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- Blood biomarkers like p-tau217, GFAP, and NfL can signal Alzheimer’s disease years before symptoms appear.
- Older adults naturally have higher biomarker levels. This means doctors need different ways to read results for each age group.
- Women—especially postmenopausal women—often show higher levels of Alzheimer’s biomarkers than men.
- Women with the APOE4 gene face uniquely higher Alzheimer’s risk. This is due to a mix of their genes and hormones.
- Getting a detailed risk profile for each person could change how we find dementia early and work to prevent it.
Finding dementia early is key for treatment and managing the condition. But the tests we use might not work as well for everyone. New studies on blood tests are showing that age, sex, and hormone changes like menopause greatly affect how Alzheimer’s and other kinds of dementia show up in the body. This article looks at how these things affect blood tests for dementia, why this is important, and how using this information in testing could lead to better care for each person and better outcomes.
What Are Dementia and Alzheimer’s Blood Biomarkers?
Dementia is a set of symptoms that show a slow decline in thinking abilities. Alzheimer’s disease (AD) is the most common reason people get dementia. It’s hard to find Alzheimer’s early on, but brain research is moving fast thanks to tests that find biomarkers in blood.
Blood-based biomarkers are signs found in the blood that show what’s happening in the brain. Blood tests are low-cost, simple, and can be used widely. This is different from spinal fluid tests or expensive brain scans.
Here are the main blood biomarkers researchers are looking at or already using
P-tau217
Phosphorylated tau at threonine 217 (p-tau217) is one of the most reliable markers for Alzheimer’s. Tau is a protein that helps nerve cells stay stable. In AD, it changes and builds up into clumps. P-tau217 levels go up a lot as the disease gets worse. They can even start going up before people show any symptoms.
Neurofilament Light Chain (NfL)
NfL is a general marker for nerve cell damage. It’s not just for Alzheimer’s. It can also show nerve damage in conditions like multiple sclerosis, brain injuries, and frontotemporal dementia. NfL levels in the blood go up when nerve cells get hurt. While it doesn’t point only to AD, it’s an important part of checking overall brain health.
Glial Fibrillary Acidic Protein (GFAP)
Astrocytes, which are support cells in the brain, make GFAP. This marker shows when these cells are active, when there’s swelling, and when brain tissue is hurt. Higher GFAP levels are seen more and more as an early sign of stress on these support cells. This happens before mental decline, especially as Alzheimer’s gets worse.
Aβ42/40 Ratio
Amyloid-beta proteins Aβ42 and Aβ40 come from another protein called APP. In AD, Aβ42 often collects and forms clumps in the brain. By measuring the ratio of Aβ42 to Aβ40 in blood, doctors can get an idea if amyloid clumps are building up. These clumps are a key sign of Alzheimer’s.
Together, these Alzheimer’s markers help create a biological “picture” of AD before symptoms start. This allows for finding the disease earlier and planning steps to help (Jack et al., 2018).
Age and Its Influence on Biomarker Expression
Getting older is the biggest risk factor for Alzheimer’s disease besides genes. Aging causes important body and cell changes that can affect blood biomarkers.
Baseline Increases with Age
Many studies over time show a clear pattern: levels of p-tau217, NfL, GFAP, and even amyloid markers naturally rise as people get older. This happens even in people whose thinking is still sharp. For example, NfL goes up steadily as nerve cells wear down with age. And GFAP might show that support cells are working harder due to slight swelling.
Increases related to age make early testing harder. This is because what’s “normal” for an older person’s markers might look like disease levels in a younger person. If doctors don’t use different standard ranges for different ages, a 65-year-old with slightly higher NfL might get a wrong diagnosis. But a 40-year-old with the same level could be starting to get dementia.
Need for Age-Specific Cutoffs
To deal with these differences, researchers say doctors should use different test standards for different age groups. If doctors don’t use these flexible standards, even the best Alzheimer’s markers might not be as useful in clinics.
Furthermore, ongoing studies suggest that looking at changes over time—how biomarker levels rise or fall—might be a better way to guess risk than just one test at one time.
Sex Differences in Blood Biomarkers: What the Research Shows
For a long time, people didn’t pay enough attention to sex differences in Alzheimer’s. More women get Alzheimer’s than men, but the reasons are more than just that women tend to live longer.
Inherent Biological Differences
Studies now show that even among people with normal thinking, women often have higher starting levels of markers like GFAP and tau, including p-tau217. This might mean that women either have stronger early signs of disease or their bodies and nerve cells react differently than men’s.
Here’s what stands out
- GFAP levels are often higher in women, even before any thinking problems start.
- Women might see a faster rise in p-tau217 after midlife. This could be linked to hormone changes.
Sex-Specific Disease Trajectories
Some brain science ideas suggest that women’s brains, in how they are built and how they work, react differently to nerve cell damage. These differences matter for how we read biomarker tests. They show we need to sort testing, training, and treatment plans based on sex.
If the current standards for clinical tests are mostly based on studies with more men, then biomarker tests could either say men are at higher risk when they aren’t or miss the risk in women. This could mean women get help later.
Menopause: A Biological Game-Changer for Women’s Brain Health
Menopause is more than just a change in periods. It causes big changes in the brain.
Estrogen and Neuroprotection
Estrogen helps protect nerve cells. It affects how nerve cells connect, how the power parts of cells work, and how the body handles swelling. When estrogen levels drop during menopause, the brain can become weaker against harm, amyloid buildup, and tau problems.
Biomarker Evidence
A key study by Wang et al. (2025) shows this link clearly. They found big increases in dementia markers in women after menopause
- P-tau217 and GFAP levels went up by 20–50% after menopause.
- Women who started menopause during the study had the fastest increases in all markers.
- Those who had early menopause had even higher marker levels.
These results suggest that menopause is a turning point where Alzheimer’s problems might speed up, even when there are no clear symptoms. This “risky time” is important for checking things out and planning ways to prevent problems.
Genetic Layers: APOE4 and Its Intersections
The APOE gene comes in three common forms: ε2, ε3, and ε4. The ε4 form is the strongest known gene-related risk factor for late-onset Alzheimer’s disease. It greatly affects Alzheimer’s biomarkers.
Sex and APOE4 Interactions
Data shows a worrying link between being female, going through menopause, and having the APOE4 gene
- Women with the APOE4 gene have much higher levels of amyloid and tau markers compared to men with the gene and people without the gene.
- Women after menopause with APOE4 might face even higher risk. This is because of both their gene and less hormones (Wang et al., 2025).
This link suggests that Alzheimer’s markers react to both things you are born with (genes) and outside things (hormones). This makes the disease get worse faster in some groups of people.
Implications for Screening
Testing for the APOE gene along with tracking biomarkers could really help target prevention efforts better. For instance, testing plans could suggest checking more often or starting lifestyle changes earlier for women who have APOE4 and are starting menopause.
Real-World Application: Rethinking One-Size-Fits-All Diagnostics
Using dementia biomarkers in clinics still faces some problems. The main one is using the same standard test results for everyone.
Problems with Uniform Cutoffs
Biomarker levels naturally differ based on sex, age, and menopause status. So, using the same rules for everyone when reading results often leads to mistakes. This could mean
- Getting a positive result for risk when there is none: This might happen for older women whose higher marker levels are normal for them.
- Missing problems: This could happen for women before menopause or younger women who have brain changes but are below the current standard levels.
- Unequal care: This means missing high-risk groups like women with APOE4, people from different racial and ethnic groups, or those with early menopause.
Solutions
The way forward is to use computer models that include facts about each person when reading biomarker results. These models should consider
- Age group
- Biological sex
- Hormone changes (like menopause)
- Gene markers
- Starting level of thinking ability
These models that sort risk for each person could help decide not only who needs more tests but also what help to start and when.
A Step Toward Neurology for Each Person
We are moving into a new era: looking at neurology based on each person.
Detailed Risk Profiling
Just like cancer care changed to use details about a tumor for specific treatments, brain care is moving toward using biomarkers to guide prevention. Instead of seeing Alzheimer’s as a problem that only happens late in life, we can now check brain health many years earlier.
Here are some real examples
- Checking markers in middle age to find each person’s starting levels.
- Checking for changes in p-tau217 or GFAP every year for those more likely to be at risk.
- Planning changes to diet, sleep, or hormone treatment based on biomarker patterns.
Connecting Lifestyle and Biology
Checking details about a person’s life—like how much they exercise, what they eat, how much alcohol they drink, and how they sleep—along with biological risk factors could also help create complete care plans.
Challenges in Making This Happen
It’s not easy to take these findings and use them in daily medical care. There are several system-wide problems
Limited Demographic Representation
Most studies on dementia biomarkers include people who are not very diverse. They are mainly older, white, and male. We urgently need
- More women taking part.
- People from many different racial and ethnic groups.
- A wider range of ages, especially women before menopause.
Resource Constraints
Blood tests cost less than brain scans or spinal taps. But new tests still need to be proven to work, made standard across labs, and paid for by health systems. This means
- Updating equipment and systems.
- Changing insurance rules.
- Studying if these tests save money in the long run.
Clinician Education
Many doctors need to learn how to understand biomarker results that are different for men and women. Training programs need to catch up quickly with new research. This will make sure doctors can give fair care based on the best facts.
The Future of Finding Alzheimer’s Before Symptoms
The main aim is to have a simple testing process driven by data.
AI and Algorithmic Integration
Computer systems are being made that put together
- Biomarkers (from blood, genes, scans).
- Facts about the person (age, sex, menopause).
- Thinking test results.
These systems can give a changing risk score, point out worrying patterns, and even suggest prevention steps automatically in a person’s medical chart.
Hormone-Informed Medicine
Adding details about a woman’s period history, menopause status, and hormone treatment to medical records can help create highly specific paths for brain health care.
Why This Matters: Public Health and Prevention
Alzheimer’s disease costs billions every year and hurts families and caregivers deeply. Focusing on prevention that is specific to each person isn’t just smart science. It’s something we must do for public health.
What Needs to Happen
- Add regular biomarker checks to yearly exams for people in middle age.
- Teach patients, especially women, about brain health and hormone changes.
- Create clinical trials and data sets that are fair and include many different kinds of people.
Taking steps early could delay or even stop symptoms for millions. Now is the time to make this approach common.
Key Takeaways
- Blood biomarkers like p-tau217, GFAP, NfL, and Aβ42/40 are changing how we find dementia.
- Age, biological sex, and menopause status greatly affect biomarker levels.
- Postmenopausal women, especially those with the APOE4 gene, show the highest levels of Alzheimer’s biomarkers.
- Using the same test standards for everyone risks getting the wrong diagnosis. We urgently need test standards that consider sex and hormones.
- Making screening that fits each person more common can help find problems earlier. It can also lead to prevention steps that are right for specific people and help make sure everyone gets fair access to brain health care.
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Citations
- Jack, C. R., et al. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia, 14(4), 535–562. https://doi.org/10.1016/j.jalz.2018.02.018
