Can I Predict My Future Risk of Dementia? The New Frontier of Alzheimer’s Diagnostics: Utilizing Biomarkers for Prevention and Treatment, Part I
For decades, the diagnosis of Alzheimer’s disease (AD) was a process of elimination, often confirmed only after significant cognitive decline or through postmortem examination. Today, we have entered the “Biomarker Era.” Breakthroughs in fluid-based assays- specifically measuring beta-amyloid 42/40 ratios, phosphorylated Tau (p-tau 181 and p-tau 217), and Neurofilament Light chain (NfL)- are transforming Alzheimer’s from an invisible thief into a manageable, and preventable condition. I want to explain to you how to best use these biomarkers in both prevention and treatment of not just Alzheimer’s dementia, but other neuroinflammatory conditions.
In some cases, when we know the potential origin of the neuroinflammation, for example, if we suspect that it is primarily from a bacterial infection like Lyme disease (Borrelia burgdorferi) which is driving amyloid production as well as biofilm and phosphorylated tau production… (yes, Lyme disease does that) … we can potentially intervene at an early stage with treatment. We may even be able to stem the process and reverse these Alzheimer’s biomarkers to prevent future cognitive decline. How do I know? I just did it in a patient for the first time and published it in a major scientific journal. I will share these findings with you in this Substack Part II. But before we dive into this important article in the Journal of Alzheimer’s Disease Case Studies, and the massive implications of what I found (I’m not exaggerating), we need to understand what these biomarkers represent and when they are NOT specific for Alzheimer’s dementia. This is important to understand because I’m finding these Alzheimer’s biomarkers are present in a significant percentage of my chronic Lyme disease patients. I’ve asked another doctor I work with in my new consultation model to check her patients. She found the same thing. These biomarkers were present in approximately one third of her chronic Lyme patients. What does this mean?
This does not mean you or your loved ones with chronic Lyme disease/PTLDS will necessarily develop dementia, but it does mean specific clinical decision-making strategies are needed to prevent issues in the future. Similar to evaluating cardiovascular risk factors like hypertension, hyperlipidemia, metabolic syndrome and diabetes in determining future risks of a heart attack, stroke or kidney failure, these biomarkers can assist us in determining whether certain inflammatory conditions are present so we can intervene at an early stage and potentially halt and reverse what some consider to be an inexorable decline in health. As far as I’m aware, the vast majority of Lyme doctors, apart from ones I have discussed my findings with, DO NOT test for these biomarkers, and we need to be doing it. I will show you why. Be clear, this article is being written to protect you and your loved ones. These biomarkers essentially give us another tool in our toolbox to monitor inflammation, and there are things you can do about them…
Let’s examine these biomarkers in detail to understand how we can use them for diagnostics and then dive into the multifactorial nature of Alzheimer’s disease/dementia to understand best how to interpret these biomarkers during treatment.
The Basics of Alzheimer’s Disease Biomarkers
Alzheimer’s disease biomarkers reflect specific pathophysiological processes involving amyloid deposition, tau phosphorylation, and neuronal injury. The amyloid beta 42/40 ratio decreases as amyloid beta 42 become sequestered in brain plaques. This occurs while phosphorylated tau (p-tau181, p-tau 217) increases in response to amyloid pathology and tau aggregation with neurofilament light chain (NfL) arising with axonal damage.
1. Beta-amyloid 42/40 Ratio: The Early Warning System
The amyloid beta 42/40 ratio is the primary indicator of amyloid plaque.
The amyloid beta 42 is the “stickier” form which begins to clump into plaques.
The amyloid beta 42/40 ratio reflects the balance between the more aggregation prone amyloid beta 42 peptide and the more abundant amyloid beta 40 peptide. In Alzheimer’s disease, amyloid beta 42 becomes trapped in cerebral amyloid plaques, leading to decreased soluble amyloid beta 42 in cerebrospinal fluid (CSF) and blood relative to amyloid beta 40, resulting in a low amyloid beta 42/40 ratio. Therefore, the 1st most important thing to realize in interpreting your amyloid beta 42/40 test when it returns, is that you want an elevated amyloid beta 42/40 ratio, not a low ratio, since a low ratio implies that amyloid beta 42, the stickier form of the protein, is being deposited in plaques.
Sensitivity and Specificity: the sensitivity is 84 to 92%, and the specificity is 73 to 80% for detecting brain amyloidosis. This means we can pick up early beta-amyloid production in roughly 9 out of 10 people, and it will be specific for the disease process in approximately 8 out of 10 people.
The ratio is significantly more accurate than measuring amyloid beta 42 alone, as it accounts for individual differences in total protein production. The cerebrospinal fluid (CSF) shows approximately 50% reductions in amyloid beta 42/40 in individuals with amyloid pathology, while plasma levels shows a more modest decrease of less than 20%, likely due to peripheral production of amyloid, binding to plasma proteins. When determining the diagnostic accuracy of plasma amyloid beta 42/40 ratios compared to amyloid PET scans (which are expensive and time consuming), in a cohort of 465 patients, the study below proved it is a robust measure for detecting amyloid plaques and can be used in the diagnosis of AD.
Role in Prevention and Treatment
Prevention: This ratio becomes abnormal up to 20 years before the 1st symptom appears. It allows for “secondary prevention” where individuals are identified in the preclinical stage for clinical trials or aggressive lifestyle interventions.
Treatment: Modern anti-amyloid immunotherapies (like lecanemab or donanemab) use this ratio to confirm the presence of the drugs target. Without a positive amyloid test, these multi-billion-dollar treatments cannot be prescribed.
Non-Alzheimer Disease Causes for Positive Results
Cerebral Amyloid Angiopathy (CAA): Amyloid buildup happens in the walls of the brain’s blood vessels. Keep in mind, infections that have entered the Central Nervous System (CNS) are able to cause amyloid production, although most times the infections trigger amyloid deposition in brain tissue not blood vessels (although it can happen). Infectious pathogens that have been linked to amyloid production include but are not limited to bacteria (Borrelia burgdorferi, Chlamydia pneumonia), viruses (HSV 1, HIV), and fungi (Candida). A growing body of research posits that Amyloid-Beta is an antimicrobial peptide produced by the innate immune system to “trap” invading pathogens. Pathogens like Chlamydia pneumoniae and Herpes Simplex Virus (HSV) have been shown to “seed” and accelerate Aβ plaque formation in the brain. Lyme disease has also been associated with biofilm, beta-amyloid and phosphorylated tau.
Kidney disease and Renal Impairment: Poor kidney function can slow protein clearance, occasionally skewing blood-based ratios.
Remember that there is still controversy as to whether amyloid is the primary reason why individuals develop AD. We discussed this in a prior Medical Detective Substack:
2. Phosphorylated Tau: p tau 181 and p tau 217:
If amyloid is the “match” that starts the fire, Tau is the “fire” that spreads and kills neurons. Phosphorylation causes Tau proteins to detach from structural microtubules and form “tangles.” Phosphorylated tau in blood and CSF reflects Alzheimer’s disease specific pathology, with concentrations increasing 1.5-3.5 fold in AD compared to controls. Interestingly, CSF phosphorylated tau biomarkers show stronger correlations with amyloid beta plaques than with tau tangles themselves, suggesting P tau elevation is an early response to amyloidosis rather than a direct marker of tangle burden.
P tau 181: The Established Marker
Clinical Utility: It effectively differentiates Alzheimer’s disease (AD) from non-neurodegenerative conditions, but it is slightly less precise than newer variants in distinguishing AD from other dementias.
Sensitivity/Specificity: approximately 90%/78%
P tau 217: The New Gold Standard
Clinical utility: p tau 217 is highly specific to AD pathology. It increases very early- even before tangles are visible on scans- making it the most powerful blood-based tool for early diagnosis and monitoring “tau spread.” P tau 217 also outperforms P tau 181 in several key metrics: it shows a 13 fold increase in AD dementia versus non-AD; demonstrates stronger correlations with amyloid-PET (Positron Emission Tomography) and tau-PET; and achieves higher accuracy for differentiating AD from other neuro- degenerative diseases. P tau 217 becomes abnormal approximately 20 years before mild cognitive impairment onset in autosomal dominant AD, even before tau-PET positivity.
Sensitivity/Specificity: approximately 92%/86% (often approaching the accuracy of expensive PET scans) for detecting AD pathology.
Non-A/D Causes for Positive Results
Traumatic Brain Injury (TBI): Acute head trauma can cause temporary spikes in tau.
Chronic Kidney Disease (CKD): Can lead to false elevations due to reduced blood filtration.
Heterophilic Antibodies: Rare immune proteins in some patients can interfere with the lab assays themselves.
Neurofilament Light Chain (NfL): The Damage Gauge
Unlike Amyloid and Tau, which are specific to Alzheimer’s Disease, NfL is a non-specific marker of neurodegeneration and axonal damage. When a neuron dies or is damaged, NfL leaks into the CSF and blood. NfL is in axonal scaffolding protein essential for axonal growth, stability and synaptic organization. It functions as a nonspecific marker of neural axonal injury, released into the CSF and blood proportionally to the degree of axonal damage regardless of the underlying cause. AD shows moderate NfL elevations and is the highest fold change among AD biomarkers after total tau.
The problem is that NfL concentrations increase with age, complicating interpretation and necessitating specific reference values and the highest NfL levels occur in frontotemporal dementia, vascular dementia, HIV-associated dementia, ALS and atypical Parkinsonian disorders, not Alzheimer’s disease.
Sensitivity for NfL: is high, i.e. greater than 90% for detecting some form of neurodegeneration
Specificity for NfL: is low, around 40 to 50% for Alzheimer’s disease specifically. NfL cannot tell you why the brain is hurting, only how fast it is happening.
Other Conditions with Abnormal Biomarkers Beyond AD
ALS: Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease): has the highest NfL elevations among all neurological conditions.
Multiple Sclerosis (MS): has moderate NfL elevations, but much less than ALS
Frontotemporal Dementia (FTD): NfL is often higher than in AD
Stroke: acute, transient NfL elevations depend on infarct size and timing.
Dementia with Lewy bodies (DLB): appx. 2/3 show CSF AD biomarkers (low amyloid beta 42/40 ratios, elevated p-tau). When amyloid co-pathology is removed, NfL and Glial Fibrillary Acidic Protein (GFAP), another marker of inflammation remains elevated.
Creutzfeldt-Jakob disease (CJD): shows extremely high total tau with relatively normal p-tau, creating a distinctive pattern with low p-tau/tau ratio
A-T+ Biomarker profile (normal amyloid, elevated p-tau): 20% of cognitively intact adults present this way, and may represent non-Alzheimer’s tauopathy, age-related tauopathy, or altered CSF dynamics. This is what I have oftentimes been finding in CLD/PTLDS. See below.
Normal aging: NfL naturally increases as we age (does it have to?... I will answer that question later), requiring age-adjusted cutoffs.
Role in Prevention and Treatment
Prevention: Rapidly rising NfL levels serve as a smoke alarm, prompting doctors to search for an underlying cause before permanent damage occurs.
Treatment: NfL is used to monitor “disease modifying” effects. If a drug is working, NfL levels should stabilize and drop.
Important: Chronic Medical Conditions Significantly Affect AD Biomarker Levels
In a study of over 2000 dementia free participants, anemia, kidney disease, cerebrovascular disease and heart disease were all associated with variations in P tau 181, Total tau, Neurofilament light and another marker of brain injury called GFAP (Glial Fibrillary Acidic Protein) levels. The number of co-occurring chronic diseases associated with higher concentration of these biomarkers was directly influenced by systemic inflammation. You are probably aware that one of the major switches inside our cells called NF kappa B, releases inflammatory chemokines and cytokines including TNF alpha, IL-1 and IL-6. Elevated IL-6 especially amplifies these AD biomarker concentrations. So when a chronic Lyme disease patient with associated co-infections has these elevated biomarkers, it tells us that there is still ongoing inflammation. Where is the inflammation coming from? I previously published on the role of all 16 MSIDS factors in AD:
If these biomarkers are positive, you need to go back and determine where the inflammation is coming from by doing a full MSIDS review.
Patient Examples of Elevated AD Biomarkers and MSIDS Variables
These patient examples are not published in the journal article in the Journal of Alzheimer’s Disease Case Reports that I will share with you next week (the article has been accepted but the production team is a bit slow...). I want to give you a sense of how often I am finding these biomarkers. These imply that either the patient has not done enough biofilm/persister drug therapy like dapsone combination therapy with good CNS penetration, since according to work by Dr Judith Miklossy, Dr Eva Sapi and colleagues, Borrelia has been associated with biofilms, amyloid and phosphorylated tau in autopsy studies of individuals who died with Alzheimer’s disease as well as Parkinson’s disease. If these biomarkers are present, it also implies that other sources of inflammation on the 16 point MSIDS map apart from Borrelia may be affecting brain tissue. See below:
Patient 1: A 77 year-old female had a past medical history significant for chronic Lyme disease, Babesiosis, Mycoplasma exposure, CMV, HSV, elevated heavy metals (lead and aluminum), low vitamin D, metabolic syndrome, obesity (she lost over 60 lbs. with semaglutide), Obstructive Sleep Apnea (OSA), with evidence of inflammation. Her CRP (C-reactive protein) was elevated, which is an indirect marker of IL-6 elevation, which as we just discussed, amplifies production of these AD Biomarkers. She also had an elevated PLAC, a cardiovascular risk factor for strokes. When I ran her Alzheimer’s biomarkers, she had elevated levels of p-tau 181 at 1.36 (normal ˂ 0.97) and p-tau 217 elevated at 0.30 (normal ˂ 0.18). See below:
She got through 6 weeks of the double dapsone protocol, not eight, and did 3 days of HDDCT at the end, not four for CLD/PTLDS. When I last saw her at the end of 2025, before finishing one on one clinical practice, although she did get some initial benefit from doing the dapsone protocol, with less joint pain, improved energy and cognition, she was still complaining of some ongoing fatigue. She attributed this in part to her sleep apnea, as she was only averaging between three and five hours per night. She also had some issues with balance as well as memory/concentration problems and word finding problems. Not unexpected sleeping 3 hours a night! I discussed with her the need to address any and all of the 16 MSIDS variables which were driving inflammation, which in her case included finishing up the full course of double dose dapsone combination therapy for the biofilm/persister forms of Borrelia, getting over to her pulmonary doctor to address her CPAP therapy to improve her sleep apnea, detoxing her heavy metals, and continuing to work on her cardiovascular risks. My advice was based on not only a literature review, but our upcoming published study which showed that we can reverse p-tau 217 and improve beta-amyloid ratios in chronic Lyme disease/PTLDs with the full 8 to 9 week dapsone combination therapy while addressing MSIDS variables. She never finished the full course.
Patient 2: An 89-year-old white male with a past medical history significant for hypertension, hyperlipidemia, metabolic syndrome, chronic kidney disease, anemia and MGUS (Monoclonal Gammopathy of Unknown Significance) as well as chronic Lyme disease complained of increasing memory/concentration problems and difficulty walking. His beta-amyloid ratios were normal, but he had a significantly elevated p-tau 181 and NfL. He had never done double dose dapsone combination therapy or high dose dapsone Combination Therapy due to his anemia from MGUS.
As we discussed, anemia and chronic kidney disease are associated with elevations in p- tau 181 and NfL. Midlife hypertension and diabetes can also be associated with more rapid rises in NfL. So although it is likely that some of the untreated Lyme disease (not using a biofilm/persister drug regimen) contributed to these results, cardiometabolic factors and age could also be contributing factors. The above patients BTW were ApoE 3/3, not the genetic subtype normally associated with AD.
Patient 3: A 77-year-old white female had a past medical history significant for hypertension, hypothyroidism, osteoporosis, allergic rhinitis, chronic Lyme disease, exposure to Bartonella, and mold toxicity. Her chief complaints were fatigue, insomnia with frequent awakening, migratory joint pain, neuropathy and memory/concentration problems. She decided to do low dose minocycline (50 mg per day) and low dose dapsone at a dose of 25 mg her day for 1-2 years, because she was concerned with the side effects of higher dose dapsone (especially Herxheimer reactions) and noticed prior help with low dose dapsone regarding her cognition which was much better. However, once she stopped dapsone and minocycline, she relapsed off the drugs, although she was still better than when she started. These were her AD biomarkers:
We discussed doing the full double dose dapsone protocol and high dose dapsone pulse for the biofilm/persister forms of Borrelia (the migratory aspect of her pain told me the infections were still active) while addressing her mycotoxin exposure. This case illustrates that even though low dose dapsone may improve cognition, it is not enough to lower AD biomarkers.
Patient 4: A 50-year-old female had a past medical history significant for chronic Lyme disease, babesiosis (Babesia FISH positive) and Bartonellosis (Bartonella FISH positive), with hypothyroidism and overlapping mold toxicity. Primary symptoms included some fatigue, electric shocks in the lower and rarely upper extremities with some memory issues. Her last Immunoblot showed exposure to Borrelia specific bands (the 34 kDa, Osp B is highly specific as is the 23 kDa, OspC):
She did not want to do the full double dose dapsone combination therapy protocol or high dose dapsone pulses needed for chronic Bartonella due to her demanding job and being a mother having to take care of a child. She chose instead to do several two week pulses of high dose dapsone Combination Therapy, which significantly improved her clinical status. However, her AD markers showed an elevated p-tau 217/amyloid beta 42 ratio, putting her potentially at increased risk years from now. See below:
I advised her to follow these biomarkers after doing a more comprehensive dapsone protocol to treat her active infections and detoxify her mold toxins.
Patient 5: A 78 year-old male presented with a PMH significant for Alzheimer’s dementia years ago. He was diagnosed by a neurologist after having a positive F-18 PET scan and was placed on lecanemab, the monoclonal antibody that helps to remove amyloid plaque. However, his neurologist never checked him for Lyme or co-infections like Babesia and Bartonella, even though he lived in Massachusetts! He was positive for Lyme disease, Bartonella (by FISH), mold toxicity (high), elevated serum lead, phase 2 Adrenal dysfunction, and low RBC magnesium. These were from the last set of bloods:
Starting on 4/18/2025, the beta-amyloid 42/40 ratio was 0.094 (low) which is indicative of amyloid deposition, and improved on 9/19/2025 to 0.103, which normalized after doing dapsone combination therapy. Good! His p-tau levels had slowly increased however over the past year (the p-tau 217 on 4/18/2025 was 0.49 and increased on 9/19 to 0.56 but began stabilizing recently). He just finished his 4th dapsone pulse for chronic, active Bartonella, while intermittently detoxing his mold, and we are waiting to evaluate his repeat AD markers several months post pulse. Take home point: we can’t just name a disease (Alzheimer’s) and throw drugs at it that don’t affect the long-term progression (lecanemab), while putting the patient at risk for brain shrinkage and brain bleeds, a known potential side effect of these drugs. You need to look at all 16 MSIDS factors to understand where the inflammation is coming from. The 5 case studies listed above all highlight AD biomarker changes in CLD, but I did not have pre and post levels because all my patients had already done dapsone by the time these biomarkers became widely available. The patients also had not finished addressing all of the underlying sources of inflammation, requiring longer-term follow-up.
Protecting Your Future Health: Biomarker Monitoring & 5 Strategic Ideas
The availability of these tests, such as the blood-based Quest AD-Detect or PreclivityAD2 offers a blueprint for lifelong brain health management:
1. Establish a Cognitive Baseline: Much like a colonoscopy at age 45, since colon cancer is now appearing much more frequently in young individuals, individuals with a family history of A/D could get blood tests of AD biomarkers in their fifties to establish a baseline.
2. The “High-Stakes” Screen: Before making major late life decisions (e.g. retirement, moving to a care community), biomarkers can provide clarity on whether current “Forgetfulness” is benign aging or a clinical progression.
3. Lifestyle Validation: If the patient tests “amyloid positive” but “tau negative” they are in a critical window where and aggressive Mediterranean diet, aerobic exercise, and sleep hygiene may delay the onset of symptoms for years.
4. Clinical Trial Enrollment: These markers allow you to join trials for drugs that prevent plaque from ever forming, rather than waiting for the brain to be damaged. Next week, I will tell you about my idea for a very interesting study (and would suggest it gets funded with urgency based on my recent findings that I will be sharing in the next SUBSTACK).
5. Monitoring Non-A/D Brain Health: Use NfL as a part of an annual wellness check to monitor for subclinical brain damage from high blood pressure, diabetes, or undiagnosed sleep apnea.
Summary: We are moving towards a future where a blood test can reveal the molecular status of the brain. By combining the amyloid beta 42/40 ratio for early warning of amyloid deposition, Phosphorylated tau for diagnostic certainty of tau tangles/pathology, and Neurofilament light for damage monitoring, we can finally shift the focus of dementia and Alzheimer’s care from management of loss to prevention of decline. Up until now in the published medical literature, the only interventions proven to reverse Alzheimer’s biomarkers have been anti-amyloid monoclonal antibodies (lecanemab, donanemab) which both clear amyloid plaques and demonstrate downstream effects on tau pathology. In the TRAILBLAZER-ALZ trial, donanemab reduced plasma p-tau 217 by approximately 23%.
In our upcoming article in the Journal of Alzheimer’s Disease Case Studies, which I will discuss in detail in next week’s Substack, I highlight for the first time in the published medical literature that:
All 16 MSIDS factors are associated with AD and
Demonstrate the ability of a biofilm/persister drug regimen (dapsone combination therapy) to reverse AD biomarkers and biomarkers of inflammation in CLD/PTLDS.
We have pre and post levels in that particular patient who had never previously done dapsone combination therapy and was a clear case of CLD/PTLDS (no one will argue with this case when you read the article). Why is this groundbreaking news?
This is the first study to not only show the relationship of MSIDS factors with Alzheimer’s disease, but we proved we can lower p-tau 217 even more effectively than using anti-amyloid monoclonal antibodies!
To learn more about this study, please listen to the interview I did with Dr Christine Burke on the upcoming Alzheimer’s disease Summit from Doctors Talks. It is free to sign up, and you will learn about cutting edge techniques to support brain health. Don’t miss this!
https://drtalks.com/summits/alzheimers/turmeric-brain-health-curcumin?uid=944&oid=111&ref=3029
