The Swedish BioFINDER program, based at Lund University, is founded on a groundbreaking premise: neurodegenerative diseases should be measured and staged biologically rather than deduced from symptoms alone. The program spans BioFINDER-1, BioFINDER-2, and the new BioFINDER Primary Care/"ADetect" initiative, focusing on longitudinal, biomarker-rich cohorts. This includes comprehensive clinical phenotyping combined with blood, CSF, MRI, and PET imaging (amyloid and tau) to (1) detect pathology earlier, (2) improve differential diagnosis, (3) explain symptom-pathology mismatches through co-pathologies, and (4) enhance trial efficiency by selecting appropriate patients and outcomes.

1) Cohort Architecture: Why BioFINDER Became a "Diagnostic Engine"

BioFINDER is not a single study but a network of coordinated cohorts. BioFINDER-1 (ClinicalTrials.gov NCT01208675) established the core approach - integrating biochemical methods with imaging to clarify Alzheimer's pathophysiology in clinically characterized participants. BioFINDER-2 (NCT03174938), launched in 2017, expanded in scale, incorporating state-of-the-art tau-PET to explore tau biology across preclinical and symptomatic stages and dementia syndromes, using a separate population from BioFINDER-1.

A crucial operational principle is that biomarkers are not "adjuncts" - they are the foundation for diagnosis and staging. This is why BioFINDER consistently revisits the same clinical questions: in real-world cognitive complaints, what biology is present, what stage is it, and what else is contributing when the clinical picture does not align with Alzheimer biomarker load.

2) The Blood Biomarker Pivot: p-tau217 and the Move from Specialty to Scale

BioFINDER's most transformative contribution has been the rigorous validation of blood-based biomarkers that approach (and sometimes achieve) "gold-standard" performance against amyloid-PET, tau-PET, and CSF assays, reducing the need for lumbar puncture and PET in many diagnostic pathways.

Plasma %p-tau217 as a High-Performance Alzheimer Signal

A pivotal study demonstrated that plasma %p-tau217 can be clinically equivalent - or superior - to commonly used FDA-cleared CSF tests for detecting Alzheimer pathology, with robust performance against both amyloid-PET and tau-PET, including in BioFINDER-2 subcohorts. The research highlights that ratios/percent-phosphorylation approaches can stabilize interpretation and enhance clinical applicability.

ADetect (BioFINDER Primary Care): Translating Performance into a Workflow

BioFINDER Primary Care (ClinicalTrials.gov NCT06120361) addresses the diagnostic bottleneck: cognitive complaints are prevalent in primary care, but specialist access and confirmatory testing capacity are limited. The study enrolls symptomatic patients from over 20 primary care centers in southern Sweden to improve diagnostic accuracy and referral precision.

The most significant output from BioFINDER Primary Care so far has been a prospective evaluation of APS2 (Amyloid Probability Score 2; a combined plasma biomarker approach) and %p-tau217 using predefined cutoffs, demonstrating high diagnostic accuracy in both primary and secondary care settings. This work operationalizes what many health systems require: a blood-based "front door" that can rule out Alzheimer biology, confirm it with high confidence, and reserve PET/CSF for uncertain intermediates, avoiding unnecessary, costly pathways.

An additional line of BioFINDER-adjacent research has examined "two-cutoff" strategies for plasma p-tau217 in real-world populations, creating a low-risk rule-out zone and a high-confidence rule-in zone to reduce confirmatory testing load while maintaining safety and accuracy.

3) p-tau231, p-tau181, p-tau217, and MTBR-tau243: What Each Marker Is For

BioFINDER’s biomarker narrative is not about one tau marker prevailing. It is more akin to a cascade: early amyloid-associated phosphorylation signals, followed by downstream tangle biology that better tracks neurodegeneration.

• p-tau217 has emerged as a consistently high-performing blood marker for Alzheimer biology across multiple platforms and cohorts, increasingly regarded as the leading general-purpose blood tau marker for clinical triage pathways.
• p-tau181 remains widely studied and useful, but multiple comparative studies indicate that p-tau217 generally outperforms it for identifying Alzheimer pathology and aligning with PET/CSF evidence.
• p-tau231 is often considered an earlier signal in the Alzheimer cascade (particularly amyloid-linked shifts), and BioFINDER publications frequently include it as part of the "very early biology" toolkit rather than the best late-stage tracker.
• MTBR-tau243 is the staging specialist: BioFINDER-2 work helped establish MTBR-tau243 as a biomarker closely linked to insoluble tau aggregates (tangles) rather than the upstream phosphorylation state alone. In CSF, MTBR-tau243 was validated as specific to tau tangle pathology and compared directly against multiple p-tau epitopes in BioFINDER-2 and an independent cohort. More recently, a Nature Medicine paper extended this into plasma eMTBR-tau243, testing whether blood levels track symptom-linked tau biology in BioFINDER-2 and another cohort.

The practical takeaway is that a future-ready diagnostic framework will likely separate two clinical tasks: (1) detecting Alzheimer biology early and accessibly (p-tau217 ± Aβ42/40-derived scores like APS2) and (2) quantifying "tangle burden / downstream neurodegenerative momentum" (MTBR-tau243), particularly when staging severity and prognosis are critical.

4) Biological vs Clinical Staging: Discordance as a Clue, Not an Error

A major conceptual contribution from BioFINDER is treating symptom-biomarker mismatch as diagnostically meaningful. In JAMA Neurology, researchers evaluated revised criteria for biological and clinical staging and demonstrated that when the clinical stage appears worse than the biological stage, it may indicate that other pathologies or processes are significantly contributing to symptom burden—precisely the scenario in which clinicians should broaden their focus beyond "pure AD."

This perspective is important as real patients frequently exist at the intersection of Alzheimer pathology, vascular injury, Lewy body disease, TDP-43, medication burden, sleep disorders, and systemic illness. BioFINDER’s staging work suggests that biology-first diagnosis should not narrow thinking—rather, it should refine it: once Alzheimer biology is measured, the remaining unexplained impairment becomes a targeted search for co-pathology and modifiable factors.

5) Tau-PET as a Trial Instrument: Individualized ROIs and Power

BioFINDER has also advanced methodology to make tau-PET more sensitive as a longitudinal outcome measure. A JAMA Neurology study compared group-level versus individualized brain regions of interest (ROIs) for measuring tau-PET change, finding advantages to individualized ROI strategies for capturing longitudinal tau progression and improving the power to detect treatment effects—exactly what sponsors and trialists need when outcomes are costly and effect sizes are modest.

6) Why BioFINDER Matters Now: Precision Medicine Meets Care Delivery

BioFINDER’s research is timely, as disease-modifying therapies require biologic confirmation, safety stratification, and scalable monitoring. The program’s trajectory—high-quality cohort biology leading to validated blood tests, primary care workflows, staging frameworks, and trial optimization—aligns directly with what health systems aim to construct: a comprehensive pipeline from initial complaint to biologically informed treatment planning.

If desired, I can rewrite this as a GUL-style publication for Mind the Gulf, adjusting the tone, cadence, and clinic-facing framing. Additionally, I can include a practical "Implementation Appendix" detailing a streamlined workflow: rule-out / rule-in / intermediate zone, confirmatory testing triggers, and strategies for addressing clinical > biological discordance without prematurely diagnosing mixed dementia.