Frequent pain moderates the association between brain-derived neurotrophic factor and plasma Alzheimer's disease biomarkers in early midlife

Abstract

Brain-derived neurotrophic factor (BDNF) is a neurotrophin regulating neuroplasticity and is reduced in Alzheimer's disease (AD). Whether BDNF relates to AD pathophysiology in dementia-free individuals and under what conditions remain unknown. Pain, a prevalent midlife condition and AD risk factor, engages BDNF signaling. We examined whether frequent pain moderated associations between BDNF and AD plasma biomarkers (ptau217, BD-tau) in early midlife (Mean age=45.8). Among individuals with frequent pain, higher BDNF was associated with lower BD-tau and ptau217. No associations emerged among pain-free individuals. These findings suggest BDNF-indexed neuroplasticity may buffer against AD pathology and neurodegeneration in the context of pain.

Keywords

Alzheimer's disease brain-derived neurotrophic factor brain-derived tau midlife neurodegeneration pain ptau217

Introduction

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity and synaptic integrity centrally implicated in Alzheimer's disease (AD) pathophysiology.¹ BDNF supports neuronal survival, dendritic integrity, and synaptic plasticity, with higher circulating BDNF levels associated with reduced hippocampal atrophy, slower cognitive decline, and lower dementia risk.^2–4 However, whether BDNF relates to markers of AD pathophysiology in dementia-free individuals in early midlife remains poorly understood, as most prior work has focused on individuals with established disease. Moreover, whether BDNF interacts with prevalent risk factors of AD in early midlife to influence AD pathophysiological processes remain underexplored. Because AD pathophysiological processes of amyloid-β (Aβ) deposition and tau propagation begin decades before clinical symptom onset and often in early midlife,^5,6 understanding how protective neurobiological factors and modifiable risk factors jointly shape AD pathophysiology during this window becomes critically important for informing targeted AD prevention and intervention.

Pain is a prevalent midlife condition and a risk factor for cognitive decline and AD.^7–9 Individuals with persistent pain exhibit accelerated memory decline and greater risk of incident dementia.^7–9 Notably, pain is also intrinsically linked to BDNF signaling. Persistent pain involves maladaptive BDNF-dependent plasticity that drives nociceptive sensitization,¹⁰ yet BDNF also participates in descending pain modulation at supraspinal levels to attenuate pain hypersensitivity.^11,12 Although BDNF is widely considered neuroprotective due its roles in supporting neuronal survival and maintaining dendritic integrity,^2,13,14 its nuanced relationships with pain raise the question of whether its neuroprotective effects on AD-related pathophysiology may vary in the presence or absence of pain, especially in early midlife when both pain and AD-related pathophysiological processes often emerge.

Advances in blood-based biomarkers now permit minimally invasive and highly sensitive detection of AD pathophysiology in non-clinical community populations to address these research gaps. Plasma phosphorylated tau at threonine 217 (ptau217) and brain-derived tau (BD-tau) are two AD-specific biomarkers that align closely with the amyloid/tau/neurodegeneration [A/T/(N)] framework. ptau217 is a promising biomarker of AD pathology (– that is, Aβ, tau) with high accuracy, while BD-tau indexes AD-type neurodegeneration.^15,16 To our knowledge, studies examining the associations between BDNF and AD plasma biomarkers remain scarce in dementia-free individuals in early midlife. Moreover, whether the relationship between BDNF and AD pathophysiology varies as a function of pain status remains unexplored.

In this study, we examined whether plasma BDNF is associated with plasma AD biomarkers (ptau217, BD-tau) in dementia-free early midlife adults, and whether frequent pain status (defined as pain occurring ≥ 3 days per week) moderates these associations. We hypothesized that higher BDNF would be associated with lower ptau217 and BD-tau levels, reflecting its neuroprotective role against early AD-related pathophysiology. Given BDNF's complex involvement in pain processing, we further hypothesized that frequent pain status would moderate these associations, with BDNF's neuroprotective effects being particularly salient in individuals experiencing frequent pain, where recurring nociceptive stress may increase the biological demand on BDNF-dependent neuroplastic systems, rendering individual differences in BDNF more consequential for early AD-related pathophysiology.

Methods

Participants

Fifty participants recruited from the local community (56% female; mean age = 45.8 years, SD = 6.46; range = 35–55 years) without neuropsychiatric disorders and chronic diseases were included in the present study. Neuropsychiatric exclusions included: self-report clinical diagnosis (– for example, depression, anxiety) and usage of neuropsychiatric medications, irrespective of formal diagnosis.

Frequent pain

Frequent pain was defined by pain presence and frequency ≥ 3 days a week. Pain presence was assessed using: (1) “Do you experience pain in your body?” [Yes/No], and (2) the Short Form 36 (SF-36) quality of life scale's item 21, which asked participants “How much bodily pain have you had during the past 4 weeks?”. Participants rated their pain on a 6-point Likert-type scale from “None” (1), “Very Mild” (2), “Mild” (3), “Moderate” (4), “Severe” (5), “Very Severe” (6). Participants who reported “Very Mild to “Very Severe” on the SF-36 question, “Yes” on the pain experience question, and frequency of pain as occurring 3 or more times a week were coded as having frequent pain. Otherwise, participants were coded as not having pain consistently. Because we did not have information on pain duration extending beyond the 4 weeks, we focused on frequent pain (occurring ≥ 3 days per week), as this phenotype represents pain that is currently persistent or in transition to persistence for many. It is also clinically meaningful as it is related to functional decline (equivalent to people 2–3 decades older) and lower quality of life.^17,18

Biomarkers

All biomarkers were assayed from plasma samples using commercially available ultra-sensitive Simoa technology (Quanterix, Billerica, MA, USA). BDNF was assayed using the BDNF Discovery Kit, p-tau217 was measured with the ALZpath p-Tau-217 Kit, and BD-tau was assayed using the Human Neurology 4-plex D (N4PD) Kit. Standard exclusion criteria were hemolysis and plasma concentrations with a coefficient of variation >0.20. All biomarkers were log-transformed and winsorized at ±3 SD.

Statistical analysis

All analyses were done in R version 4.5.1. Spearman rho correlations were used to examine preliminary associations among study variables. For our main analysis, linear regressions were conducted using lm(). These models regressed levels of plasma AD biomarkers (ptau217, BD-tau) on pain status (frequent pain versus no pain), BDNF, and their interaction (multiplicative term between pain status and BDNF). All models were adjusted for age, sex, and body mass index (BMI). Significant interactions were probed using simple slope analyses from package emmeans. Because of the modest sample size, the lm() models were bootstrapped using the boot package with 5000 resamples.

Results

Preliminary analyses

Twenty-three participants reported having frequent pain (46%). Participants with frequent pain were similar to those without frequent pain on all demographic and biomarker measures (ps > 0.10; see Table 1). Age was not correlated with levels of BDNF or AD biomarkers (ps > 0.10). Higher level of ptau217 was significantly correlated with higher level of BD-tau (r = 0.56, p < 0.001).

Table 1.

Participant characteristics.

		Overall	Frequent pain	No frequent pain
		(N = 50)	(N = 23)	(N = 27)	t or χ²	df	p
Age (years)	M (SD)	45.8 (6.46)	46.0 (5.18)	45.6 (7.47)	0.22	43.6	0.830
Age (years)	[Min, Max]	[35.0, 55.0]	[37.0, 55.0]	[35.0, 55.0]
Education (years)	M (SD)	18.0 (1.97)	18.1 (2.07)	17.9 (1.91)	−0.50	40.5	0.623
Education (years)	[Min, Max]	[13.0, 21.0]	[13.0, 21.0]	[13.0, 21.0]
Sex
Male	n (%)	22 (44.0%)	9 (39.1%)	13 (48.1%)	0.05	1	0.821
Female	n (%)	28 (56.0%)	14 (60.9%)	14 (51.9%)
BMI	M (SD)	28.9 (4.86)	29.3 (5.94)	28.5 (3.80)	−0.49	33.3	0.627
BMI	[Min, Max]	[19.6, 44.8]	[19.6, 44.8]	[22.0, 35.1]
BDNF (ng/mL)	M (SD)	3900 (6355)	3868 (8008)	3929 (4596)	−0.08	29.6	0.938
BDNF (ng/mL)	[Min, Max]	[66.6, 39405]	[66.6, 39405]	[134, 20076]
ptau217 (pg/mL)	M (SD)	0.103 (0.0641)	0.108 (0.0665)	0.0960 (0.0619)	0.43	44.5	0.671
ptau217 (pg/mL)	[Min, Max]	[0.009, 0.258]	[0.010, 0.233]	[0.009, 0.258]
BD-tau (pg/mL)	M (SD)	5.55 (2.65)	5.06 (2.73)	5.95 (2.56)	0.91	42.7	0.369
BD-tau (pg/mL)	[Min, Max]	[1.04, 11.9]	[1.04, 10.8]	[1.04, 11.9]

BDNF: brain-derived neurotrophic factor; BD-tau: brain-derived tau; ptau217: phosphorylated tau at threonine 217. Continuous variables compared using Welch's t-test; Sex compared using χ² test. df: degrees of freedom.

Main analyses

Because preliminary analyses yielded no significant main associations of BDNF or frequent pain with AD biomarkers, we proceeded with main analyses focusing on interaction effects. After adjusting for age, sex, and BMI, we observed significant Frequent Pain × BDNF interactions for both BD-tau (β = -0.85, SE = 0.304, p = 0.020), and ptau217 (β = -0.73, SE = 0.292, p = 0.030) (Table 2). Simple slope analyses for both BD-tau and ptau217 indicated that higher BDNF was associated with lower BD-tau and ptau217 among individuals with frequent pain (β = -0.68, SE = 0.21, p = 0.002; β = -0.65, SE = 0.22, p = 0.005, respectively) (Figure 1). In contrast, BDNF was unrelated to BD-tau or ptau217 among those without frequent pain (ps > 0.3).

Table 2.

Models assessing interactive associations of frequent pain and BDNF with ptau217 and BD-tau.

	Outcome: ptau217				Outcome: BD-tau
	β	SE	CI	p	β	SE	CI	p
(Intercept)	−0.30	0.252	[-0.82, 0.17]	0.207	−0.78	0.534	[-1.83, 0.28]	0.138
Age (scaled)	−0.09	0.149	[-0.36, 0.22]	0.570	−0.21	0.150	[-0.48, 0.11]	0.182
Sex (female)	0.65	0.337	[-0.05, 1.28]	0.066	0.59	0.320	[-0.08, 1.19]	0.072
Frequent Pain	−0.24	0.304	[-0.80, 0.39]	0.462	−0.44	0.298	[-0.97, 0.22]	0.174
BDNF (scaled)	0.08	0.174	[-0.26, 0.42]	0.665	0.17	0.187	[-0.19, 0.54]	0.353
BMI (scaled)	0.20	0.140	[-0.08, 0.47]	0.162	0.26	0.127	[-0.01, 0.49]	0.055
Frequent Pain × BDNF	−0.73	0.292	[-1.26, -0.10]	0.030	−0.85	0.304	[-1.39, -0.20]	0.020

BDNF: brain-derived neurotrophic factor; BD-tau: brain-derived tau; ptau217: phosphorylated tau at threonine 217. All continuous predictors scaled (z-scored). Models adjusted for age, sex, and body mass index. Models were bootstrapped with 5000 resamples.

Discussion

In community-dwelling dementia-free early midlife adults, frequent pain status moderated the association between plasma BDNF and AD biomarkers of pathology and neurodegeneration, such that higher BDNF was associated with lower ptau217 and BD-tau levels in individuals with frequent pain, whereas no such association was observed in individuals without frequent pain. These results suggest that in early midlife, BDNF's neuroprotective role in AD-related pathology and neurodegeneration may be particularly pronounced under conditions of recurring nociceptive stress. Although no prior work has investigated the BDNF-AD pathophysiology associations in the context of pain, our findings are consistent with the broader notion that biological protective factors such as BDNF that promotes neuroplasticity may become particularly consequential under conditions of heightened neural stress.^19,20 Frequent pain, through its demands on BDNF-dependent neuroplastic systems,¹⁰ may represent precisely such a condition, rendering individual differences in BDNF more salient for AD-related pathological processes in early midlife. More broadly, these findings have potential clinical implications given growing interest in BDNF-targeted interventions for AD prevention.¹ The fact that BDNF's association with AD-related pathophysiology was specifically detectable in individuals with frequent pain suggests that this subgroup may represent a target population for BDNF-related AD prevention strategies, where bolstering BDNF signaling may confer neuroprotective benefit against AD-related pathophysiology as early as midlife.

The converging associations of BDNF with both plasma biomarkers of AD-related pathology and neurodegeneration are worth noting. BD-tau reflects tau released from brain tissue and is considered a marker of AD-type neurodegeneration, unlike other non-specific plasma biomarkers of neurodegeneration such as total-tau, neurofilament light chain.¹⁶ Similarly, ptau217 is tightly coupled with early Aβ pathology and tau deposition, and elevated levels are detectable at preclinical stages of AD prior to overt neurodegeneration.^15,21,22 The significant Frequent Pain × BDNF interaction on both AD-specific biomarkers suggest the neuroprotective role of BDNF may operate on both Aβ-associated tau phosphorylation and neurodegeneration-related processes in individuals with frequent pain. These results are consistent with preclinical and experimental evidence that BDNF protects against tau-related neuronal loss and synaptic degeneration,²³ and attenuates tau phosphorylation through TrkB-mediated activation of the PI3K-GSK3β signaling cascade.²⁴

Moreover, pain engages overlapping nociceptive circuits within the hippocampus and prefrontal cortex, regions central to tau propagation in AD.^25–27 BDNF, acting through its TrkB receptor, supports synaptic integrity, dendritic stability, and neuronal survival through PI3 K/Akt and MAPK/ERK signaling pathways.^28,29 In the context of pain, where central sensitization and frequent nociceptive input place demands on these circuits, adequate BDNF signaling may help maintain neuronal homeostasis and limit the release of tau from damaged neurons. Individuals with frequent pain who exhibit a more robust BDNF response may potentially be more biologically protected against the early neurodegenerative consequences of this frequent neurological stress. Consistent with this, higher circulating BDNF levels have been linked to reduced hippocampal atrophy and lower dementia risk in observational studies,^4,13 and work in midlife adults demonstrated that BDNF was prospectively associated with tau burden as measured by PET imaging.³⁰ Future longitudinal work is needed to examine whether the association between BDNF and AD-related pathophysiology observed here in early midlife individuals with frequent pain extends into later adulthood when AD-related pathological burden is more pronounced. Incorporating PET imaging measures alongside plasma biomarkers would further elucidate the structural and pathological correlates of these associations.

Collectively, our findings highlight the importance of studying AD risk processes during midlife, decades before typical dementia onset.^5,6 Pain is prevalent in midlife yet its biological links with long-term brain health remain largely unexamined in the context of dementia prevention.^31,32 Rather than acting as a direct driver of tau pathology or neurodegeneration, pain may instead function as a biological context that interacts with BDNF to influence AD-related pathophysiology in early midlife. Individuals with frequent pain and low BDNF may represent a biologically vulnerable subgroup warranting further investigation. If replicated in larger samples, these findings suggest that frequent pain status may help identify midlife individuals for whom BDNF-targeted prevention efforts such as exercise, may be most impactful.

Several strengths and limitations should be considered. The use of plasma-based AD biomarkers enabled assessment of early AD-related pathophysiology in midlife, a period that remains critically understudied in dementia research yet represents a key window for AD prevention and intervention. Robust statistical approaches were employed to account for potential outliers and heteroskedasticity, strengthening confidence in the stability of the observed associations. A few limitations warrant consideration. First, the modest sample size limits statistical power and generalizability, though it provides preliminary evidence that justifies larger longitudinal investigations. Second, frequent pain was characterized using brief self-report measures that did not capture subtype or chronicity, which may engage distinct biological pathways. Future work should incorporate validated multidimensional pain assessments to better characterize these relationships. Third, the cross-sectional design precludes causal inference. Longitudinal studies are needed to determine whether these associations predict trajectories of AD-related pathophysiology over time. Fourth, a small proportion of participants reported pain medication use (10%), which may influence BDNF levels. Given the sample size, excluding them would have substantially reduced statistical power. Future large-scale studies should examine whether the moderation replicates in medication-naïve samples.

Conclusion

The present study provides novel evidence that frequent pain moderates the association between plasma BDNF and AD-related pathophysiology in community-dwelling dementia-free early midlife adults, such that BDNF's neuroprotective effect appears particularly pronounced in the presence of frequent pain. These findings highlight frequent pain as a potential biologically meaningful context that may shape the relationship between BDNF and early AD-related pathophysiology. Individuals with frequent pain may represent a target population for BDNF-centered prevention efforts in early midlife. Longitudinal replication is needed to establish the temporal dynamics of this relationship and its implications for AD risk across the lifespan.

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iD

Rongxiang Tang

Ethical considerations

This study was approved by Texas A&M University's Institutional Review Board (Protocol #2024-1132).

Consent to participate

All participants provided written informed consent prior to participation.

Consent for publication

Not applicable

Author contribution(s)

Tyler R. Bell: Conceptualization; Formal analysis; Investigation; Methodology; Visualization; Writing – original draft.

Brianna N. Lockwood: Data curation; Investigation; Project administration; Writing – review & editing.

Kayleigh N. Muniz: Data curation; Investigation; Writing – review & editing.

Lydia C. Kang: Data curation; Investigation; Writing – review & editing.

Makenzie N. Laughery: Data curation; Investigation; Writing – review & editing.

Sophia S. Stowell: Data curation; Investigation; Writing – review & editing.

Sana M. Bham: Data curation; Investigation; Writing – review & editing.

Rongxiang Tang: Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing – original draft; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute on Aging (Grant #K01AG081559 to TRB, Grant #K01AG084815 to RT) and Texas A&M University (Start-up fund to RT).

Declaration of conflicting interests

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

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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