One paper, one week: plasma biomarkers of Alzheimer's, how good are they?

Ladan Kalani
Mar 21
4 min read

Updated: Mar 23

This blog is based on a recent publication by Dr. Cheryl Wellington's team at the University of British Columbia in Vancouver, BC, Canada; most of the work was done by Jennifer G. Cooper. The paper is titled "APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors", see full reference at the end.

When biomarkers speak silently.

What if the biology of Alzheimer’s disease is present… but the symptoms never arrive?

That’s the question at the heart of this week’s paper, which explores a remarkable group of individuals known as “Super-Seniors” aged 85+ who remain cognitively healthy and free from major age-related diseases.

These individuals offer something rare in biomedical research: a window into resilient aging.

Beyond diagnosis: what are we measuring?

Modern Alzheimer’s research increasingly relies on blood-based biomarkers. In this study, four were examined:

amyloid beta ratio (Aβ42/40) → linked to amyloid plaque accumulation (Li et al., 2022)
Phosphorylated tau (p-tau181) → linked to tau pathology and amyloid burden (Karikari et al., 2020)
Neurofilament light (NfL) → marker of neurodegeneration (Mattsson et al., 2019)
Glial fibrillary acidic protein (GFAP) → marker of astrocyte activation and inflammation (Pang et al., 2017)

Shown in their Figure 2 is the measure of the four plasma biomarkers in the epsilon 4 carrier and non-carrier participants.

Concentrations of plasma biomarkers of Alzheimer's

These markers are often interpreted as early signs of disease, but they are also influenced by age, sex, BMI, comorbidities, in turn complicating their interpretation.

This study removes that noise by focusing on a healthy high-functioning elderly.

A rare window into healthy aging

The design is one of the strongest aspects of this work.

Participants were carefully screened to exclude dementia, diabetes & cardiovascular disease, cancer and underwent functional and cognitive tests to confirm their resilience.

This allowed the authors ask: How does APOE ε4, a genetic risk factor for Alzheimer’s, affect biomarker levels in healthy aging?

At first glance, several biomarkers differed between groups. APOE ε4 carriers showed:

slightly lower Aβ42/40,
higher p-tau181,
and higher GFAP.

But after adjusting for demographic variables, most of these signals faded.

Only one stood out: p-tau181.

Even after accounting for age, sex, and BMI, p-tau181 was consistently higher in APOE ε4 carriers. The association was particularly pronounced in females.

And yet, these individuals remained cognitively normal.

Rethinking what biomarkers mean

This is where the story becomes especially compelling.

If a biomarker associated with Alzheimer’s pathology is elevated in people with normal cognition, what is it measuring?

Two possibilities emerge:

Silent pathology: biological changes are present, but do not progress to symptoms [perhaps if we figure to live beyond 110 years, symptoms may surface].
Resilience mechanisms; protective factors buffer the brain against decline, such as minimizing chronic stress and neuroinflammation.

Either way, this challenges a simple interpretation of biomarkers as direct indicators of disease.

They may reflect underlying biological stress or vulnerability.

Limitations, what remains unknown.

The absence of neuroimaging or cerebrospinal fluid data means they cannot directly confirm underlying Alzheimer’s pathology. Other physiological variables beyond age, sex, and BMI may also influence biomarker levels.

Additionally, APOE was analyzed as ε4 carrier vs non-carrier, leaving open questions about dose effects, and the cohort lacked ethnic diversity, which is important given known variation in APOE distribution.

The takeaway

This study shows that p-tau181 is strongly associated with APOE ε4 status, even in healthy aging, and that this relationship persists independent of key demographic factors.

But more importantly, it reframes how we think about biomarkers:

They don’t just signal disease. They reveal underlying biology that may take years before outcomes diverge.

Funding

This research was supported by the Canadian Institute of Health Research (CIHR).

Consent statement

Every study participant provided informed consent.

References

Cooper, J.G., M. Ghodsi, S. Stukas, S. Leach, A. Brooks-Wilson, and C.L. Wellington. 2024. APOE epsilon4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors. Alzheimers Dement. 20:4373-4380.

Karikari, T.K., T.A. Pascoal, N.J. Ashton, S. Janelidze, A.L. Benedet, J.L. Rodriguez, M. Chamoun, M. Savard, M.S. Kang, J. Therriault, M. Scholl, G. Massarweh, J.P. Soucy, K. Hoglund, G. Brinkmalm, N. Mattsson, S. Palmqvist, S. Gauthier, E. Stomrud, H. Zetterberg, O. Hansson, P. Rosa-Neto, and K. Blennow. 2020. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 19:422-433.

Li, Y., S.E. Schindler, J.G. Bollinger, V. Ovod, K.G. Mawuenyega, M.W. Weiner, L.M. Shaw, C.L. Masters, C.J. Fowler, J.Q. Trojanowski, M. Korecka, R.N. Martins, S. Janelidze, O. Hansson, and R.J. Bateman. 2022. Validation of Plasma Amyloid-beta 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. 98:e688-e699.

Mattsson, N., N.C. Cullen, U. Andreasson, H. Zetterberg, and K. Blennow. 2019. Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 76:791-799.

Pang, Z., A. Kushiyama, J. Sun, T. Kikuchi, H. Yamazaki, Y. Iwamoto, H. Koriyama, S. Yoshida, M. Shimamura, M. Higuchi, T. Kawano, Y. Takami, H. Rakugi, R. Morishita, and H. Nakagami. 2017. Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes. FASEB J. 31:4053-4063.

When biomarkers speak silently.

What if the biology of Alzheimer’s disease is present… but the symptoms never arrive?

That’s the question at the heart of this week’s paper, which explores a remarkable group of individuals known as “Super-Seniors” aged 85+ who remain cognitively healthy and free from major age-related diseases.

These individuals offer something rare in biomedical research: a window into resilient aging.

Beyond diagnosis: what are we measuring?

Modern Alzheimer’s research increasingly relies on blood-based biomarkers. In this study, four were examined:

amyloid beta ratio (Aβ42/40) → linked to amyloid plaque accumulation (Li et al., 2022)

Phosphorylated tau (p-tau181) → linked to tau pathology and amyloid burden (Karikari et al., 2020)

Neurofilament light (NfL) → marker of neurodegeneration (Mattsson et al., 2019)

Glial fibrillary acidic protein (GFAP) → marker of astrocyte activation and inflammation (Pang et al., 2017)

Shown in their Figure 2 is the measure of the four plasma biomarkers in the epsilon 4 carrier and non-carrier participants.

These markers are often interpreted as early signs of disease, but they are also influenced by age, sex, BMI, comorbidities, in turn complicating their interpretation.

A rare window into healthy aging

The design is one of the strongest aspects of this work.

Participants were carefully screened to exclude dementia, diabetes & cardiovascular disease, cancer and underwent functional and cognitive tests to confirm their resilience.

This allowed the authors ask: How does APOE ε4, a genetic risk factor for Alzheimer’s, affect biomarker levels in healthy aging?

At first glance, several biomarkers differed between groups. APOE ε4 carriers showed:

But after adjusting for demographic variables, most of these signals faded.

Only one stood out: p-tau181.

Even after accounting for age, sex, and BMI, p-tau181 was consistently higher in APOE ε4 carriers. The association was particularly pronounced in females.

And yet, these individuals remained cognitively normal.

Rethinking what biomarkers mean

This is where the story becomes especially compelling.

If a biomarker associated with Alzheimer’s pathology is elevated in people with normal cognition, what is it measuring?

Two possibilities emerge:

Silent pathology: biological changes are present, but do not progress to symptoms [perhaps if we figure to live beyond 110 years, symptoms may surface].

Resilience mechanisms; protective factors buffer the brain against decline, such as minimizing chronic stress and neuroinflammation.

Either way, this challenges a simple interpretation of biomarkers as direct indicators of disease.

They may reflect underlying biological stress or vulnerability.

Limitations, what remains unknown.

The absence of neuroimaging or cerebrospinal fluid data means they cannot directly confirm underlying Alzheimer’s pathology. Other physiological variables beyond age, sex, and BMI may also influence biomarker levels.

Additionally, APOE was analyzed as ε4 carrier vs non-carrier, leaving open questions about dose effects, and the cohort lacked ethnic diversity, which is important given known variation in APOE distribution.

The takeaway

This study shows that p-tau181 is strongly associated with APOE ε4 status, even in healthy aging, and that this relationship persists independent of key demographic factors.

But more importantly, it reframes how we think about biomarkers:

They don’t just signal disease. They reveal underlying biology that may take years before outcomes diverge.

Funding

This research was supported by the Canadian Institute of Health Research (CIHR).

Consent statement

Every study participant provided informed consent.

References

Cooper, J.G., M. Ghodsi, S. Stukas, S. Leach, A. Brooks-Wilson, and C.L. Wellington. 2024. APOE epsilon4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors. Alzheimers Dement. 20:4373-4380.

Mattsson, N., N.C. Cullen, U. Andreasson, H. Zetterberg, and K. Blennow. 2019. Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 76:791-799.

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