Legislation watch: A bill is introduced which would cover preventive screening with blood tests for Alzheimer's disease.

The legislation -as proposed - would create a new benefit at 1861(s)(2), under KK, Alzheimer early detection test (follows the recently added JJ, lymphedema compression services). And (nnn) defines these as proteomic, genomic, etc - very broadly.

###

From Aspirational Biomarkers to Attainable Analytics: Why AD Blood/CSF Assays Finally Work

Early Alzheimer biomarker research (1980s–2000s) consistently produced intriguing biological hypotheses but rarely reproducible clinical assays. The failure was not principally conceptual; we already understood that tau hyperphosphorylation and Aβ42 dysregulation were tightly coupled to disease progression. Rather, the failure was technological—we simply could not measure the relevant molecular analytes at the required concentrations, nor could we control the biochemical environments that distorted them.

The difference between those early assays and current success is best understood as a convergence of three domains:

Analytical sensitivity
Analytical specificity
Pre-analytical stability and standardization

1. Analytical Sensitivity: The Concentrations Were Below the Floor

The most striking feature of modern Alzheimer assays is not just low concentration, but pathologically meaningful low concentration.

Your example—tau values < 0.047 pg/mL (picograms per milliliter)—is emblematic. A typical ELISA of the 1980s–1990s could confidently quantify in the low ng/mL range, perhaps high pg/mL for well-behaved targets. Below that, the signal collapsed into background noise.

But Alzheimer-relevant species are frequently:

Sub-picogram
Single pg/mL range
With clinically meaningful thresholds separated by a factor of 2 or less

This is not just a sensitivity problem—it is a dynamic range problem.
To discriminate disease, an assay must not merely detect:

“Tau is present,”

but rather:

“Tau is 0.047 pg/mL rather than 0.062 pg/mL.”

Those are differences on the order of tens of femtograms in often 50–100 µL of sample.

Pre-digital immunoassays could not approach that problem.

The technological rupture came with:

Electrochemiluminescence (MSD)
Immuno-PCR
Simoa (single-molecule array)
Digital ELISA
Mass spectrometry with nanospray ionization

These systems moved biological measurement from ensemble averaging to quantal counting, turning a continuum problem into a digital-statistical one.

The result is an assay environment where tau or Aβ concentrations of 0.5 pg/mL vs 1 pg/mL become not only measurable, but clinically interpretable.

2. Analytical Specificity: The Targets Were Biochemically Messy

Tau and amyloid are not monolithic molecules; they exist as:

Multiple isoforms
Cleavage fragments
Post-translationally modified species
Aggregated vs soluble pools

In the 1990s, “tau ELISA” usually meant recognition of an epitope on some tau species, with cross-reactivity to:

degraded fragments
phosphorylated variants
heterogeneous aggregates
unrelated cytoskeletal proteins

In plasma, which has enormous protein complexity, the situation was worse:

Off-target capture dominated signal
Collapse of low-abundance epitopes occurred spontaneously
Autoantibodies masked epitopes

Modern assays solve this using:

Monoclonal pairs against well-defined cleavage events
Phospho-specific antibodies (e.g., p-tau181, p-tau217)
Mass-spec peptide fingerprinting
Immunoprecipitation-MS workflows
Cleavable cross-linkers
Digital binning of single binding events

Thus, for the first time, assays measure the actual pathogenic species, not the tau-ish sludge generated by proteolysis and sample handling.

3. Pre-analytic Instability: Sticky Proteins in Fragile Microenvironments

Even with perfect antibodies, Alzheimer biomarkers are biophysically hostile analytes.

Properties include:

Surface-adhesion to plastics
Adsorption to albumin complexes
Rapid degradation by proteases
Freeze-thaw susceptibility
Diurnal variation
Differential recovery based on tube polymer composition

The key here is that clinical differences often depend on shifts of 20–80% around vanishingly small baselines.

So if tau is truly 0.047 pg/mL, but you irreversibly adsorb 40% of it to polypropylene, your measurement becomes biologically meaningless.

The early Alzheimer biomarker literature is full of:

Non-replicable findings
Site-dependent variability
Contradictory conclusions

These were not theoretical disputes—they were failures of pre-analytic physics.

Modern protocols now employ:

Low-binding plastics
Standardized centrifugation
Defined collection tubes (e.g., EDTA vs heparin)
Immediate cooling
Protease inhibitors
Strict timing to aliquot
Bar-coded workflow enforcement
ISO-level SOPs

It is no accident that Alzheimer biomarker diagnosis evolved only once the field adopted biopharma-grade sample handling, not academic-style biochemistry.

4. The Ratio Problem: Tiny Numerical Windows for Biological Reality

Your example underscores an even deeper issue:

pathological classification occurs within ratios that differ by less than a factor of two.

ratio > 0.00738 = positive
ratio < 0.0037 = negative

The absolute difference is < 0.004, which can be obliterated by:

adsorption losses
dilution error
matrix interference
pipetting variation
calibration drift
freeze-thaw cycles

This is not niche pedantry—it is a fundamental chemical barrier.

Only digital-counting immunoassays, mass-spec standardization, and pre-analytic control can reliably resolve such narrow biological windows.

Why It Works Now

The reason Alzheimer biomarkers are suddenly "real" is not that biology changed, but that measurement caught up.

Modern assays combine:

Femto- to attomolar sensitivity
Isoform-specific detection
Proteomic-grade reproducibility
Digital quantification
Industrial pre-analytic control
Harmonized SOPs and QC materials
Biostatistical calibration

This enables not just detection, but diagnostic interpretation at clinically meaningful thresholds.

We went from “Can we detect tau in plasma?” to:

“Is tau 0.047 pg/mL or 0.056 pg/mL, and what is the p-tau217:p-tau181 ratio?”

That transition is not trivial—it is a generational shift driven by 30 years of proteomic and analytical chemistry innovation.

Conclusion

The inability of early AD assays to achieve clinical viability was not a failure of hypothesis, but a failure of technology:

Too insensitive
Too nonspecific
Too vulnerable to pre-analytic noise

The reason current tests work is because modern platforms finally resolve signals at concentrations, dynamic ranges, and biochemical fragility that earlier immunoassays could not approach, especially in plasma.

In practical terms, the AD field evolved from assays that could detect protein presence, to assays that can measure pathogenic states with sub-picogram accuracy in a hostile biological matrix.

That change—more than any conceptual breakthrough—is what turned Alzheimer biomarkers from wishful science into actionable diagnostics.

###

Modern Alzheimer biomarker assays achieve extraordinary sensitivity and precision at sub-picogram concentrations because they combine digital detection physics, molecular specificity, and rigorous control of pre-analytic noise.

First, platforms such as single-molecule array (Simoa), electrochemiluminescence, and mass-spectrometry with nanospray ionization do not measure bulk averages; they count individual binding events or defined peptide ions. This effectively converts a weak analog signal into digital statistics, enabling reliable discrimination between, for example, 0.04 pg/mL and 0.06 pg/mL. Sensitivity is further enhanced by microfluidic confinement, which increases local analyte concentration and lowers background.

Second, modern assays use high-affinity monoclonal pairs and phospho- or isoform-specific epitopes, sharply reducing cross-reactivity with abundant plasma proteins. This improves signal-to-noise ratio and analytical specificity, which is critical when the clinically meaningful signal changes only twofold over baseline.

Third, performance is enabled by stringent pre-analytic standardization: low-binding plastics, controlled centrifugation, immediate cooling, protease inhibitors, and harmonized SOPs. These steps prevent adsorption, degradation, and matrix interference, which previously overwhelmed true biological differences.

Together, digital detection, molecular precision, and industrial-grade sample handling allow highly reproducible measurement of fragile, low-abundance proteins in hostile matrices, transforming picogram-level biomarkers into reliable clinical diagnostics.

####

In the K242706 FDA decision summary, the sensitivity and precision are explicitly documented, not just marketing claims.

The assay is a fully automated two-step sandwich chemiluminescent enzyme immunoassay (CLEIA) on the Lumipulse G1200, using AMPPD substrate, which gives a very strong light signal even at very low antigen levels.
2025 fda 0515 K242706 (Plasma T…
For pTau217, the LoB = 0.025 pg/mL, LoD = 0.041 pg/mL, and LoQ = 0.047 pg/mL, with a validated measuring interval of 0.047–10 pg/mL. For Aβ42, LoB = 0.128 pg/mL, LoD = 0.207 pg/mL, LoQ = 0.8 pg/mL, measuring interval 0.8–500 pg/mL.
2025 fda 0515 K242706 (Plasma T…
Linearity studies show R² ≈ 0.999 across these ranges, meaning the signal tracks concentration almost perfectly.
2025 fda 0515 K242706 (Plasma T…
Precision studies (within-run, day-to-day, lot-to-lot, and site-to-site) give CVs typically ~2–8%, even near the clinical cut-offs, and additional simulations confirm acceptable %CV for the ratio itself.
2025 fda 0515 K242706 (Plasma T…
Extensive interference and cross-reactivity testing against lipids, bilirubin, immunoglobulins, drugs (including anti-amyloid antibodies), and related tau/Aβ species showed ≤±10% effect and <0.2% cross-reactivity at high challenge concentrations.
2025 fda 0515 K242706 (Plasma T…

Together, these data explain why the FDA accepted that this plasma ratio can reliably discriminate across such tiny concentration and ratio differences.

Discoveries in Health Policy

Monday, December 1, 2025

LegislationWatch: Proposed: Bill for Alzheimer Blood Testing in Medicare, H.R. 6130