As a New RNA Biomarker Test for Alzheimer’s Nears, I Can’t Help but Wonder if my Grandmother Was Better Off Not Knowing

My grandmother had what must have been Alzheimer’s disease, but no one ever called it that.

When I visited her in the 1970s from college, all I’d noted was that her mind was in the past. She still appeared to remember me and my husband-to-be Larry, but she would repeat the same stories from her deep, deep past every time we saw her – about my then sixty-something uncle Bernie who’d lost his coat when he was 6 years old. As a budding biologist, I was transfixed by the brain’s ability to conjure great detail in a very distant memory. I didn’t think of her as being sick, as having a disease.

Grandma Sarah was extremely fortunate to have spent her final months in what may have been one of the first dementia facilities at what was then Long Island Jewish Medical Center, now Northwell Health. My two uncles – her sons – were prominent physicians there, and they made sure that their mother had the most expert care available at the time.

Although Alzheimer’s disease was officially named in 1910, I’m glad my mother and uncles never uttered that term, at least to me, to describe my grandmother. My uncles had to have known.

My mother only rarely used the word dementia to describe her mother. And to me, my grandmother wasn’t sick. She was just Grandma Sarah, living in the past, happy to have her many visitors. A spinal tap, brain scan, blood marker test, or a disease name weren’t needed to see that she was losing some of who she was, transitioning, painlessly, to who she had been, to a happier time, when two of her four children were very young. I like to believe that she was at peace, her brain somehow, protectively, returning, again and again, to a cherished memory.

For more the past 15 years, diagnosing Alzheimer’s disease has included assaying levels of two telltale proteins, amyloid beta and tau. Now, RNA is being tracked too. Researchers at the Icahn Genomics Institute at Mount Sinai have identified patterns of RNA-containing nanoparticles in the blood that may serve as a new type of biomarker for impending Alzheimer’s disease. The report appears in the June 22 Nature Communications.

My Recent Experience with Alzheimer’s Testing

A few months ago, I began revising the most complicated chapters of my human genetics textbook, the ones that update CRISPR and other biotechnologies. New editions have evolved into simpler revisions as paper books have become extinct. I’m a long-time author – the term content creator is demeaning.

I’ve been writing and revising this book since I scribbled the table of contents on a napkin at a publishing meeting circa 1990, so swapping in new examples, cases, and stories should be a no-brainer. Yet this time around, I found myself repeating revisions I’d already written. Most alarming was my addition of the recent case of a young woman from a prominent family whose chromosome 3 had spontaneously inverted, placing a sleeping oncogene next to a gene that revs up cell division. The result was a deadly leukemia.

I wrote the leukemia story on a Wednesday, scribbling in red marker in an actual paper textbook in the upper left corner of a page.

On Thursday morning, I picked up where I’d left off. And in the lower right corner, in green marker, I scribbled in the details of the case. Then I sat back and noticed the other add-in-edit in the upper left corner of the page. I’d written the same story, with disturbingly few differences – but enough to reveal that I’d completely forgotten that I’d already written up the case.

After this happened a few more times, I made an appointment with a neurologist.

I “aced” all the cognitive tests, just like our brilliant president, exhibiting a heretofore unrecognized special flair for rapidly counting backwards from a random number by 7s. The PA was astonished, but couldn’t stump me with math. And I lucked out – the “name as many animals as you can in one minute” challenge was easy for a biologist. I easily babbled out a rapid-fire roster of insects and rare mammals. I shudder to think how I would have fared if asked to name car parts or members of a football team.

Then, the PA took my blood to look for levels of the telltale Alzheimer’s biomarker proteins. I requested the new early Alzheimer’s test that probes the ratio of standard biomarkers amyloid beta and tau, but apparently Medicare wasn’t quite up to date – I had to settle for the older amyloid 42/40 ratio. But that was okay. I was right in the middle range of normal. (DNA Science covered new Alzheimer’s tests here.)

Disclosure: For a few years I participated in the Alzheimer’s Disease Neuroimaging Initiative, and was even a spokesperson, describing how the study had identified two brain tumors in a friend, saving her life. Participation entailed taking cognitive tests every 6 months, then, eventually, brain scans, like my friend had had. You have to listen to a short story and then repeat it. My story, the day ADNI fired me, was about a little girl finding a fossil – something that had actually happened to me, so you’d think I’d remember it. Well, my husband decided that would be a good time to clean out the cat box just a few feet away from me, shattering whatever concentration I had with the repetitive motion of scraping feline feces from the bottoms of the boxes. I had a meltdown, screaming about cat shit, all thoughts of little girls and fossils leaving my brain. So I failed. An email soon informed me that the study was over — which apparently it isn’t.

A Tale of Two Proteins

Quick review: In Alzheimer’s disease, two types of protein accumulate in brain neurons. Amyloid beta forms plaques outside neurons, while tau forms tangles mostly inside the cells, particularly in the emanating axons.

Some brain regions become more blocked in proteinaceous gunk than others – the amygdala (seat of emotion) and hippocampus (the memory center) are especially vulnerable. Changes also unfold among the several types of glial cells that are part of the brain.

FDA approved two drugs that can slow the progression of Alzheimer’s disease by targeting amyloid beta: Leqembi (lecanemab) in 2023 and Kisunla (donanemab) in 2024. Both are infusions. Symptoms may progress once treatment stops, and long-term effects aren’t yet known.

A year later, new blood tests came along. One assay measures the ratio of specific variants of tau and amyloid, and the most recent test assesses the level of pTau181. The number denotes a phosphate (a phosphorus atom bound to three oxygen atoms) attached to the 181th amino acid in the sequence of Tau protein.

For now, pTau181 testing is used to rule out eventual Alzheimer’s in patients with mild cognitive impairment (MCI) or mild dementia. It isn’t yet clear what elevated pTau181 means in an individual with normal cognition. Investigations that look backwards from people with Alzheimer’s indicate that elevated tau is a highly predictive biomarker. So people with Alzheimer’s once had elevated pTau181, but not everyone with greater-than-average levels of the biomarker goes on to develop Alzheimer’s. Time will tell.

RNA Reflects Gene Expression as a Disease Unfolds

RNA biomarkers in blood are joining amyloid and tau proteins in revealing early Alzheimer’s changes. Unlike the slow buildup of these diagnostic proteins, RNA is a more fleeting molecule, its levels reflecting the undulations of a particular gene’s expression as a pathological process progresses. The collective set of mRNAs in a cell at any given time is termed its transcriptome; transcription means RNA synthesis.

(Another quick review: DNA encodes RNA, which encodes proteins, such as tau and amyloid. So mRNA levels and identities, aka gene expression, mirror what’s going on in a body.)

In 2007, researchers identified RNA molecules outside cells, transported in body fluids in tiny membranous bubbles called extracellular vesicles (EVs). The surface is identical to that of a cell membrane – a lipid bilayer with embedded proteins and sugars. EVs can harbor bits of DNA too. Another mode of transport, an extracellular particle (EP), does not have the outer membrane – it’s more like a simple bubble.

DNA, RNA, and proteins can also travel in the bloodstream unfettered, dubbed “cell-free.” These bits of bloodstream matter, once discarded as debris, may be emissaries of gene activity and provide clues to physiology – and pathology.

The surfaces of vesicles and particles are festooned with “molecular signatures” that indicate the cell type of origin, a little like a person wearing a tee shirt from a college or town. And surface features can function as biomarkers.

EVs reflect activities at their sources. Circulating EVs from the brain offer a soup of biomarkers that reveal not only how cells are communicating, but how efficiently brain tissue is clearing out damaged cells – such as telltale plaques and tangles. More specifically, EVs in a blood sample can reveal the high levels of pTau181 that may foretell Alzheimer’s disease.

The New Findings

The Mount Sinai researchers compared RNA and protein signatures from EVs in brains and blood of 26 deceased individuals, 10 of whom had died of Alzheimer’s disease.

Their main question: could the circulating RNAs act similarly to a “liquid biopsy” used to detect tumor DNA in a blood sample? Indeed, they could. And the team discovered a variety of small blood nanoparticles, dubbed “SECmeres,” which carry the telltale molecular signs of Alzheimer’s-related brain signals more clearly than do standard extracellular vesicles. Detecting these nanoparticles, enriched with brain-specific markers, may offer a minimally invasive way to diagnose the beginnings of Alzheimer’s.

“SECmeres may hold promise as a real-time, non-invasive diagnostic tool for the living human brain. Our study demonstrates that blood EVPs (extra-vesicular particles) carry brain-specific RNA information that could be used for liquid biopsy approaches, pending validation in larger blinded clinical trials. EVP-derived RNAs may reveal disease-related changes earlier in the disease process, before proteins or pathology become detectable,” said investigator Navneet Dogra.

The several new ways to detect early or even future Alzheimer’s disease are astonishing. Will that knowledge enable intervention? I can’t help but wonder whether my grandmother was better off not knowing.

NOTE: I’ve just learned that my blog DNA Science, which I’ve written since 2012, is being discontinued, along with other PLoS blogs. I’m sad. But I will continue to post my thoughts on genetics occasionally at my website, www.rickilewis.com. I’m open to finding a new blog host!