.”

Although DIAD is categorised differently than other forms of Alzheimer’s due to genetic inheritability, bar developing the disease at an earlier age the actual symptoms are very similar to more common varieties.

While Alzheimer’s Society research manager Lotty Davies clarifies that everybody’s experience of Alzheimer’s is unique, the main difference between those with DIAD and others living with Alzheimer’s is that younger persons are simply less likely to suffer from other age-related illnesses. She explains: “The difference in younger person is that you're potentially affected at a time of your life where you mobility is still much better, and you're probably still at work, whereas when you’re over the age of 65 you're more likely to be retired, more likely to be living a slower pace of life.”

Adding to the point, McDade notes that older persons are more likely to have other pathologies in their brain, such as evidence of mild vascular disease. A build-up of amyloid plaques and neurofibrillary (or tau) tangles are thought to contribute to the symptoms of Alzheimer’s disease, but in older brains you’re more likely to see other additional proteins, making research and treatment complicated.

“If you find a therapy that targets amyloid plaques that dramatically slows down the onset of symptoms or reverses some of the memory problems, that gives you much greater faith that the therapy has that effect on the disease,” McDade explains. “In an older population, if you do the same thing but they have two or three other pathologies in their brain, that therapy might be working on amyloid, but, because potentially they have other contributing factors to their cognitive symptoms, you actually might miss the true effect of the drug or pathology that you're testing.

It is the near certainty that individuals with this genetic mutation will develop Alzheimer’s that make them so vital to wider study and research efforts hoping to understand and treat the disease.

“Because of the ability to bring in people at all these different phases of the disease, genetic carriers versus those who exhibit mild symptoms versus those who have clear Alzheimer's dementia, we can look at a whole host of other different potential mechanisms,” says McDade. “Whether it is tau, inflammation, the way the body usually gets rid of abnormal proteins in the brain, anything that becomes a hot topic in Alzheimer's disease pathology – this population allows us to look at it across the whole disease spectrum.”

With non-familial Alzheimer’s, any study would have to analyse thousands of people to establish who might be at risk of developing the disease. The DIAD community – while incredibly small at around 600 families worldwide – allows researchers to do the same thing on a much reduced sample size of participants.

While there are three separate mutations that may lead to a person developing DIAD, all three converge on a similar neurological pathway causing an alteration in the production of amyloid protein, leading to amyloid plaques. It is because of this intrinsic link to amyloid that the main focus of the research into autosomal DIAD has been into amyloid proteins.

“We think that with late onset Alzheimer’s, similar to with DIAD, that amyloid protein actually starts to develop 15 to 20 years before symptoms start,” says McDade, “there seems to be a similar trajectory of when that amyloid develops, and how quickly it develops throughout the brain. We think that if it's effective in this Alzheimer’s population, it certainly has the potential to show effects in the prevention phase of the disease before significant symptoms have started. We believe there will be clear translations from this rare form to the much more common form of the disease.”