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Plasma phospho-tau217 as a predictive biomarker for Alzheimer’s disease in a large south American cohort

Alzheimer's Research & Therapy volume 17, Article number: 1 (2025) Cite this article

Abstract

Background

Blood-based Alzheimer’s disease (AD) biomarkers have been increasingly employed for diagnostic, prognostic, and therapeutic monitoring purposes, due to accuracy in distinguishing AD pathophysiologic process. Compared to other p-tau isoforms, plasma p-tau217 exhibits stronger associations with AD hallmarks in CSF and brain. However, most studies have been conducted in non-Hispanic Whites, limiting our understanding of the performances and utility of these biomarkers across ethnicities.

Methods

We examined a cohort of Peruvians from the GAPP study, a recently established cohort of Peruvian mestizos from Lima and indigenous groups from Southern Peru (Aymaras and Quechuas). We tested plasma levels of p-tau using the Quanterix Simoa ALZpathp-tau217 assay in 525 samples and tested the association between p-tau217 and clinical diagnosis (healthy controls n = 234 vs. AD n = 113) using generalized mixed regression models, adjusting for sex, age, education, APOE-e4 allele (fixed effects) and study site (random effect). We also tested biomarker levels in MCI (n = 178) vs. other groups. The receiver operating characteristics area under the curve (ROC-AUC) was used to evaluate the biomarker’s classification performances.

Result

Participants showed on average 80% Native American ancestry. p-tau217 was significantly associated with AD (β = 2.61, 95%CI = 0.61–4.29) and its levels were inversely correlated with cognitive performances; p-tau217 levels did not differ between controls and MCI (p-value > 0.05). p-tau217 levels were higher in participants carrying at least one APOE-e4 allele (OR = 2.31, 95%CI = 1.85–2.90). The ROC-AUC for p-tau217 was estimated at 82.82% in the fully adjusted model.

Conclusion

To our knowledge, this is the largest study conducted in a South American cohort phenotyped for AD with available p-tau217. Most investigations have previously focused on highly selected cohorts with established AD-endophenotypes (CSF biomarkers, autopsy report, PET etc.), while data on cohorts with clinical assessment are currently lacking, especially in non-European populations.

Background

Alzheimer’s disease (AD) is the primary factor behind dementia, accounting for 60–70% of cases globally [1] with almost 50 million people experiencing dementia in 2020, and predicted to rise by 2030 and a further threefold increase by 2050 [2]. AD shows differences in frequency across distinct geographical areas and ethnic groups, underlying the importance of genetic and environmental differences in explaining the worldwide range of incidence and prevalence. Central and South American countries have evolved from a demographic standpoint, with prevalence of dementia has raised substantially (7.1–11.5% in individuals ≥ 65 years of age), exceeding that of Europe and the United States. Consequently, dementia in these regions is expected to rise from 7.8 million in 2013 to more than 27 million by 2050 [3].

The diagnosing tools and disease-modifying drugs have expanded notably over the last two decades, although the current therapeutic options have limited impact [4]. Plaques and tangles, aberrant forms of amyloid-β40–42 (Aβ40/42) and tau proteins, are the main pathological hallmarks of the disease, with hyperphosphorylated tau protein being detectable already in early stages of life even in absence of clinical signs of AD [5]. Phosphorylated tau at residue 217 (“p-tau217”) has been identified as a biomarker for AD, with increasing levels detected in the CSF of AD patients [6] linked to accumulation of neurofibrillary tangles and progressive severity of cognitive deterioration [7]. Furthermore, p-tau217 effectively distinguishes AD from other tauopathies, hence facilitating accurate diagnosis [8]. Understanding the role of p-tau217 in AD pathology might provide valuable knowledge about potential targets for treatments that could impact the disease’s progression [9]. p-tau217 detected in plasma is also a promising diagnostic tool and could enrich clinical trials of preclinical cohorts because it better recapitulates early cerebral Aβ alterations, prior to Aβ plaque pathology is visible [10, 11]. P-tau217 is part of a set of AD plasma tests with superior performances, compared to other biomarkers such as Aβ42, Aβ40 and their ratio: the latter are validated for CSF use, but has limitations when applied to blood [11,12,13]. As a result, plasma Aβ42/40 does not have the clinical robustness needed for standard clinical testing. In clinical practice, p-tau isoforms [14,15,16,17] have shown the best diagnostic performance in both familial and sporadic forms of AD [17].

Most of the data have been derived from studies enrolling participants of European-descend ancestry in highly-selected clinical settings (e.g. memory clinic), with gold-standard diagnostic status used to measure the biomarkers performances (CSF, autopsies, PET etc.), often non-available (or feasible) in population studies, particularly when in remote areas, low/middle income countries or part of marginalized populations. Still, small cohort studies showed that plasma biomarkers are equally effective across ethnic groups [18, 19]. These studies included mostly Hispanics from the Caribbean Islands, with very small representation of Central and south American individuals.

Here, we seek to establish the performances of p-tau217 in a large cohort of Peruvian individuals with clinical diagnosis for Mild Cognitive Impairment (MCI) and AD, available plasma p-tau217 and genetic data.

Methods

Participants

We included Peruvians from the Genetic of Alzheimer Disease in Peruvian Populations (GAPP) study. This cross-sectional case-control study was initiated in 2020 aiming to include mestizos from Lima and indigenous groups from Southern cities of Arequipa and Puno (Aymaras and Quechuas individuals) to study the effect of ancestry on AD. Participants underwent a standardized medical and neuropsychological testing, including the Clinical Dementia Rating (CDR) scores (CDR = 0, 0.5, ≥ 1 to classify healthy controls, MCI and dementia cases, respectively). Lacking the capacity to consent or a proxy to provide consent, and additional diagnosis that could account for the clinical manifestations (e.g. psychiatric conditions, drug use etc.) were among exclusion criteria. A multidisciplinary team consisting of neurologists and neuropsychologists was assembled for a consensus diagnosis of MCI and AD in accordance with the NIAA criteria [20, 21]. Further details can be found in a previous publication from our group [22]. A total of 525 samples had available whole genotype data (Illumina GSA chip) and plasma p-tau217 (see below for detailed methods). 234 were healthy controls, 113 samples were diagnosed with AD, and an additional 178 samples with MCI. Informed consent was obtained from all participants. The study protocol was approved by the Institutional Review Board of Columbia university. The study was conducted according to the principles expressed in the Declaration of Helsinki.

APOE genotyping

APOE’s single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were imputed using the TOPMed imputation server (https://imputation.biodatacatalyst.nhlbi.nih.gov). The combination of genotypes at rs429358 and rs7412 were used to define the three main APOE alleles (ε4, ε3, and ε2). Ambiguous ε2ε4/ε1ε3 genotypes were coded as ε2/ε4 since the frequency of ε1 allele is very rare. We used the ε3/ε3 genotype as a reference genotype. A subset of GAPP participants (N = 278) also received direct genotyping at rs7412 and rs429358, revealing virtually identical results in APOE’s alleles calling compared to those from imputed SNPs.

Plasma sample collection for biomarker identification

Blood was collected by standard venipuncture in K2EDTA tubes in non-fasting participants. Plasma was isolated by centrifugation for 15 min a 2000 g-2500 g at 4 °C within 2 h of collection. Plasma was promptly frozen in aliquots of 0.5 ml in clear polypropylene tubes at -80 °C.

P-tau217 plasma measurements were performed on the Quanterix HD-X platform. Plasma samples were rapidly thawed and plated, and analyzed using the Quanterix Simoa ALZpath p-tau v2 kit #104,371, using supplied calibrators, per manufacturer instructions, and using laboratory controls. All samples were analyzed in duplicate; samples that failed on first analysis (3.5% of total) or had intra-duplicate COV greater than 15% (2.0% of total) were repeat analyzed. Overall intra-duplicate COV was 4.3% and intrasample repeat reproducibility was 4.8%.

Analysis

We used the ADMIXTURE software (v1.3.0) [23], to inference global ancestry assuming a three-way admixed scenario, i.e., Native-American (NAA), European (EUR), and African (AFR) ancestry, employing the Human Genome Diversity project (HGDP) [24] as reference panel. We conducted generalized mixed models employing the lmε4 R package to test the association between levels of p-tau217 and diagnostic status (healthy controls vs. AD vs. MCI), adjusting for age, sex, and education as fixed effects, and recruitment site as a random effect. To examine the relationship between p-tau217 levels and APOE isoforms, we additionally employed a linear mixed-effects model with the ε4 allele dosage as main predictor, adjusting again for education, age, sex as fixed effects and recruitment site as a random effect. Lastly, we tested if genetic ancestry was associated with p-tau217 levels, using the same statistical models. All continuous predictors were rank invariant normalized (RNOmni R library). The receiver operating characteristics area under the curve (ROC-AUC) was used to evaluate the biomarker’s classification performances using the pROC R package [25]. As secondary analyses, the Rowland Universal Dementia Assessment Scale (RUDAS) score [26] was employed in place of the diagnostic categories. The RUDAS scale measures executive function, memory, language, and perceptual motor function, has minimal educational bias and can be administered in few minutes, even in patients with low literacy [27].

Results

Demographic and genetic profile

Table 1 reports the characteristics of the GAPP individuals included in the study. The average age of the participants was 71.6 years (68.2 healthy controls; 74.0 age at onset for AD cases), and 67% were women. The average years of education was 9 years. 14.8% of participants carried the APOE-ε4 allele, while the ε2 allele was present in 2% of individuals. Global admixture analyses are depicted in Fig. 1 via principal component analyses (left panel shows GAPP cohort, right panel the cohort stratified by recruiting site): 80% Native American global ancestry (NAA), followed by European ancestry (18%) and African ancestry (2%). The median p-tau217 level was 0.227 pg/mL (IQR = 0.221).

Table 1 Demographic and genetic characteristics of the GAPP Study cohort
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Fig. 1
figure 1

Principal component analyses for the GAPP participants (left panel non-stratified; right panel stratified by recruitment site), along with the HGDP reference groups

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Association between p-tau217 and AD

P-tau217 was significantly associated with AD (β = 2.61, 95%CI = 0.61–4.29), further confirmed after adjustment by APOE-ε4 allele presence (β = 2.07, 95%CI = 0.59–3.49; Table 2). In contrast, we did not observe any significant associations between p-tau217 and MCI (p-value > 0.05). Figure 2 shows the distribution and statistical significance of p-tau217 levels across diagnostic groups.

Table 2 Generalized mixed regression models. First set of models are adjusted for sex, age, education (fixed effects) and site of recruitment (random effect); second set of models also adjusted for APOE-ε4 allele presence
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Fig. 2
figure 2

p-tau217 levels across diagnostic groups

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When contrasting healthy individuals vs. AD, the ptau217 AUC was estimated at 68.5% (95%CI 0.62–0.75; Fig. 3). The best p-tau217 threshold that maximized its performance showed Specificity = 71.8%, Sensitivity = 69.1%, Negative Predictive Value (NPV) = 83.6% and Positive Predictive Value (PPV) = 52.8%.

Fig. 3
figure 3

ROC-AUC for the three regression models

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The AUC raised up to 82.8% (95%CI 0.77–0.87) for the full adjusted model including sex, age, education and APOE- ε4 allele (Specificity = 70.5%, Sensitivity = 83.2%, Negative Predictive Value (NPV) = 90.2% and Positive Predictive Value (PPV) = 56.3%.).

On the other hand, the AUC for healthy controls vs. MCI was estimated at 58.4% (data not shown).

As secondary analyses, we employed the RUDAS score in place of the diagnostic categories. We observed a significant correlation between levels of p-tau217 and total RUDAS scores (spearman r=-0.22, p < 0.001; Fig. 4).

Fig. 4
figure 4

Correlation scatterplot between p-tau217 levels and the RUDAS score

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APOE-ε4 allele dosage on p-tau217 levels

Individuals who carried at least on APOE-ε4 allele showed a substantial increase in p-tau217 levels (OR = 2.31, 95%CI = 1.85–2.90, p-value = 1E-12). p-tau217 levels were tendentially higher across the three diagnostic groups (Fig. 5), with AD cases who were ε4 non-carrier showing the lowest levels.

Fig. 5
figure 5

Distribution of ptau217 levels across diagnostic groups and APOE-e4 carrier status

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Effect of ancestry, education on the association between ptau217 and AD

p-tau217 levels and AD associations did not show any significant confounding effect from global ancestries (Native American ancestry β=-0.79, 95%CI=-2.17-0.60) or education (β = 1.52, 95%CI=-0.79-3.83).

Discussion

Our study substantially adds to the field by presenting findings from a large cohort of admixed individuals phenotyped for AD with available blood biomarkers data. Plasma p-tau217 shows robust performances and consequently a potential peripheral biomarker to supplement the AD diagnostic process when other precise instruments are not available/feasible (amyloid imaging, CSF biomarkers etc.). This is particularly relevant to low-to-middle income countries, remote areas, or marginalized populations. Importantly, specificity was found robust across all models, including the unadjusted one (71.8%), with no improvement when all covariates (sex, age, education, APOE-ε4) were included in the model (70.5%); hence, our findings underscore the ability of p-tau217 to correctly classify an individual as disease-free.

As of right now, measuring Aβ and p-tau levels in CSF or PET scans substantially adds to a precise diagnosis or prognosis. However, the development of less-invasive blood-based biomarker testing has potential for both wider clinical applicability and effective patient screening in investigation. In clinical practice today, biomarkers that target this epitope are essential [14,15,16,17]. Current studies have confirmed p-tau isoform optimal performance in AD, but have focused mostly on European-descent populations with established AD-endophenotypes, such as CSF Aβ/tau levels, autopsy diagnosis, PET scans, etc. For example, the Mayo Clinic Study of Aging (MCSA) study showed that plasma p-tau217 and p-tau181 could predict amyloid-beta (Aβ) PET positive (AUC = 0.81–0.86) and tau PET positive in entorhinal cortex (AUC > 0.80) [28]. One of the earliest studies on plasma p-tau217 showed its high discriminative accuracy for clinical AD dementia vs. other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93–0.98]), also significantly higher than other biomarkers (plasma P-tau181, NfL, and MRI measures) [6]. This study was conducted on the BiofFINDER Swedish cohort (https://clinicaltrials.gov/study/NCT03174938), indeed employing a clinical diagnosis that still utilized amyloid PET and CSF in its diagnostic protocol. It has to be noted that our and previous investigations employed different commercially available plasma pTau217 assays (ALZpath p-tau217, Janssen p-tau217+), hence comparison might be biased by this technical aspect [11].

Data is limited for population/cohort studies with clinical assessments, especially in marginalized groups, which emphasizes the importance of our study in broadening the knowledge of AD diagnostic pipelines across populations. Hispanic/Latino individuals from the Washington Heights-Inwood Columbia Aging Project (WHICAP) showed that increased plasma p-tau217 and p-tau181 were associated with AD diagnosis [18]: as for other studies, higher performances were observed with autopsy reports (N = 29; p-tau181 AUC = 82%; p-tau217 AUC = 85%), while lower AUCs reported when clinical diagnosis (N = 100) was employed. Our study does not possess a brain biobank, hence further analyses with neuropathological diagnosis of AD could not be carried out. Nevertheless, we showed a robust performance for p-tau217 even with clinical assessment only, with an AUC > 82% in the fully adjusted model. Recent studies showed high sensitivity and specificity of plasma biomarkers in distinguishing individuals with preclinical AD from healthy individuals [13, 29]. The Shanghai Aging Study [30], participants with amnestic MCI at baseline had significantly higher p-tau217 levels, with the latter increasing stepwise from healthy controls to amnestic MCI (single-domain) to amnestic MCI (multi-domain). Participants with higher quartile concentrations of baseline p-tau217 had six-times higher risks of incident AD than those in the lower quartile. For participants who volunteered to Aβ PET scanning, those who were Aβ + had significantly higher p-tau217, compared to Aβ- participants. In our study, MCI participants did not show significant changes in p-tau217 levels: this could be due to the nature of our recruitment at the country level in both urban and rural area, resulting in lesser precision in preclinical stages of the disease and the lack of specialized testing (e.g. PET assessment available in the Shanghai study).

Different soluble p-tau forms in CSF, such as p-tau181, p-tau217, and p-tau231, vary with stage as AD progresses. Specifically, p-tau217 performs consistently better than p-tau181 when it comes to identifying CSF and PET positive biomarker status as well as differentiating AD from other conditions when assessed through various assays. Both p-tau231 and p-tau181 show similar efficacy in the later stages of AD; however, in the preclinical stages, p-tau231 increases earlier and more closely correlates with Aβ and tau PET markers [31].

The APOE-ε4 allele is a major genetic factor associated with risk for AD and earlier onset. Nonetheless, it is still unclear how APOE affects risk of AD. ε4-carriers have higher Aβ in their brains, even in the absence of any neurological disorder. Additionally, APOE-ε4 is linked to more activated microglia in AD brains along with Aβ plaques, which suggests that it plays an essential role in inflammation. Research on earlier inflammatory processes and Aβ in APOE-ε4 carriers who don’t have neurological issues is limited [32]. As demonstrated in older populations with intact cognitive function, the ε4 allele is associated with a decline in the blood-brain barrier, a factor that is predictive of cognitive decline. These investigations highlight the role of the ε4 allele in promoting neuroinflammation and beta-amyloid accumulation markers which are early indicators of AD pathology and cognitive impairment [32]. The association between APOE-ε4 and tau phosphorylation is complex, since APOE has the capacity to worsen tau phosphorylation by interacting with several physiological pathways [33]. This interaction affects the aggregation of amyloid-beta, synaptic dysfunction, and neuroinflammation [33, 34]. Prior studies have shown that ε4-carriers have elevated levels of CSF p-tau, depending on the number of copies of the ε4-allele [10, 35]; consistently, we showed that ε4-carriers have higher levels of plasma p-tau217. Future research, possibly using longitudinal studies of APOE ε4 carriers, should expand on this observation, especially in the early stages of AD [36].

Conclusion

To our knowledge, this is the largest study ever carried out on a South American population phenotyped for AD using plasma p-tau217. We find an AUC ranging 68–82% which ultimately validated this blood biomarker’s robust performances in a non-White population. Moreover, our study didn’t find a significant link between ancestry and p-tau217 levels, suggesting that the former may not impact p-tau217 performances. The APOE-ε4 findings and the use of a neuropsychological endophenotype provided additional validations. Prior studies have primarily been conducted on highly selected cohorts with established AD-endophenotypes; at the present time, there is a dearth of information on population cohorts with clinical assessment, particularly in non-European cohorts.

Data availability

Data can be obtained from the corresponding author.

Abbreviations

AD:

Alzheimer’s disease

Aβ:

amyloid-β

APOE e4:

Apolipoprotein e4 allele

ROC-AUC:

receiver operating characteristics area under the curve

CSF:

Cerebrospinal Fluid

PET:

Positron Emission Tomography

MCI:

Mild Cognitive Impairment

p-tau217:

Phosphorylated tau protein at the position threonine 217

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Acknowledgements

Not applicable.

Funding

Research reported in this publication was supported by the NIA/NIH awards. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

GAPP is supported by NIA/NIH award U01AG081817 and R56AG069118.

Author information

Authors and Affiliations

  1. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA

    Neetesh Pandey, Zikun Yang, Basilio Cieza, Dolly Reyes-Dumeyer, Min Suk Kang, Lawrence S. Honig & Giuseppe Tosto

  2. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA

    Dolly Reyes-Dumeyer, Min Suk Kang, Lawrence S. Honig & Giuseppe Tosto

  3. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA

    Dolly Reyes-Dumeyer, Min Suk Kang, Lawrence S. Honig & Giuseppe Tosto

  4. Unidad de diagnóstico de deterioro cognitivo y prevención de demencia, Instituto Peruano de Neurociencias, Lima, Perú, USA

    Rosa Montesinos & Nilton Custodio

  5. Universidad Católica San Pablo, Arequipa, Peru

    Marcio Soto-Añari

  6. Instituto de Neurociencia Cognitiva, Arequipa, Peru

    Marcio Soto-Añari

  7. G.H. Sergievsky Center, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain Department of Neurology, Columbia University Medical Center, 630W 168th street, room PH19-314, New York City, NY, 10032, USA

    Giuseppe Tosto

Authors
  1. Neetesh Pandey
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  2. Zikun Yang
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  3. Basilio Cieza
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  4. Dolly Reyes-Dumeyer
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  5. Min Suk Kang
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  6. Rosa Montesinos
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  7. Marcio Soto-Añari
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  8. Nilton Custodio
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  9. Lawrence S. Honig
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  10. Giuseppe Tosto
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Contributions

GT, NC contributed to the conception and design of the study.GT, NP, NC, ZY, BH, RM, MSA, LH, MSK, DRD contributed to the acquisition and analysis of data. GT and NP contributed to drafting the text or preparing the figures.

Corresponding author

Correspondence to Giuseppe Tosto.

Ethics declarations

Ethical approval and consent to participate

Informed consent was obtained from all participants. The study protocol was approved by the Institutional Review Board (IRB) of Columbia university Medical Center (CUMC) (Approval number: AAAT2447). The study was conducted according to the principles expressed in the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Pandey, N., Yang, Z., Cieza, B. et al. Plasma phospho-tau217 as a predictive biomarker for Alzheimer’s disease in a large south American cohort. Alz Res Therapy 17, 1 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13195-024-01655-w

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13195-024-01655-w

Keywords

Alzheimer's Research & Therapy

ISSN: 1758-9193