Improving biomarkers of inflammation including phosphorylated tau in a patient with chronic Lyme disease/post-treatment Lyme disease syndrome using dapsone combination therapy: A case study and literature review

Abstract

Background

Borrelia burgdorferi, the agent of Lyme disease, has been found to co-localize in Alzheimer's disease autopsy brain tissues with biofilm, amyloid, and phosphorylated tau.

Objective

To determine whether dapsone combination therapy (DCT), a biofilm/persister antibiotic regimen with good central nervous system penetration can improve p-tau and peripheral inflammatory markers in a patient with chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDs).

Methods

A 67-year-old female with CLD/PTLDs, and Ehrlichia, Babesia, Bartonella, and Coxiella burnetii had a 15-year history of joint pain with inflammation and mild cognitive impairment despite prior treatment with doxycycline. She was checked for changes in peripheral inflammation, i.e., rheumatoid factors (RFs) and changes in serum p-tau181, p-tau 217, and amyloid-β (Aβ) 42:40 ratios before and after treatment with DCT.

Results

Elevated RFs at 20 IU/mL decreased into normal range three months post treatment accompanied by a decrease in pain with improved flexibility. An initially elevated serum p-tau 217 level in the blood at 0.33 pg/mL (normal range <0.15 pg/mL) prior to using DCT normalized, decreasing to 0.12 pg/mL three months post therapy, while p-tau 181 levels remained within normal limits. Aβ ratios simultaneously improved post DCT increasing from 0.185 pg/mL to 0.216 (normal range >0.170) accompanied by subjective improvements in concentration and recall.

Conclusions

This is the first case study proving that a short term, biofilm/persister drug regimen, i.e., DCT, can potentially improve peripheral autoantibodies (RFs) and pathological triggers of neuroinflammation (p-tau, Aβ) in a patient with CLD/PTLDs.

Keywords

Alzheimer’s disease amyloid-β 42:40 ratio chronic Lyme disease dapsone combination therapy double dose dapsone combination therapy p-tau 181 p-tau 217 post-treatment Lyme disease syndrome rheumatoid factor

Introduction

Lyme disease, due to an infection with Borrelia burgdorferi (Bb) is spreading worldwide with global Bb seroprevalence estimated at 14.5% of the global population.¹ Approximately 33% of those infected with Bb may go onto develop chronic persistent symptomatology despite treatment with antibiotics, known as ‘chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDs).² Symptoms of CLD/PTLDs oftentimes overlap those of other chronic fatiguing, musculoskeletal, cardio-pulmonary, neuropsychiatric illnesses, including Long COVID.³ Patients with both acute and CLD/PTLDs may complain of debilitating fatigue, joint and muscle pain, nerve pain, i.e., neuropathy, headaches, sleep disorders, significant memory/concentration problems,⁴ as well as neuropsychiatric presentations.⁵ Patients with CLD/PTLDs have a disease burden comparable to those suffering with chronic congestive heart failure,⁶ and have reported significantly lower health quality status, more bad mental and physical health days and greater activity limitations.⁷ Finding a solution is of paramount importance due to the spreading nature of the infection and broad-based symptoms overlapping other diseases causing significant disability.

Researchers have been debating the etiology of CLD/PTLDs for decades.⁸, ⁹ Although prior National Institutes of Health (NIH) randomized, controlled trials did find some benefit in retreatment with antibiotics, improving fatigue in the Krupp trial,¹⁰ and memory/concentration in the Fallon trial,¹¹ there was a relapse in both fatigue and cognitive symptoms once antibiotics were discontinued in both NIH trials. This has led to several hypotheses as to why the effectiveness of anti-infective therapy wore off. One of the leading hypotheses is that Bb is a biofilm/persister bacteria,¹² which may cause significant inflammation and relapse once antibiotics have been discontinued.¹³ Other potential etiologies to explain how Lyme disease causes ‘Infection-Associated Chronic Illness’ apart from persistent infection, includes associated immune and autonomic nervous system dysfunction, autoimmunity, and microbiome disruption.¹⁴ Horowitz and Freeman have published on a multifactorial, 16-point model known as Multiple Systemic Infectious Disease Syndrome (MSIDS), where overlapping sources of inflammation and their downstream effects can account for the multi-systemic nature of CLD/PTLDs, helping to explain individual variations and responses to treatment.¹⁵

An untreated or inadequately treated infection with Bb can lead to neurocognitive impairment, ranging from mild cognitive impairment to full blown dementia. In a recent, broad scoping review, “In comparison to healthy control populations, Long-standing Lyme Disease patients displayed deficits in working memory, verbal learning/memory, non-verbal learning/memory, alertness … and frontal executive functions.”¹⁶ These are similar symptoms overlapping AD and associated dementias.

Alzheimer's disease (AD) is presently affecting 6.9 million Americans aged 65 or older and is expected to grow to 13.8 million Americans by 2060, affecting an estimated 55 million people worldwide.¹⁷ A 2025 study found the average lifetime risk of dementia for adults over 55 years old is now approximately 42%.¹⁸ Although there is not one established pathology underlying AD dementia, many individuals have brain changes associated with more than one cause.¹⁹, ²⁰ All 16 MSIDS factors that have been published to be associated with CLD/PTLDs and Long COVID have also been found to be associated with AD and dementia.³ This implies that a multifactorial etiology may be underlying cognitive impairment and dementia which can include up to six primary sources of inflammation and ten downstream effects of inflammation on the MSIDS map. In the case of AD and dementias, this includes infectious etiologies, i.e., bacterial (Bb, Chlamydia pneumoniae, Treponema spp., Porphyromonas gingivalis, H. pylori, Coxiella burnetii),^21–26 viral (HSV-1, HHV-6, EBV, CMV, SARS-CoV-2, HCV),²⁷, ²⁸ parasitic (Toxoplasma gondii),²⁹ and fungal infections (Candida, Malassezia),³⁰, ³¹ environmental toxins (air pollution, particularly fine particulate matter/PM2.5, heavy metals, pesticides),^32–34 microbiome abnormalities (decreased diversity/abundance of beneficial bacteria, i.e., Firmicutes, Bifidobacteria),³⁵, ³⁶ intestinal hyperpermeability with ‘leaky gut’ with or without mast cell activation syndrome (MCAS),³⁷, ³⁸ vitamin and mineral deficiencies (B2, B6, B9, B12, Vitamin D, Vitamin E, copper),^39–41 and sleep disorders.⁴² Ten potential downstream effects of this inflammation on the MSIDS map can include mitochondrial dysfunction,⁴³ hormonal and immune dysregulation,^44–46 autoimmunity,⁴⁷, ⁴⁸ liver disease,⁴⁹ neurological and psychological dysfunction,⁵⁰, ⁵¹ autonomic dysfunction,⁵²,⁵³ deconditioning,⁵⁴ and/or pain syndromes.⁵⁵, ⁵⁶ Apart from genetic predispositions,⁵⁷ any or all of these factors may be responsible in part for the formation of amyloid-β (Aβ) peptides, tau phosphorylation and the subsequent plaques and neurofibrillary tangles associated with neurocognitive decline.

Prior scientific studies have demonstrated a potential association between Bb and AD, as the bacterial infection is a spirochete, similar to syphilis, a known cause of dementia.⁵⁸ In a meta-analysis of case controlled studies, there was greater than a ten-fold increased occurrence of AD when there was detectable evidence of a spirochetal infection.⁵⁹ This is consistent with prior research showing that Aβ has anti-microbial properties.⁶⁰

Miklossy et al. have published several studies showing that there is a direct association between an infection with Bb and AD, as chronic bacterial infections are frequently associated with amyloid deposition.⁶¹, ⁶² In an analysis of the evidence following Koch's and Hill's criteria, the results showed a statistically significant association between spirochetes and AD.⁶³ When all types of spirochetes were analyzed, spirochetes were found in more than 90% of AD cases (including periodontal Treponemas), and Bb was detected in the brain in 25.3% of AD cases analyzed, 13 times more frequent in AD compared to controls.⁶³ Prior evidence suggests that Bb persists in the brain in chronic Lyme neuroborreliosis and may be associated with amyloid plaques,⁶⁴ in some cases causing secondary dementia.⁶⁵

Bb, the agent of Lyme disease, can form biofilm and ‘persister’ forms that are able to persist despite standard antibiotics.⁶⁶ The phenomenon of persisters is a common mechanism in most bacterial species to survive harsh environmental conditions where the bacteria becomes slow-growing or dormant for long periods of time in biofilms and then reactivates when conditions are more favorable.⁶⁷, ⁶⁸ The presence of Borrelia biofilm in human infected skin tissues has recently been confirmed,⁶⁹, ⁷⁰ and bacterial amyloid and spirochete-specific DNA in biofilms have been found in senile plaques in AD.⁷¹ Recently, Sapi et al. showed that Bb has been found to co-localize in AD autopsy brain tissues with not only biofilm and amyloid, but also phosphorylated tau.⁷² That study, along with others by Miklossy et al., provided evidence for an association between Bb, other spirochetal infections and subsequent biofilm formation, AD pathology, and chronic neurodegenerative diseases. Prior evidence has been based on brain autopsy tissue of patients diagnosed with either AD or Parkinson's diseases, but not in vivo case studies. This case study is therefore the first published in vivo account demonstrating improvements in p-tau 217 and Aβ ratios in a patient with CLD/PTLDs using dapsone combination therapy (DCT), a short term, oral antibiotic protocol which addresses the biofilm and persister forms of Bb.

We present the case of a 67-year-old female with a history of CLD/PTLDs who had evidence of prior co-infections with Ehrlichia, Babesia, Bartonella, and Coxiella burnetii. The patient initially denied any major cognitive complaints, attributing her adequate concentration and recall to her meditation practice. Her primary symptoms prior to using DCT was long-standing joint pain in the knees and fingers for 15 years post tick bites, despite treatment with doxycycline and anti-malarial therapy. She had persistently positive Lyme disease testing (CDC + IgM/IgG western blots/immunoblots) during a 15-year interval with her immune system continuously recognizing Borrelia specific bands (23, 31, 41 kDa) during that time, with positive rheumatoid factors (RFs) indicating ongoing inflammation. RFs are not specific for rheumatoid arthritis, as several infections and diseases may elicit RFs. Prevalence studies of RF positivity in infections have highlighted that chronic, constant exposure to microbial antigens are needed for the development of RFs.⁷³

Recently, AD blood-based biomarkers such as Aβ ratios, p-tau 181, p-tau 217 and neurofilament light (NfL) became commercially available.⁷⁴, ⁷⁵ These biomarkers may increase years before cognitive impairment is significant enough to be observed clinically using mini-mental state examinations,⁷⁶ or other clinical tools like the Mini-Cog test and Addenbrooke's Cognitive Examination-Revised.⁷⁷ AD blood-based biomarkers were therefore performed in advance of treatment of the patient's CLD/PTLDs using a biofilm/persister drug therapy, i.e., DCT.⁷⁸ She was found to have elevated p-tau 217 in her blood prior to DCT with positive RFs indicating ongoing peripheral inflammation and elevation of a pathological protein (p-tau 217) that can trigger neuro-inflammation. The patient was therefore prescribed double dose dapsone combination therapy (DDDCT), a 9-week oral antibiotic protocol previously published to have statistical efficacy in the treatment of CLD/PTLDs,⁷⁹ improving both joint pain and cognitive symptoms. Clinical status and laboratory values were followed before, during and after treatment. Table 1 indicates the 16 MSIDS variables that were screened prior to treatment with DDDCT which were potentially contributing to symptomatology.

Table 1.

Overlapping MSIDS variables potentially contributing to symptomatology in a patient with CLD/PTLDS prior to dapsone combination therapy (DCT).

1. Infections	Borrelia burgdorferi (Lyme ELISA + [8.38, positive > 1.09], C6 ELISA + [3.83, positive > 1.09], CDC + IgM western Blot (23, 31, 41 kDa); CDC + IgG western blot; CDC + Lyme IgM Immunoblot (23, 41)
	Erythema migrans rash +
	Babesia microti IgG 1:40+
	Ehrlichia chaffeensis IgG 1:128 +
	Coxiella burnetii (Q-fever) IgM antibody 1:32 + (negative <1:16) IgG 1:64 +
	Bartonella henselae IgG 1:128+ (normal range <1:64)
	Bartonella quintana IgG 1:256+ (normal range <1:64)
	Helicobacter pylori antibody +, breath test negative
	SARS-CoV-2: positive exposure 2021
2. Environmental toxins	Heavy metals + on a 6-h urine dimercaptosuccinic acid (DMSA) urine challenge (lead, i.e., Pb 21 μg/g creat, normal range <2 μg/g creat; mercury, i.e., Hg 11 μg/g creat, normal range <4 μg/g creat)
	Serum aluminum levels borderline elevated (3 mcg/L, normal range < 7 mcg/L).
3. Intestinal hyperpermeability	Elevated IgG antibodies against cow's milk (64.2 μg/mL, normal range <2 μg/mL), wheat (14 μg/mL, normal range <2 μg/mL), and eggs (10.9 μg/mL, normal range <2 μg/mL) with negative gluten markers (negative anti-gliadin antibodies, negative tissue transglutaminase tTG IgA)
4. Vitamin and mineral deficiencies	Borderline low B12 levels (329 pg/mL, normal range ≥400 pg/mL)
5. Sleep disorders	None
6. Hormonal dysregulation	Metabolic syndrome (HbA1c 5.8%) and reactive hypoglycemia were present intermittently during the illness
	Hypercortisolemia (significantly elevated cortisol in the am)
7. Tau pathology biomarkers	p-tau 217 elevated at 0.33 pg/mL (normal range < = 0.15)
	p-tau 181 normal at 0.6 pg/mL (normal range < = 1.07)
	Aβ42:40 ratio normal at 0.185 (normal range > = 0.170)
8. Autoimmune markers	Rheumatoid factor + 33.8 (normal range 0–13.9) with a negative cyclic citrullinated peptide (CCP) at 4 units (weak positive 20–39 U; strong positive >59 U)
	Negative Anti-nuclear antibody (ANA)
9. Postural Orthostatic Tachycardia Syndrome (POTS)/Dysautonomia	No evidence of low blood pressure and elevated heart rates or dizziness going from sitting to standing position
10. Microbiome Abnormalities/Mast Cell Activation	No microbiome studies performed; mast cell markers (tryptase, chromogranin A, histamine) were negative
11. Mitochondrial Dysfunction	Possible, due to evidence of inflammation; Treated post DCT but no specific mitochondrial testing performed
12. Neurological Symptoms	Peripheral Neuropathy (tingling, numbness, stabbing sensations) and tremors; Mild cognitive impairment
13. Psychological Symptoms	None
14. Immune Dysfunction	No evidence of immune deficiency
15. Pain Syndromes	Knees/hands
16. Deconditioning/Orthopedic Complaints	Osteoporosis on DEXA scan; (T score -2.6; osteoporosis > -2.5) and an elevated urine N-telopeptide test at 80 nM (normal range 4–64 nM BCE/nM creat)
	Knee pain, status post motor vehicle accident (MVA); Heberden's nodules consistent with osteoarthritic overlap

Methods

Institutional Review Board approval was not required since this was a retrospective review of a patient's chart who was undergoing treatment for tick-borne illness under the care of the author. After signing informed consent forms that outlined the proposed benefits and potential risks of therapy, she took DDDCT at our medical center. This was based on the drug's action on persister and biofilm forms of the bacteria and established efficacy in treating eight major Lyme symptoms including musculoskeletal/arthritic symptoms and neurocognitive complaints.⁸⁰ There was no known allergy to dapsone (DDS), or any medication used in the trial, and she was excluded from having any significant laboratory abnormalities including anemia or glucose-6-phosphate dehydrogenase deficiency prior to using DCT.

Case study

A 67-year-old female, with a past medical history significant for several embedded tick bites came to our medical office in 2010 for the first time. She had exposure to Bb (Lyme disease) with a CDC + IgM western blot (23, 31, 41, 93 kDa bands), CDC + IgG western blot (18, 39, 41, 45, 58, 66, 93 kDa bands), positive Bb C6 Peptide (3.83, positive >1.09), positive Lyme ELISA IgM/IgG antibodies (8.38, positive >1.09) as well as exposure to Babesia microti (IgG 1:40 +; normal range <1:40) and Ehrlichia chaffeensis (IgG 1:128 +, negative <1:64). She complained of a several year history of chronic fatigue, migratory joint pain in her knees and occasionally in the hips, pelvis, shoulders and heels, with intermittent night sweats and intermittent neuropathic symptoms in her toes described as “tingling” sensations that would come and go. Other past medical history was significant for exposure to H. pylori (antibody positive, breath test negative), borderline low B12 levels (329 pg/mL, normal range ≥400 pg/mL), and elevated levels of heavy metals (lead, i.e., Pb 21 μg/g creat, normal range <2 μg/g creat; mercury, i.e., Hg 11 μg/g creat, normal range <4 μg/g creat) on a 6-h urine dimercaptosuccinic acid urine challenge. She also had a positive RF at 33.8 (normal range 0–13.9) with a negative cyclic citrullinated peptide (CCP) at 4 units (weak positive 20–39 U; strong positive >59 U) consistent with joint inflammation, ruling out active rheumatoid arthritis; with some evidence of intestinal hyperpermeability/leaky gut with multiple food allergies. She had significantly elevated IgG antibodies against cow's milk (64.2 μg/mL, normal range <2 μg/mL), wheat (14 μg/mL, normal range <2 μg/mL), and eggs (10.9 μg/mL, normal range <2 μg/mL) with negative gluten markers (negative anti-gliadin antibodies, negative tissue transglutaminase tTG IgA). A Dehydroepiandrosterone (DHEA)/cortisol saliva test showed a significantly elevated cortisol in the am, suggestive of stress and an overactive adrenal cortex. She was prescribed 30 days of hydroxychloroquine (Plaquenil) 200 mg PO BID, doxycycline 100 mg BID and atovaquone/proguanil 250/100 mg, two PO BID for her Lyme, Ehrlichia and Babesia exposure, along with Nystatin 500,000 Units two PO BID with a low carbohydrate elimination diet with probiotics and bovine immunoglobulins for gastrointestinal support. She was also given sublingual B12 supplementation 1000 mcg/d for her borderline low B12 levels, and we discussed meditation and stress reduction with adrenal adaptogenic herbs for her hypercortisolism.

Several weeks into the antibiotic/anti-malarial protocol there was a slight increase in symptoms consistent with a mild Herxheimer reaction and killing off of spirochetes (presumptively since other infections were present) with the patient complaining of intermittent cognitive difficulties with increased headaches, sweats, and shortness of breath, with knee pain eventually improving in intensity and frequency. One month later during an in-person visit, she felt good where all her major symptoms had resolved except for early awakening at 4 am. She was switched to cefdinir 300 mg PO BID for one month with Nystatin two PO BID and again noticed a slight return in migratory joint pain in her knees which was fleeting after the introduction of a cell wall antibiotic. Symptoms, however, remained in remission after another 30 days, so all antibiotics were discontinued after a total of two months of treatment. She was placed on an herbal support protocol for the next several months (Byron-White AL formula).

For the elevated heavy metals, the patient chose to use Chemet, i.e., low dose dimercaptosuccinic acid (DMSA) 500 mg HS twice a week with Ethylenediaminetetraacetic acid suppositories (Detoxamin, 750 mg) to chelate her heavy metals for a period of three months, replacing minerals during day, while remaining on a low mercury diet, decreasing larger fish. She was told to look into her water supply as a potential source of her Pb exposure and to consider a DEXA scan in the near future (she was peri-menopausal) since Pb may come from bones breaking down over time with osteopenia or osteoporosis. She refused to get an X-ray of her knees to rule out overlapping osteoarthritis since her knee pain had improved.

One year after completing the initial antibiotic therapy, her only rare symptoms were intermittent tingling in her toes that would come and go transiently, once a week, consistent with either a possible Lyme peripheral neuropathy or neuropathy related to heavy metal exposure, as well as rare joint pain in her left knee, which she attributed to an old injury and being off her diet. As long as she remained on a low carbohydrate organic diet, avoiding her sensitive foods, she felt fine, but noticed if she was off her diet with too many simple carbohydrates, she felt some fatigue, joint pain and irritability. This was consistent with both reactive hypoglycemia and history of leaky gut. There was a family history of type 2 diabetes (father, brother), but the patient's HbA1c levels were all within normal limits (WNL) except for a borderline HbA1c one time at 5.8%, which subsequently decreased into normal range with a stricter diet. Six months later, the tingling in the lower extremities resolved, as the levels of Pb and Hg decreased over time (Pb decreased from 21 to 11 μg/g creat; Hg from 11 to 6.5 μg/g creat) although the patient noted a slight hand tremor when she stopped her Lyme herbal protocol along with intermittent, sharp knee pains once a week.

During a follow-up visit three months later, the patient complained of a skin rash which was itchy and painful on the right side of her chest, initially thought to be possible shingles, although no vesicles were noted. An EM rash and re-exposure to Lyme disease was suspected by her primary care physician as Lyme testing was positive again. Her primary symptoms were a sore throat, swollen glands, headaches, ear pain and new right shoulder pain (there was an injury in the past with a frozen shoulder) and her IgM Bartonella henselae antibody testing turned low positive at 1:200 (LabCorp, negative testing <1:100) along with new positive testing for Coxiella burnetii (Q-fever). Q-fever titers which had been previously been negative turned low positive with a Q-fever IgM antibody at 1:32 + (negative <1:16) and Q-fever IgG antibody at 1:64+ (negative <1:16). Rocky Mountain Spotted Fever IgM antibodies were negative, ruling out cross-reactivity. We placed her on 30 days of hydroxychloroquine 200 mg BID, Nystatin 500,000 U BID, doxycycline 200 mg PO BID and rifampin 300 mg BID with a low carbohydrate diet and three different probiotics, including saccharomyces boulardii twice a day for gastrointestinal support. Two months later during a follow-up visit, she felt 100% back to normal with good energy, and no joint pain or neuropathy. Physical therapy helped the range of motion of her frozen shoulder. All symptoms had otherwise resolved within one week on the doxycycline and rifampin and repeat Q-fever titers were negative.

Timeline: During the next several years, from 2014 until her follow-up annual check-up in late 2017, she felt the Lyme was in remission with improved knee pain, and was given a slip for a DEXA scan, checking routine labs. These included a Lyme ELISA, C6 ELISA, Lyme western blot, Bartonella titers, RF and B12 levels through LabCorp. Her C6 Lyme ELISA turned negative, while her ELISA titers gradually decreased during the past several years (2.47, 1.34, to 1.21; Normal range: <0.91). Bartonella titers were positive with an IgG antibody at 1:128 (normal range ≤1:64) but remained stable. The only indication that Borrelia was still active was a new 23 kDa band (Osp C) on her local western blot from four years prior. Rheumatoid factors decreased from 18 to 16 to 14, but remained low positive, consistent with ongoing inflammation.

During the patient's next follow-up in June 2018 she complained of bilateral knee swelling, forcing her to stop running, which she attributed to a running injury and possible Bakers cyst. There was also some intermittent thumb pain and an unsteady grip, with a minor tremor and menopausal symptoms of flushing. She needed to remain on a Lyme herbal protocol with Beyond Balance herbs to stay in remission. All labs otherwise were WNL, and her Babesia microti, Babesia duncani, and Bartonella henselae antibodies and vascular endothelial growth factor (VEGF) levels were negative, with her RF turning negative for the first time in years (12.1 IU/mL; normal range 0–13.9 IU/mL).

During the next follow-up April 2019, the patient complained of a Lyme flare-up after getting a viral infection. There was heaviness in her limbs with shoulder pain, and some migratory symptoms in her left arm, feet, legs and back. Rheumatoid factor was elevated again at 15 IU/mL (normal range <14 IU/mL). She went back on her Beyond Balance herbs and felt better. Her only ongoing complaint was bilateral knee pain with decreased dexterity of her hands but was found to have decreased cartilage on knee X-rays after an orthopedic consultation. Since the majority of her Lyme symptoms resolved she did not feel like she needed antibiotics.

Her DEXA scan was positive for osteopenia especially in the lumbar-sacral spine. She was referred for physical therapy for her knee pain with bone strengthening exercises for her spine, along with light weights and resistance training along with vitamin D/calcium supplementation. Raloxifene (Evista) 60 mg once a day was prescribed for the osteopenia and family history of breast cancer (mother), and occupational therapy was prescribed for the decreased dexterity in her hands. At that point, her Lyme ELISA was equivocally positive at 0.96 (negative <0.91; positive >1.09) with levels continuing to decrease gradually over time.

The next visit was several months into the COVID pandemic in June 2020 where the patient felt well. Her Lyme ELISA IgM/IgG finally turned negative, Q-fever titers remained negative, ruling out a persistent infection, but her IgG Bartonella henselae titer increased after turning negative, becoming low positive at 1:64+. Serum Pb levels were borderline elevated at 1 mcg/dL (reference range was <5 mcg/dL). Since she remained stable, we primarily discussed COVID prevention measures including nutritional supplementation with N-acetyl cysteine, alpha lipoic acid and glutathione to block NFκB, with zinc and vitamin D for immune support. This was based on early case reports where glutathione helped to decrease the severity of respiratory symptoms in COVID-19.

In June 2021, one year later, she received the Pfizer COVID vaccine and had a brief flare-up of joint pain which promptly resolved. Her primary complaints were a swollen knuckle, stiffness of her fingers, and worsening of knee pain with decreased range of motion. X-rays of the hands revealed moderate osteoarthritic changes at the proximal interphalangeal joints and metacarpophalangeal joints with mild soft tissue swelling. She otherwise stated she was in good health and felt she was functioning at 100% of normal. Six months later, however, by December 2021, she had her first case of COVID-19 and her functioning was impaired. She described “feeling under the weather” with generalized aches and pains and myalgias. Some joint and muscle pains were migratory in nature, suggestive of reactivation of her underlying Lyme disease and/or Bartonella. Her Bartonella quintana titer increased to 1:256+ (normal range <1:64) during that time. She also had the feeling there was a respiratory infection brewing as she was beginning to get a cough but denied shortness of breath. She had received her second Pfizer COVID vaccination by that time and had remained on her nutritional supplementation to block NFκB, now expanding them out to include nutraceuticals that stimulated the Nrf2 pathway. These included curcumin and broccoli-seed extract (sulforaphane glucosinolate) while using Beta glucan for immune/natural killer cell support. Doxycycline 100 mg BID with Nystatin 500,000 U two BID was prescribed with triple probiotics twice a day for two weeks for her cough to prevent an overlapping bacterial superinfection.

The next follow-up was July 2022. She was feeling 100% back to normal except for some mild depression, due to living alone during the pandemic with social restrictions. She completely recovered from COVID-19 without sequelae or ongoing Lyme flare-ups. Physical examination revealed osteoarthritic changes in her hands with Heberden nodules but was otherwise unremarkable. We discussed a stricter low carbohydrate/hypoglycemic diet for her mildly elevated HbA1c at 5.8, consistent with metabolic syndrome. A repeat DEXA showed a worsening of bone density with osteoporosis (T score −2.6; osteoporosis > −2.5) and an elevated urine N-telopeptide test at 80 nM (normal range 4–64 nM BCE/nM creat) consistent with increased bone turnover. We added a calcitonin-salmon nasal spray since she did not want to consider bisphosphonates.

One year later, in July 2023 during her annual follow-up, she still denied significant active Lyme symptoms and attributed her ongoing knee pain and stiffness to lack of cartilage. She was still able to exercise and go for fast walks. We rechecked tick-borne titers and her Bartonella henselae antibody titer remained low positive at 1:64 + (normal range <1:64) with her Bartonella quintana titers decreasing to 1:64+ (normal range <1:64). Rheumatoid factors remained WNL and a VEGF was below normal range, not suggestive of a Bartonella relapse. HbA1c levels came down into the normal range at 5.3% (normal <5.7%). She had a positive Cologuard during that time, and with her family history of colon cancer she was sent for a colonoscopy which was negative.

The patient returned to see us in March of 2025 with ongoing complaints of arthritic symptoms in the hands and knees with a mild tremor of her left hand. We repeated her Lyme testing and her Lyme IgM Immunoblot remained CDC positive. She was positive for the 23 kDa (Osp C) and 31 kDa (Osp A) bands which are Borrelia specific bands, along with the 41 kDa flagellar protein. I explained that her immune system should not normally be recognizing Borrelia specific proteins 15 years post treatment if there was no active infection and that IgM antibodies are frequently seen in CLD/PTLDs. We also repeated a RF which rose again and was elevated at 20 IU/mL (normal range <14 IU/mL) with a negative CCP, proving ongoing peripheral joint inflammation.

Since the patient believed her grandmother had a history of AD, we discussed checking neuro-inflammatory markers as Bb had been published to be associated with biofilm, Aβ and p-tau in the brain. The patient denied significant cognitive problems at the time and attributed her ability to concentrate due to her regular meditation practice. We sent off a Quest laboratory profile to evaluate her AD markers and APOE status and checked a CBC, comprehensive metabolic profile (CMP), thyroid functions, 25-OH vitamin D, C-reactive protein, Anti-nuclear antibody, VEGF, serum heavy metals, Bartonella and Q-fever titers along with a glucose-6-phosphate dehydrogenase level (G6PD). These were evaluated to rule out any overlapping factors accounting for her symptoms and to see whether she was a candidate for the 9-week, oral DDDCT. This short-term antibiotic protocol had been published to have efficacy against the biofilm/persister forms of Bb with good efficacy against eight major Lyme symptoms including joint pain and cognition. Labs all returned WNL except for a borderline increase in aluminum levels (3 mcg/L, normal range <7 mcg/L). Her hemoglobin was 13.9 grams with a hematocrit of 40.8 with a normal G6PD level (15.1 Ug/Hgb; normal range 7–20.5 Ug/Hgb) making her a good candidate to do DCT since the protocol can cause a temporary folic acid induced anemia. Her APOE status was 3/3, indicating a low genetic risk of AD, but her plasma p-tau 217 returned elevated at 0.33 pg/mL (normal range <=0.15). P-tau 181 was WNL at 0.6 pg/mL (normal range <=1.07) and her Aβ42/40 ratio was also WNL at 0.185 (normal range >=0.170).

Since both peripheral inflammatory markers (rheumatoid factors) and pathological triggers of neuroinflammation (p-tau 217) were positive with ongoing joint pain and a Lyme immunoblot indicated ongoing exposure to Bb, the patient agreed to do the DDDCT protocol. She signed informed consents for DCT and methylene blue. DCT typically involves the use of a tetracycline, rifampin, dapsone, azithromycin, and methylene blue with nutraceutical support⁷⁹ including high dose folic acid (Leucovorin, L-methyl folate). This biofilm/persister protocol has been published to effectively address eight major Lyme symptoms (including joint pain and cognitive difficulties), while simultaneously helping to lower potential side effects of dapsone. We discussed potential side effects including a temporary dapsone-induced anemia, Herxheimer reactions with potential increases in joint pain with the possibility that the protocol could bring out underlying symptoms, rashes (the patient had no sulfa sensitivity) and temporary elevations in methemoglobin, normally controlled with antioxidants and methylene blue. The patient was instructed to go for a CBC, CMP and methemoglobin level weekly starting week 3 of the treatment protocol, and to follow up with labs post protocol until her anemia resolved. She finished the 9-week dapsone protocol in September 2025, finishing with a 4-day high dose dapsone combination therapy (HDDCT) pulse, and then completed treatment with a one-month mitochondrial regeneration protocol post DDDCT. Mitochondrial support post DCT is a standard part of the protocol to account for temporary increases in oxidative stress. She tolerated the protocol well but did have what appeared to be a temporary Herxheimer reaction with increased fatigue and headaches which resolved post treatment.

Results

Repeat laboratory values were done approximately 2–3 months post-protocol. Her CBC returned to normal with a slightly higher hemoglobin at 14.2 g/dL without evidence of macrocytosis post dapsone. CMP was WNL. Rheumatoid factors decreased to normal at 12 IU/mL (normal range <14 IU/mL) from 20 IU/mL; p-tau 217 levels decreased from 0.33 pg/mL and normalized at 0.12 pg/mL (normal range <= 0.15 pg/mL); p-tau 181 remained WNL at 0.83 pg/mL (normal range <= 1.07 pg/mL) and her Aβ42/40 ratio improved, increasing from 0.185 to 0.216, potentially reducing future risk of cognitive impairment.

Figure 1.

QUEST AD detect beta-amyloid 42/40 ratio indicating improvement post DDDCT.

A follow-up interview with the patient several months post DCT indicated that:

My left knee is pain-free. My right knee has residual discomfort on stairs from a car accident years ago. I have greater ease and flexibility in my knuckles with the exception of my left index finger. In the past I have attributed my mental focus/concentration/memory strength to my daily meditation practice, but in recent weeks I have had immediate, accurate concentration, insight and memory recall. I thought, wow, my meditation practice is really delivering for me, but it was more immediate and acute than before, and now I can make the connection to the P tau levels being normal.

Discussion

The primary hypotheses underlying AD apart from inherited genetic mutations including APOE, includes a vast array of theoretical groupings. These include the amyloid cascade hypothesis, tau hypothesis, neuroinflammation hypothesis, cholinergic hypothesis, mitochondrial dysfunction hypothesis, vascular hypothesis, along with emerging theories involving infectious agents, neurotoxicity (Al, Hg, pesticides), cholesterol dis-metabolism, brain insulin resistance, white matter injury and dysbiosis in the gut microbiome affecting the gut/brain axis.⁸¹ Although the amyloid hypothesis has been one of the primary mechanisms to explain the pathogenesis of AD, recent evidence points to multi-factorial causation. Apart from the above pathologies, the prion hypothesis, mutational accumulation hypothesis and autoimmune hypothesis have also been postulated to play a role, where oxidative damage in the brain from free radicals, due to infections, breakdown of the blood-brain barrier and glymphatic dysfunction may contribute to AD pathogenesis.⁸² These hypotheses are not mutually exclusive and likely interact to produce the complex pathology observed in AD. Our case study had multiple overlapping etiologies on the 16-point MSIDS map,⁸³ accounting for both peripheral inflammation and an elevated tau pathology biomarker. Infections, especially Bb and potentially Bartonella henselae and Bartonella quintana, along with hyperphosphorylated tau, heavy metals, autoimmunity, leaky gut/intestinal hyperpermeability, and metabolic syndrome were all present at some point in her illness. In her case however, based on her clinical response, infections (Bb), driving autoimmune phenomenon and hyperphosphorylated tau likely played a predominant role in ongoing symptomatology, although we cannot rule out the role of having simultaneously treated other infections and heavy metals, accounting for her clinical improvement.

The amyloid cascade hypothesis remains the most extensively studied framework, positing that an imbalance between production and clearance of Aβ peptides, particularly Aβ42 initiates a pathological cascade.⁸⁴ This hypothesis is strongly supported by genetic evidence as all autosomal dominant early-onset AD mutations occur in either the amyloid-β protein precursor or presenilin genes. Our patient did not have evidence of elevated Aβ, but interestingly, her Aβ ratios improved three months post therapy with a biofilm, persister antibiotic protocol, i.e., DDDCT. DCT has been proven to be effective in culture against the biofilm/persister forms of Bb,⁸⁵ and has been shown in the animal model in studies from Tufts University to cure CLD,⁸⁶ when Borrelia persisted despite standard antibiotic therapies. A seven- to eight-week protocol of DDDCT for CLD/PTLDS also has previously resulted in symptom remission in approximately 50% of patients for one year or longer, where published culture studies indicated that higher doses of dapsone demonstrated efficacy against resistant biofilm forms of Bb.⁸⁷ The improvement in Aβ ratios post DCT is therefore consistent with Lyme spirochetes increasing Aβ,⁶¹ and Aβ having anti-microbial properties.⁶⁰

Bb, the agent of Lyme disease, may affect not only the central nervous system (CNS), but also the cardiovascular, musculoskeletal, and peripheral nervous system.⁸⁸ Subsequent inflammation may result in Lyme carditis, transient migratory arthritis, as well as a broad range of neurological symptoms, including cranial nerve palsies, signs/symptoms of meningitis, encephalomyelitis, radiculopathy, cerebellar symptoms, neurocognitive difficulties with memory and concentration problems as well as psychiatric comorbidities.⁸⁹ Our patient had musculoskeletal/arthritic symptoms which were migratory, a hallmark symptom of chronic LD/PTLDs,⁹⁰ along with intermittent Lyme neuropathy, i.e., tingling in her toes. Migratory joint pain, muscle pain and nerve pain help differentiate Lyme arthritis/myalgias and Lyme neuropathy from other potential inflammatory etiologies.⁹⁰ The improvement in joint pain and flexibility with a decrease in autoimmune reactions, RFs, and inflammation from DCT has previously been reported in the medical literature.⁹¹

The patient also had mild neurocognitive difficulties with elevated p-tau 217. Prior scientific studies have shown that Bb can co-localize with not only amyloid markers in the brain but also phosphorylated tau. This was proven in brain autopsy tissue of patients diagnosed with either AD or Parkinson's disease,⁷² but this is the first case study showing that we can reverse p-tau levels in vivo. In five separate clinical studies involving more than 365 patients, DCT led to statistically verified improvement in relieving eight major Lyme symptoms including sweats/chills (Babesia symptoms), fatigue, joint, muscle, and/or nerve pain, headaches, insomnia, and especially cognition.^3,78–80,87 Improvements in pain and cognition using DCT, and especially DDDCT and pulsed HDDCT has been one of the most consistent effects of the drug regimen when Bartonella was not active.⁹² That appeared to be the case in our patient who showed exposure to two Bartonella species (B. henselae, B. quintana) but where titers decreased over time with a negative VEGF, an indirect marker of active Bartonella.⁹³ Prior paired-samples t-tests performed on Lyme symptoms pre-DDS and post DDS confirmed that DCT showed statistical significance in improving joint pain (p < 0.001), neuropathic pain (p < 0.001), forgetfulness and/or brain fog (p < 0.001) as well as difficulty with speech and writing (p < 0.001),⁸⁰ which were all of the symptoms in our patient. However, this is the first time to our knowledge that research has shown improvement in the newer, available tau pathology biomarkers like p-tau 217 in CLD/PTLDs with a statistically significant decrease three months post therapy with DCT, a short term, oral generic antibiotic protocol.

Dapsone has previously been published to have benefit in preventing AD exacerbations and potentially represent a preventive therapeutic option for exacerbated AD.⁹⁴ In a 15-year study involving 3035 patients with leprosy (Hansen's disease) those patients receiving dapsone had significantly lower rates of AD. There was a clear causal relationship (p < 0.00001) in which the presence or absence of DDS determined the onset and prevalence of AD.⁹⁴ The theory behind the improvement was that dapsone, which has excellent penetration into the CNS, acted as an NLRP3 inflammasome inhibitor, where its antioxidant, anti-excitotoxic, and anti-apoptotic effects were of benefit in models of neurodegenerative diseases, including Parkinson's disease and AD.⁹⁵ Aβ and tau molecules can trigger NLRP3 inflammasome signaling, which then further drives tau pathology, leading to cognitive decline and AD.⁹⁶, ⁹⁷ Bb is known to activate NLRP3 inflammasomes.⁹⁸ It was not known in the study from Korea whether these patients had overlapping MSIDS factors like Borrelia driving neuroinflammation. We have no evidence that Bb activated NLRP3 inflammasomes in our patient and/or that dapsone's positive effect was not due in part to its effects as an NLRP3 inflammasome inhibitor, independent of its effects on Bb. Further research is needed in this area. Similarly, the prior results of dapsone therapy in treated/untreated leprosy patients was a retrospective-prospective study (historical cohort) showing associations of treatment with less dementia. This type of study is prone to many biases (e.g., confounding by indication, etc.) and cannot prove causation although the results certainly support further, more rigorous studies as the authors indicate.

The major limitation of our case study is non-generalizable results to larger, more diverse populations. Since most of the patients in our medical practice had already finished DDDCT and HDDCT by the time these newer amyloid and tau pathology biomarkers had become available, we did not have the opportunity to test pre and post amyloid and tau pathology biomarkers amongst a broader population of chronic Lyme/PTLDs patients. This needs to be done. The reasoning behind evaluating all sixteen factors on the MSIDS model, published to be associated with neurocognitive difficulties and dementia is illustrated below.

One other patient at our medical center, a 58-year-old female, with a history of CLD/PTLDS and a history of active Babesia and Bartonella by fluorescent-in-situ-hybridization (FISH),⁹⁹, ¹⁰⁰ with an elevated VEGF, who complained of cognitive problems had completed the initial DDDCT and 4 HDDCT pulses that are normally needed to adequately treat CLD and Bartonella. Bartonella is another common infectious agent in our chronically ill patients known to also cause neuro-cognitive symptoms.⁹² Her LabCorp testing November 2025 revealed normal levels of p-tau 181 at 0.41(normal range 0.00–0.97 pg/mL), normal levels of p-tau 217 at 0.07 (normal range ˂0.18 pg/mL), a normal Aβ42:40 ratio at 0.130 (normal range >0.102 pg/mL), and a normal plasma NfL at 1.20 (normal range 0.00–2.99 pg/mL). Her amyloid and tau pathology biomarkers were negative post DCT without pre-treatment values for comparison, but she still complained of cognitive difficulties. Although a repeat Babesia FISH and Bartonella FISH were negative, ruling out an active infection, a 16-point MSIDS review revealed that she had high levels of mold toxins, and positive exposure to West Nile virus (WNV, IgG positive). Mold toxin testing from RealTime Laboratory in Texas revealed that ochratoxins were elevated at 2.370 PPB (normal range ˂1.8 PPB), trichothecenes were elevated at 0.124 PPB (normal range ˂0.07 PPB) with borderline elevated levels of both gliotoxins at 0.719 PPB (normal range ˂0.5 PPB) and zearalenone at 0.556 PPB (normal range ˂0.5 PPB). Mold toxins are known to cause neurocognitive symptoms, through innate immune activation, direct neurotoxic effects, while poisoning mitochondria.¹⁰¹ Mold exposure is known to cause neuroinflammation and symptoms similar to AD with dementia, contributing to Aβ plaque accumulation, tau protein hyperphosphorylation, and neurofibrillary tangle formation, hallmarks of AD pathology.¹⁰² Although she did not have evidence of amyloid or tau pathology biomarkers post DCT, volumetric MRI studies have demonstrated structural brain abnormalities in mold-exposed patients, including caudate nucleus atrophy accompanied by cognitive deficits mimicking dementia.¹⁰³ We are finding close to 90% of our chronically ill Lyme disease patients are now testing positive for environmental toxins like mold,⁹² interfering with the success of DCT and contributing to ongoing symptomatology including fatigue and cognitive problems.

West Nile, a flavivirus infection, can also cause dementia-type symptoms with neuroinflammation and is associated with elevated NfL and altered Aβ pathology.¹⁰⁴ Cognitive dysfunction occurs even in patients with non-neuroinvasive disease (West Nile fever) and may be more prevalent at 2–4 years post infection compared to earlier stages.¹⁰⁵ There is evidence for viral persistence in some studies, and one investigator reported WNV RNA in urine up to 7 years following acute illness,¹⁰⁶ although other studies failed to confirm this finding. The mechanism underlying chronic symptoms, whether due to low-level persistent infection, ongoing neuroinflammation or permanent neuronal damage remains incompletely understood. Until this patient clears her mold toxins, we may not be able to see the full effects of DCT or understand the effects of prior West Nile exposure. Mold toxicity can cause severe mitochondrial dysfunction,¹⁰⁷ and activate inflammasomes,¹⁰⁸ and according to the Mitochondrial Cascade hypothesis, mitochondrial dysfunction is one potential cause of neurocognitive symptoms driving the pathogenesis of AD.¹⁰⁹ Multifactorial causes of inflammation and their downstream effects on the MSIDS map are the rule, not the exception in our practice.¹⁵

Conclusion

AD represents a major and rapidly growing global health crisis, with the number of cases more than doubling from 1990 to 2021,¹¹⁰ and projections indicating dramatic increases through mid-century. The medical literature has reported greater than a ten-fold increased occurrence of AD when there was detectable evidence of a spirochetal infection.⁵⁹ Since Lyme disease is now present in epidemic proportions worldwide with roughly one in seven individuals exposed,¹ and where a 2025 study found the average lifetime risk of dementia for adults 55 years or older is now approximately 42%,¹⁸ evaluating patients pre-test probability of exposure to Lyme disease and associated co-infections is vitally important when neurocognitive difficulties are present. This is especially the case when accompanied by classical physical symptoms seen in acute and CLD such as migratory pain,⁹⁰ which was present in our patient. Pre-test screening can be done with a validated symptom questionnaire and evaluating the presence of Borrelia specific bands on a western blot or immunoblot.⁹⁰ Lyme is a clinical diagnosis, and two-tiered testing with an ELISA followed by a western blot may miss up to 60–75% of early cases presenting with erythema migrans.¹¹¹ Testing in later stage Lyme disease is also problematic. The mean sensitivity for all tests and samples was 59.5% and 53.7% respectively when two-tier methodology was used (an ELISA followed by a western blot), where the two-tier test generated over 500 times more false-negative results than two-stage HIV testing.¹¹², ¹¹³ Using an FDA approved Lyme immunoblot with recombinant DNA, checking for multiple species of pathogenic Borrelia has improved sensitivity and specificity and positive and negative predictive value since the original two-tiered testing was developed using only one species of Borrelia,¹¹⁴, ¹¹⁵ and immunoblots check up to nine pathogenic strains.¹¹⁶ Although our patient had evidence of both CDC positive ELISAs, C6 ELISAs, western blot and immunoblots with a history of an EM rash, meeting all classical definitions for CLD/PTLDs, many of our patients with CLD and Bartonella do not meet ‘classical definitions’. They are immunosuppressed from Lyme and Bartonella, lacking adequate antibody production, preventing the physician from obtaining a proper diagnosis just using serological criteria.^15,92 Evaluating the presence of even one Borrelia specific band on an immunoblot can therefore be helpful in the right clinical setting when other etiologies have been ruled out.⁸⁰

Blood-based AD biomarker concentrations have been associated with pathological and clinical diagnoses of dementia, predicting future development of clinical AD.¹¹⁷ P-tau biomarkers like p-tau 217 are more strongly associated with Aβ plaques than with tau neurofibrillary tangles measured by PET imaging,¹¹⁸ which is consistent with our findings that Aβ ratios improved as p-tau 217 levels decreased. It is therefore possible we prevented future cognitive decline in our patient, although we did not evaluate whether the positive results we found were maintained over a long period of time without continued treatment, suggesting efficacy in stabilizing neuronal insults. Performing a placebo-controlled, multicenter, randomized controlled trial to evaluate the efficacy of DCT for CLD/PTLDs and evaluating AD biomarkers with neurocognitive testing before and after treatment during a longer time period is needed in this regard. Considering the public health impact of AD where it is the fifth leading cause of death of Americans age 65 and older,¹⁷ and where Medicare patients have rates of Lyme disease up to seven times higher than the general population,¹¹⁹ this randomized controlled trial is of paramount importance. Since all sixteen MSIDS factors have been associated with AD, cognitive decline, and dementia,^21–56 shifting the paradigm from simply naming a disease and using medication to treat symptoms, to performing a differential diagnostic work-up to discover all the potential underlying causes of neuroinflammation is essential if we are to improve healthcare outcomes in AD and lower associated healthcare costs.

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iD

Richard Horowitz

Author contribution(s)

Richard Horowitz: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.

Funding

The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: I would like to thank the MSIDS Research Foundation for their support in helping to publish this article.

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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