New Pathology Testing on the Horizon for Early Alzheimer’s Dementia Diagnosis
The evidence has evolved remarkably over the past 3–5 years for early Dementia diagnosis. There is now broad international consensus that plasma phosphorylated tau (pTau), particularly pTau217, is the most accurate blood biomarker currently available for detecting Alzheimer’s disease pathology, although it is not yet considered a standalone diagnostic test. Current Australian and international recommendations still advise interpreting these biomarkers alongside clinical assessment, cognitive testing, structural brain imaging, and, where appropriate, confirmatory amyloid PET or CSF biomarkers.
At Ocean Medical Practice – Bondi’s trusted medical centre, our GPs explore the current pathology investigations for early Alzheimer’s Dementia diagnosis. Our earlier article ‘Weekly Health Insights: Our Bondi doctors & Bondi Medical Centre GPs explain Dementia’ detailed the various type of Dementia and diagnostic difficulties for GPs and doctors.
This article focuses on the new diagnostic tests for Alzheimer’s Dementia in clinical trials.
What is plasma phosphorylated tau?
Tau is a normal protein found inside neurons where it helps stabilise microtubules, the internal “transport network” of nerve cells.
In Alzheimer’s disease, tau undergoes abnormal chemical modification called phosphorylation. When tau becomes excessively phosphorylated, it detaches from microtubules, misfolds, and forms neurofibrillary tangles, one of the two hallmark pathological features of Alzheimer’s disease (the other being amyloid-β plaques).
Small amounts of these abnormal phosphorylated tau proteins can be detected in cerebrospinal fluid (CSF) and, with highly sensitive assays, in blood plasma. Different blood tests measure phosphorylation at different amino acid sites on the tau protein, including:
- pTau181
- pTau217
- pTau231
Among these, pTau217 currently has the strongest evidence for detecting Alzheimer’s disease pathology. International workgroups now regard it as the best-performing blood biomarker for identifying amyloid-associated Alzheimer’s disease.
Why does pTau rise?
Current evidence suggests that abnormal amyloid-β accumulation triggers a cascade of events that leads to increased tau phosphorylation. This means plasma pTau levels often begin to rise many years before dementia symptoms appear, during the preclinical or mild cognitive impairment stages of Alzheimer’s disease.
For this reason, pTau is increasingly viewed as a marker of the underlying biological disease rather than simply a marker of cognitive impairment.
Which forms of Alzheimer’s disease show elevated pTau?
Current evidence indicates that plasma pTau217 is elevated across the major amyloid-positive Alzheimer’s disease phenotypes, including:
Typical amnestic Alzheimer’s disease
This is the most common presentation.
Patients typically develop:
- episodic memory loss
- repetitive questioning
- difficulty learning new information
pTau217 performs particularly well in this group.
Mild Cognitive Impairment (MCI) due to Alzheimer’s disease
Many patients with MCI who have underlying Alzheimer’s pathology already demonstrate elevated pTau levels, often before dementia develops.
This is one reason these biomarkers are attracting so much interest—they may help identify Alzheimer’s disease at an earlier stage.
Early-onset Alzheimer’s disease (<65 years)
Most patients with early-onset Alzheimer’s disease who have amyloid-positive disease also show elevated plasma pTau217.
Late-onset Alzheimer’s disease
The majority of sporadic Alzheimer’s disease cases also show elevated plasma pTau217.
Atypical Alzheimer’s disease
Elevated pTau is also seen in many atypical Alzheimer’s syndromes where Alzheimer’s pathology is the underlying cause, including:
- Posterior cortical atrophy (visual variant)
- Logopenic variant primary progressive aphasia
- Corticobasal syndrome caused by Alzheimer’s pathology
These patients often have non-memory symptoms initially but still exhibit the characteristic amyloid and tau changes associated with Alzheimer’s disease.
Which dementias usually do NOT show elevated pTau?
This is where the test is clinically valuable. Plasma pTau217 is generally not elevated to the same extent in several common non-Alzheimer neurodegenerative diseases.
Frontotemporal dementia (FTD)
Typically normal or only minimally elevated.
This distinction is clinically useful because FTD can resemble Alzheimer’s disease but has different underlying pathology involving proteins such as TDP-43 or non-Alzheimer tau aggregates.
Dementia with Lewy bodies (DLB)
Usually not significantly elevated unless there is co-existing Alzheimer’s pathology.
Mixed pathology is common in older adults, so some patients with DLB may have raised pTau if they also have amyloid deposition.
Parkinson’s disease dementia
Generally low unless concomitant Alzheimer’s pathology is present.
Vascular dementia
Typically normal or only mildly elevated. Cognitive impairment in vascular dementia results from cerebrovascular disease rather than amyloid and tau pathology.
Huntington’s disease
Usually not elevated.
Progressive supranuclear palsy (PSP)
This is an important nuance. PSP is a tauopathy, but it involves a different form of tau aggregation (predominantly 4-repeat tau) than Alzheimer’s disease. Plasma pTau217 is generally not markedly elevated, highlighting that these assays are relatively specific for the Alzheimer’s-type tau changes rather than all tau disorders.
Corticobasal degeneration (CBD)
Similarly, corticobasal degeneration is another non-Alzheimer tauopathy. Plasma pTau217 is generally not substantially elevated unless the patient has concomitant Alzheimer’s pathology.
Creutzfeldt–Jakob disease (CJD)
Usually not elevated in the characteristic pattern seen in Alzheimer’s disease.
Why don’t all tau diseases have elevated pTau?
This is one of the most fascinating discoveries in recent biomarker research.
Although PSP, corticobasal degeneration and some forms of FTD are all tauopathies, they involve different tau isoforms, phosphorylation patterns, and mechanisms of aggregation compared with Alzheimer’s disease.
The current pTau217 and pTau181 assays appear to detect phosphorylation events that are closely linked to amyloid-driven Alzheimer’s disease, rather than serving as universal markers of all tau-related neurodegenerative disorders.
Can pTau be elevated without Alzheimer’s disease?
Yes, but this is relatively uncommon.
Potential causes include:
- mixed Alzheimer’s pathology with another dementia
- advanced cerebral amyloid angiopathy
- some cases of traumatic brain injury
- rare neurological disorders
In general, plasma pTau217 demonstrates high specificity for amyloid-associated Alzheimer’s disease when interpreted in the appropriate clinical context.
Clinical implications
A raised plasma pTau217 does not, by itself, diagnose Alzheimer’s disease. Instead, it indicates a high likelihood that the patient has the biological changes associated with Alzheimer’s disease. Diagnosis still requires integration of:
- clinical history
- cognitive assessment
- neurological examination
- laboratory investigations to exclude reversible causes
- brain imaging (such as MRI or CT)
- referral to a geriatrician, neurologist, or memory clinic when appropriate
Blood biomarkers are best viewed as an adjunct to this comprehensive assessment, rather than a replacement for it.
Summary table
| Condition | Typical plasma pTau217 finding |
|---|---|
| Typical Alzheimer’s disease | Elevated |
| Mild cognitive impairment due to Alzheimer’s | Elevated |
| Early-onset Alzheimer’s disease | Elevated |
| Posterior cortical atrophy (Alzheimer’s pathology) | Elevated |
| Logopenic primary progressive aphasia (Alzheimer’s pathology) | Elevated |
| Frontotemporal dementia | Usually normal or minimally elevated |
| Dementia with Lewy bodies | Usually normal unless mixed Alzheimer’s pathology |
| Parkinson’s disease dementia | Usually normal unless mixed Alzheimer’s pathology |
| Vascular dementia | Usually normal or mildly elevated |
| Progressive supranuclear palsy | Usually not elevated |
| Corticobasal degeneration | Usually not elevated |
Overall comparison
| Test | What it measures | Main role | Overall evidence |
| pTau217 | Phosphorylated tau at amino acid 217 | Detects amyloid-associated Alzheimer’s pathology | ★★★★★ Best blood biomarker currently available |
| pTau181 | Phosphorylated tau at amino acid 181 | Detects Alzheimer’s pathology but less accurate than pTau217 | ★★★★☆ Very good |
| APOE4 | Genetic risk allele | Estimates lifetime risk only | ★★☆☆☆ Risk prediction, not diagnosis |
pTau217
Most Alzheimer’s researchers now regard plasma pTau217 as the leading blood biomarker for Alzheimer’s disease. Rather than diagnosing dementia itself, it identifies the biological process of Alzheimer’s disease, particularly tau phosphorylation associated with cerebral amyloid deposition.
Multiple studies have demonstrated that pTau217 closely correlates with:
- Amyloid PET positivity
- Tau PET positivity
- CSF Alzheimer’s biomarkers
- Neuropathological diagnosis at autopsy
- Future cognitive decline
Importantly, pTau217 often becomes abnormal years before dementia develops, making it valuable for detecting disease during the mild cognitive impairment (MCI) stage.
Diagnostic Accuracy/Performance
The largest recent systematic review (112 studies involving almost 30,000 participants) reported pooled performance of approximately:
- Sensitivity: 88.1%
- Specificity: 88.7%
- AUROC: 0.91
Another recent meta-analysis focusing on biologically confirmed Alzheimer’s disease found even stronger performance:
- Sensitivity: 93%
- AUROC: 0.95
Across studies, pTau217 generally demonstrates an AUC of 0.91–0.95, placing it among the best-performing blood biomarkers currently available.
Why is pTau217 so good?
pTau217 appears to:
- become abnormal earlier than many traditional biomarkers
- correlate extremely well with amyloid PET
- distinguish Alzheimer’s disease from frontotemporal dementia
- distinguish Alzheimer’s disease from vascular dementia
- predict progression from mild cognitive impairment to Alzheimer’s dementia
It performs particularly well in patients attending memory clinics because the pre-test probability of Alzheimer’s disease is higher.
pTau181
pTau181 was the first plasma phosphorylated tau assay to gain widespread clinical attention.
Although still an excellent biomarker, most comparative studies now conclude that pTau217 consistently outperforms pTau181.
pTau181 remains clinically valuable because it:
- rises early in Alzheimer’s disease
- correlates with amyloid pathology
- predicts progression of cognitive impairment
- has been validated in numerous cohorts
However, it is more susceptible to overlap with other neurodegenerative disorders.
Diagnostic Accuracy/Performance
Large pooled analyses report approximately:
- Sensitivity: 81–88%
- Specificity: 78–81%
- AUROC: 0.81–0.91 depending on the population studied.
Compared with pTau217:
- slightly more false positives
- slightly more false negatives
- less discrimination between Alzheimer’s disease and several non-Alzheimer dementias
Nevertheless, it remains a highly useful biomarker.
pTau217 versus pTau181
Nearly every modern head-to-head comparison now favours pTau217.
Advantages of pTau217 include:
- higher sensitivity
- higher specificity
- larger AUC
- better correlation with amyloid PET
- better correlation with tau PET
- better prediction of disease progression
- superior differentiation from frontotemporal dementia
This is why many laboratories worldwide are transitioning towards pTau217 as the preferred blood biomarker.
APOE4 testing
Unlike pTau biomarkers, APOE4 is not a diagnostic test.
It detects a person’s inherited APOE genotype.
Everyone inherits two APOE alleles:
- APOE2
- APOE3
- APOE4
The presence of APOE4 increases the probability of developing Alzheimer’s disease during life but does not mean someone has Alzheimer’s disease or will inevitably develop it.
Many APOE4 carriers never develop dementia, while many patients with Alzheimer’s disease do not carry APOE4.
Relative risk
Approximate lifetime effects:
One APOE4 allele
- approximately 2–4 times increased risk
Two APOE4 alleles
- approximately 8–12 times increased risk
Risk estimates vary between studies, sex, ancestry, and environmental factors, so these figures should be interpreted cautiously.
APOE4 is not suitable as a screening test
Its diagnostic accuracy for detecting current Alzheimer’s disease is relatively poor because it measures genetic susceptibility, not active disease.
It therefore has:
- relatively low specificity
- poor positive predictive value
- limited ability to distinguish Alzheimer’s disease from healthy ageing
Instead, APOE4 testing is useful for:
- estimating genetic risk
- counselling patients
- assessing eligibility and safety considerations for some anti-amyloid therapies
- research studies
Can these tests replace PET scans?
Not yet.
Current expert recommendations suggest blood biomarkers should complement, rather than replace, established diagnostic pathways. In many specialist settings they may be used to triage patients for amyloid PET imaging or CSF analysis, but confirmatory testing is still recommended in situations where diagnostic certainty is required, particularly before commencing disease-modifying therapy.
How should GPs use these tests?
The likely Australian clinical pathway is:
- Patient presents with memory concerns.
- GP performs:
- history
- cognitive testing
- medication review
- depression assessment
- routine blood tests
- Brain imaging where appropriate.
- Blood biomarkers (such as pTau217 and/or pTau181) may help estimate the likelihood of underlying Alzheimer’s pathology.
- Referral to a geriatrician, neurologist or memory clinic if biomarkers or clinical assessment suggest Alzheimer’s disease.
- PET imaging or CSF biomarkers may still be used when diagnostic confirmation is needed before treatment decisions.
Summary
From the current evidence:
- pTau217 is now the strongest-performing blood biomarker for Alzheimer’s disease, with pooled sensitivity and specificity close to 89–93% and AUROC around 0.91–0.95.
- pTau181 remains a robust biomarker but is consistently less accurate than pTau217, with sensitivity around 81–88%, specificity around 78–81%, and AUROC approximately 0.81–0.91.
- APOE4 is a genetic risk marker rather than a diagnostic biomarker. It identifies increased lifetime susceptibility but cannot diagnose Alzheimer’s disease on its own.
In the next article, we compare Roche Elecsys pTau217, pTau181, APOE4 genotyping, amyloid PET, CSF biomarkers, and MRI, along with other Australian diagnostic pathways and guidance on when each investigation is appropriate.
Interested in Enrolling in Clinical Trials?
Enrolment for clinical evidence and biomarker testing involving pTau217, pTau181, and APOE4 in NSW is coordinated primarily through Neuroscience Research Australia (NeuRA) and the Australian Dementia Network (ADNeT). These initiatives evaluate rapid blood-based tests to diagnose Alzheimer’s. Unfortunately, Ocean Medical Practice is NOT currently involved in research but our Bondi GPs and Doctors can help direct you to a neurologist that may be able to review your risks.
Book an appointment today at our Bondi medical centre on Bondi Road and take proactive steps toward maintaining cognitive health!
Last medically reviewed: 2 August 2026
Reviewed by: Doctors at Ocean Medical Practice – Bondi Medical Centre
Location: Bondi Road, Bondi NSW
