6.7 million Americans at risk of genetic Alzheimer's with 95% strike rate

6.7 million Americans at risk of genetic Alzheimer's with 95% strike rate
This research has huge implications for millions of Americans
This research has huge implications for millions of Americans
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This research has huge implications for millions of Americans
This research has huge implications for millions of Americans

An incredible new study has upended our understanding of genetic Alzheimer's disease, finding that nearly everyone carrying two copies of a culprit gene had distinct biological markers of the degenerative condition by the age of 65. This means the APOE4 gene may no longer merely a risk factor but the driver behind a new stand-alone genetic Alzheimer's disease type that could impact up to 10 million Americans and more than 200 million people worldwide.

"This gene has been known for over 30 years and was known to be associated with an increased risk of developing Alzheimer's disease," said Dr. Juan Fortea, director of the Memory Unit of the Neurology Service at Sant Pau Research Institute in Barcelona, Spain. "But now we know that virtually all people who have this duplicated gene develop the biology of Alzheimer's. This is important because they are between 2 and 3% of the population."

Essentially, if the team's thorough study reflects a wider population, that 2-3% is between 6.62 and 9.93 million Americans. And it all comes down to the genetic lottery of inheriting the same type of APOE gene from both parents.

There are three forms of APOE genes, which code for a protein called apolipoprotein E. This is a vital mechanism that enables the formation of lipoproteins, which transport healthy, essential cholesterol around the bloodstream. There are three common forms of APOE – e2, e3 and e4, all distinct alleles that have varying risks of Alzheimer's Disease (AD). At one end of the spectrum is e2, which reduces risk of developing AD, in the middle is the most common e3, which has no impact on disease prevalence, and then e4, which has been so implicated in AD that it's appearance is colloquially known as the 'Alzheimer's gene.'

Famously, actor Chris Hemsworth revealed in 2022 that he'd inherited two copies of the 'Alzheimer's gene' APOE4 – something that drastically increased general awareness of its hand in the likelihood of developing the disease.

Historically, it's believed that inheriting one APOE4 gene variant increased your risk of developing AD to about 15-20%, compared to a population's overall risk of 10-15%. Two copies of the e4 allele – which form a homozygous APOE4 variant – was estimated to bump the chances of developing AD by age 75 up to 35%.

But the Sant Pau Research Institute researchers, led by Dr. Fortea, have found that almost all APOE4 homozygotes showed AD pathology and high levels of AD biomarkers by the time the carrier was 55 years old. By 65, more than 95% of APOE4 homozygotes had "abnormal" levels of beta-amyloid in cerebrospinal fluid, a telltale early diagnostic measure of the onset of AD. And 75% returned positive amyloid scans, showing an accumulation of plaques.

These findings emerged after the team assessed the clinical, pathological and biomarker changes that are evident in the brains of people with APOE4 homozygosity. Data was gathered from 3,297 brain donors, including 273 APOE4 homozygotes, for the pathological study and 10,039 people drawn from five large European and US cohorts for the clinical and biomarker analyses, featuring 519 APOE4 homozygotes.

Because almost all APOE4 homozygotes revealed "near-full penetrance" of the disease's pathology and biomarkers, the researchers now believe that this variant is not just a serious risk factor but the root cause of a type of AD.

"Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined AD, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical change," the researchers noted in their paper.

The study found that people with the paired APOE4 variants had far more 'sticky' plaques – essentially, signs of AD – in their brain by the age of 55, compared to individuals with one APOE4 and one "neutral" APOE3 variant. And for those who developed AD symptoms, the cognitive decline was evident at age 65, up to a decade earlier than seen in people with other APOE combinations who developed the disease.

The researchers also found that this APOE4-homozygote had a similar disease fingerprint to the other known genetic AD types. As it stands, less than 1% of AD cases are singularly genetically determined, and the result of very rare mutations in APP, PSEN1 and PSEN2, which almost always leads to early-onset AD type (autosomal dominant AD).

And while twice as many women as men develop AD in their lifetime, for a variety of reasons, here the researchers found no discrimination based on sex in the APOE4 homozygotes cohort.

The majority of AD, until now, has been viewed as a mixing pot of variable risk depending on APOE genes, as well as lifestyle, environmental and other emerging influences that trigger the brain's advanced cognitive decline. But the researchers say their results indicate APOE4 homozygosity is not just a risk factor but has all the biological hallmarks of being a type of inherited AD.

"This study provides comprehensive evidence to propose APOE4 homozygotes as another form of genetically determined AD, similar to ADAD and Down syndrome associated Alzheimer’s disease (DSAD)," the researchers wrote.

"These data represent a reconceptualization of the disease or of what it means to be homozygous for the APOE4 gene ," Fortea concluded. "This reconceptualization of the disease is similar to the one we proposed from Sant Pau with Down's syndrome, which a few years ago was also not considered a genetically determined form of Alzheimer's."

The researchers hope their potentially very important study will now lead to clinical trials, new treatments and individualized medicine and prevention measures to mitigate the disease's biology in paired APOE4 homozygote carriers.

"The data clearly show that having two copies of the APOE4 gene not only increases the risk, but anticipates the onset of Alzheimer's, reinforcing the need for specific preventive strategies," said Dr. Alberto Lleo, a researcher in the hospital's Dementia Neurobiology Group.

"The findings emphasize the importance of monitoring APOE4 homozygotes from an early age for preventive interventions," added another of the study's researchers, Dr. Victor Montal.

The study was published in the journal Nature.

Source: Sant Pau Research Institute

The more we find out about all of these diseases, the more we discover just how much many of them are pre programmed into us...
My grandfather died from Alzheimer's, and I took care of my father for seven years before he died from Alzheimer's. I have already adopted all of the known measures to reduce my risk, so knowing if I have the gene won't have any effect on my life other than adding stress. I'd rather just live a healthy lifestyle and let the chips fall where they may. However, if they come up with a treatment based on the gene, then I may be interested in knowing if I have it. Otherwise, I'm already doing everything that can be done to prevent it.

I kind of doubt I have the combination of genes they describe since they said everyone who had it showed definitive symptoms of Alzheimer's by 55. Both my grandfather and father did not show definitive symptoms until their mid to late 70s. In fact, when a neurologist first examined my father at 75, he could only diagnose "mild cognitive impairment" which could have been caused by any number of things. His symptoms were so minor as to not clearly be identifiable as Alzheimer's. That and the fact my father was a poster boy for Alzheimer's risk factors (overweight, bad diet, sedentary, former smoker, sleep apnea, type II diabetes, high blood pressure, etc.) makes me think I may have a higher genetic risk but not a certainty.

And I'm nearing the age where I would see definitive symptoms if I have the genes they studied. To my knowledge, I don't have any symptoms. Then again, if I have Alzheimer's, maybe I have the symptoms and just don't know it. [humor]
I'm sure Trump has these genes. Both of his parents died from Dementia or Alzheimer's. then too he has been exhibiting a lot of brain fog of late so maybe it could be a worm in the brain like Kennedy had.
i'm 60. both of my parents died of alzheimer's. i likely have two copies of the gene. (awaiting 23 and me results). this is very depressing news because there is, thus far, no way to prevent it. i remember not so many years ago being "reassured" that alz was not genetic...i knew that wasn't true then, but i hate being right, now.
also, what effect, if any, does apolipoprotein e have on cholesterol?
could statins or other cholesterol lowering drugs have an effect?