A field explainer on blood-based Alzheimer’s biomarkers, with an assay-development lens on what actually limits plasma Aβ42/40 performance.
For decades, confirming Alzheimer’s pathology meant a lumbar puncture or a PET scanner. In 2025, that changed. The FDA cleared two blood tests, Fujirebio’s plasma p-tau217/Aβ42 ratio in May and Roche’s p-tau181 as a primary-care rule-out in October, and the Alzheimer’s Association published its first clinical practice guideline for blood-based biomarker tests in specialized care. A blood draw can now triage the pathology that used to require an imaging suite. But the two markers doing the work aren’t equally easy to measure, and this post is about the harder one: plasma amyloid-beta.
That’s a real milestone — and it’s where the interesting part starts. This post explains why plasma amyloid-beta is analytically unforgiving, and what that implies for assay design and interpretation.
Two Analytes, and Only One Is Easy
The blood workhorses are plasma p-tau217 and the amyloid-beta (Aβ) 42/40 ratio. p-tau217 is ascendant, and the reason is analytical: it runs roughly 3.6 to 5 times higher in amyloid-positive people than in controls, so the signal separates cleanly, and it stays stable in a tube for days.
Amyloid-beta is the harder one, but it earns its place. Amyloid moves early, accumulating years before tau pathology and before symptoms, which makes the Aβ42/40 ratio the marker of interest for preclinical detection and prevention trials, exactly the settings where catching disease early matters most.
Why Plasma Amyloid-Beta in Blood Is Genuinely Hard
Three problems stack up. Plasma Aβ42 sits at roughly 8 to 30 pg/mL, which is very low. The difference between an Alzheimer’s-positive and an Alzheimer’s-negative sample is only about a 10 to 15 percent shift in the ratio, which is very small. And plasma is a hostile matrix: albumin binds amyloid, heterophilic antibodies interfere, and the ratio starts degrading within hours at room temperature.
Put those together and the limiting factor is not what most people assume. It isn’t sensitivity. It’s precision. To resolve a 10 percent difference reliably, your assay’s coefficient of variation has to stay near or below about 5 percent, in a matrix that is actively working against you. A method can detect vanishingly small amounts of amyloid-beta and still misclassify patients if its precision drifts.
What That Reframes About Methods
This is the part worth sitting with. Reaching a low limit of detection is necessary, but it is not sufficient. Sensitivity gets amyloid-beta onto the scale; precision and matrix tolerance decide whether the number means anything.
It is why the platforms that lead on plasma Aβ42/40, single-molecule digital immunoassays like Simoa and immunoprecipitation mass spectrometry, are built for precision and matrix control, and why they cost what they cost: a digital analyzer runs a few hundred thousand dollars, and mass spec lives in specialized labs. Signal-amplified ELISA sits in a different niche. It brings more sensitivity to labs that already run plate ELISAs and can’t justify that capital, with one honest catch: a complex plasma matrix can suppress the amplification gain, so sensitivity won in buffer doesn’t fully carry over to blood.
A Thesis Doing Exactly This Work
A recent master’s thesis is a clean example of the category. (Disclosure: Cavidi supervised the work, and we’re using it here as a feasibility-stage worked example) At Uppsala University in 2026, Annie Sernelin developed a nucleic-acid-based signal-amplified ELISA, Cavidi’s Exazym® with its BOLD (Binding Oligo Ladder Detection) technology, for plasma amyloid-beta. The honest results: background dropped from about 0.6 to 0.1 OD, signal rose two- to ten-fold over the standard ELISA, and the assay reached an initial lower limit of quantitation around 1.4 pg/mL, comfortably below the plasma Aβ42 range.
In other words, it cleared the sensitivity bar. And the thesis is candid about what is left: precision and performance in complex matrices need more work before this is a research or diagnostic tool. That is not a caveat to bury. It is the field’s central challenge, stated plainly by the person who did the bench work, which is exactly what discovery-stage science should look like.
What to Keep Straight
A field this fast-moving generates overstatement, so three things are worth holding onto.
Blood tests are triage and adjuncts, not replacements for PET or CSF, at least not yet. The best cleared test still returns an indeterminate result for roughly one in five patients, and real-world false positives are real.
A lower detection limit does not equal better precision. For amyloid-beta, precision is the number that decides clinical usefulness.
And it is the Aβ42/40 ratio that carries the signal, not absolute Aβ42, which is confounded by how much amyloid a person produces in the first place.
If you’re evaluating a plasma Aβ42/40 method, look first at four things: within-run and between-run CV at the concentrations that matter, matrix and interference controls, pre-analytical handling stability, and ratio performance, not just the Aβ42 detection limit.
Signal amplification is a rational, accessible way to push a standard ELISA lower, and for plasma amyloid-beta it is early-stage feasibility work: a clear technical rationale and encouraging first data, not a finished answer. In a field this prone to hype, saying so is the point.
Want to learn more about Exazym®?
See how BOLD signal amplification works →
Read Annie Sernelin’s thesis on the DiVA archive →
Evaluating a low-abundance biomarker in a tough matrix and want a second set of eyes? Talk to the Exazym Support Team → · support@cavidi.se