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. 2025 Oct 24;57(1):2575110. doi: 10.1080/07853890.2025.2575110

The role of neutrophils, red blood cells, and platelets in the pathology of Alzheimer’s disease

Yan Xu a,b, Xiangdong Li a,b, Qingchun Zhao a,b,✉, Xiangbo Xu a,b,✉
PMCID: PMC12557828  PMID: 41134126

Abstract

Introduction

Alzheimer’s disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by core neuropathological hallmarks including abnormal deposition of β-amyloid forms neuroinflammatory plaques, hyperphosphorylated tau protein-driven neurofibrillary tangles, synaptic dysfunction, and progressive neuronal loss.

Discussion

Emerging evidence transcends the traditional central nervous system (CNS)-centric perspective, revealing that neutrophils, red blood cells (RBCs), and platelets may play critical roles in AD pathogenesis by modulating systemic inflammatory responses, disrupting blood-brain barrier integrity, and participating in the CNS-peripheral interactions.

Conclusion

This review synthesizes recent advances in understanding the contributions of neutrophils, RBCs and platelets to AD pathology, which is promising to provide a transformative perspective and evidence for the in-depth understanding of the pathogenesis of AD and developing precision interventions against AD.

Keywords: Alzheimer’s disease, neutrophils, red blood cells, platelets

1. Introduction

Alzheimer’s disease (AD) is an age-associated progressive neurodegenerative disorder, manifesting as debilitating cognitive decline, including memory impairment, language deficits, and behavioral alterations [1]. It severely compromises patients’ quality of life and social functioning, and represents the leading cause of dementia worldwide [2]. It is reported that about 55 million people worldwide are currently living with AD, and this number doubles every 5 years [3]. And it is estimated the number of people with the AD will rise to about 152 million by 2050 [3]. With its escalating global prevalence, AD imposes significant morbidity and mortality rates, posing substantial challenges to healthcare systems and caregivers.

The pathological features of AD are characterized by irreversible cerebral degeneration marked by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles, which drive progressive neuronal loss and synaptic dysfunction [4]. For decades, research has been anchored in two central mechanistic frameworks. The amyloid cascade hypothesis suggests that abnormal deposition of Aβ is the initiating factor of AD pathology, triggering tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction [5]. The tau hypothesis emphasizes that the excessive phosphorylation and abnormal accumulation of tau protein in the brain leads to the accumulation of neurofibrillary tangles (NFTs), which further destroys the normal function of neurons and causes disease [5]. Despite their foundational contributions, drugs (such as Aβ-directed monoclonal antibodies [6] and tau aggregation inhibitors [7] targeting these pathways have yielded limited therapeutic efficacy. On the one hand, they failed to fully account for the clinical heterogeneity of AD. For example, some patients have significant amounts of Aβ deposits at the time of death but do not show noticeable symptoms of dementia [8,9]. On the other hand, these pathologies ignore the role of systemic factors (such as peripheral inflammation and metabolic disorders) in the regulation of central pathology [5,10].

In recent years, the focus of research has gradually shifted to the interaction between the peripheral system and AD. Emerging evidence also highlights that peripheral blood cells, which recognized as crucial regulators in the pathological cascade of AD, play a significant role in the pathology of the AD disease by regulating systemic inflammatory response, blood-brain barrier (BBB) dysfunction, and central nervous system (CNS)-peripheral interaction [11,12]. In this review, we aim to systematically analyze the multidimensional mechanism of action of neutrophils, red blood cells (RBCs), and platelets in AD, so as to provide identification of new biomarkers for the early diagnosis of AD and lay a theoretical foundation for the development of precision treatment strategies based on peripheral blood targets.

2. Association of neutrophils and NETs with AD

Neutrophils are the most common circulating white blood cells in the body, which act as a major component of the innate immune system and play a key role for host to defend against infectious pathogens (such as bacteria, fungi and protists) or tissue damage [13]. After recognizing microbial and/or inflammatory stimuli, neutrophils rapidly migrate to the site of inflammation [14], where they exert their effector functions through phagocytosis, degranulation, production of reactive oxygen species (ROS), and release of neutrophil extracellular traps (NETs) [15].

NETs are a network structure released by activated neutrophils and are mainly made up of chromatin decorated with histones, proteases, and granular protein [16]. NETs can capture and kill pathogens, and inhibit their dissemination [17]. Besides, NETs also play a modulatory role in cells involved in inflammatory and immune responses (such as macrophages, dendritic cells and T-lymphocytes) [17]. Therefore, NETs can play a key role in immune antibacterial, which is essential for host defense against bacterial infection. However, if dysregulated, excessive NETs can further induce inflammation and organ injury, which will be harmful to the host and increase morbidity and mortality in some metabolic (type 2 diabetes and obesity), autoimmune (psoriasis, systemic lupus erythematosus and rheumatoid arthritis), autoinflammatory diseases (gout, inflammatory bowel diseases), and certain septic conditions [18].

Emerging studies from widely utilized AD transgenic models, including 3xTg-AD, 5xFAD, and APP/PS1 mice, have elucidated the critical roles of neutrophils and NETs in AD pathogenesis. (Table 1) [11,19–25]. First, in 3xTg-AD and 5xFAD mice models, studies have confirmed that pro-inflammatory signals can induce cerebral vascular endothelial cells to significantly up-regulate the expression of adhesion molecules [19], which mediates neutrophils adhesion to blood vessels and blocks blood flow, thereby reducing cerebral blood flow (CBF), affecting the cognitive function and memory function of mice, thereby promoting the disease progression of AD mice [21]. After depleting neutrophils or interfering with neutrophilic adhesion by anti-Ly6G antibody in 5xFAD and APP/PS1 mice, the number of stalled capillaries [20] and the level of Aβ1-40 in brain tissue were reduced, CBF was increased, and the performance in spatial and working memory tasks (including object replacement, Y-maze and novel object recognition) were rapidly improved [19,21]. Second, two-photon in vivo imaging showed that in 5xFAD mice, neutrophils infiltrated from blood vessels and migrated directionally to areas of Aβ deposits in the brain parenchyma [11,19]. Myeloperoxidase (MPO) and S100A8-labeled neutrophils were also observed in the cortex and vasculature of APP/PS1 mice [24]. At the same time, the presence of NETs was also confirmed by co-localization of MPO, citrullinated histone H3 and neutrophil elastase in blood vessels and brain parenchyma of 5xFAD mice [19]. Reducing neutrophil-derived MPO of 5xFAD mice also improved cognitive function [22]. Additionally, Aβ could induce impaired neurons via activating the mtDNA‐STING‐NLRP3/IL‐1β axis, initiate neutrophil infiltration in cerebra and induce neurons and cognitive function damage. With the knockout of relevant genes on this axis, the cerebral tissue was protected [25]. Therefore, neutrophils contribute to the pathology of AD by mediating vascular endothelial adhesion, blocking blood flow, infiltrating cerebra and accumulating at the site of Aβ deposition, releasing NETs in mice.

Table 1.

Neutrophils and NETs in AD mice.

Author (year) Type of mouse Age (months) Detection methods of neutrophils and NETs Main results Association of AD and Neutrophils and NETs
Baik et al. (2014) [11] 5xFAD 9–13 Two-photon microscopy Ly6C/G (Gr-1) Alexa Fluor 488-conjugated antibody labeled neutrophils aggregated towards amyloid plaques. Confirmed
Zenaro et al. (2015) [19] 3xTg-AD,5xFAD 2–10 1) SP5 confocal scanning microscope
2) Two-photon laser-scanning microscopy		 1) There was a significant increase in Ly6G+ cells in the brains of mutant mice, and the accumulation of naphthol AS-D chloroacetate esterase labeled neutrophils was observed in the brains of 3xTg-AD mice.
2) Co-localization of MPO+ cells and H3Cit and NE was observed in the blood vessels and cerebral parenchyma of 5xFAD mice at 4 months of age; Co-localization of Gr-1+ cells with IL-17 was observed in the cortex and hippocampus of 3xTg-AD mice at 6 months of age.
3) CMTPX labeled neutrophils adhered to the vascular endothelium and migrated into the areas with Aβ plaques and less neuronal fluorescence in 5xFAD mice brain parenchyma.
4) There was a significant improvement in the performance of mice in the Y-maze spontaneous alternation task and contextual fear-conditioning test after their neutrophils were depleted with anti-Ly6G or anti-Gr-1 antibody.		 Confirmed
Bracko et al. (2019) [20] APP/PS1 10–22 Two-photon excited fluorescence microscope 1) There was a significant improvement in the performance of APP/PS1 mice at 15–16 months of age in the object replacement, Y-maze tests of spatial and working short-term memory after their neutrophils were depleted with anti-Ly6G antibody.
2) There was a significant decrease in capillary stalling and a significant increase in CBF in APP/PS1 mice at 21–22 months of age after their neutrophils were depleted with anti-Ly6G antibody.		 Confirmed
Cruz Hernández et al. (2019) [21] APP/PS1, 5xFAD 3–25 1) Two-photon excited fluorescence microscopy
2) ELISA
3) ASL-MRI		 1) Ly6G labeled neutrophils were observed in the stalled capillary in AD mice.
2) There was a significant decrease in the number of stalled capillaries and the level of Aβ1-40, a significant increase in cortical CBF, and a significant improvement in the performance in OR, Y-maze and NOR in AD mice after their neutrophils were depleted with anti-Ly6G antibody.		 Confirmed
Volkman et al. (2019) [22] 5xFAD 2–10 1) RT-PCR
2) Western blot assay		 There was a significant improvement in cognitive ability of AD mice after their neutrophil-derived MPO deficiency. Confirmed
Kong et al. (2020) [23] 3xTg-AD 12 1) PET imaging
2) Western blot analysis
3) Immunohistochemistry assay		 1) 68Ga-PEG-cFLFLFK labeled neutrophils were observed in the brain of AD mice.
2) There was a significant increase both in the expression of the FPR1 and CAP37 and in the number of neutrophils labeled with MPO in AD mice.		 Confirmed
Smyth et al. (2022) [24] APP/PS1 4/12 Immunostaining MPO and S100A8 labeled neutrophils were observed in the cortex and vasculature of 12 month old APP/PS1 mice. Confirmed
Xia et al. (2023) [25] APP/PS1 8 Immunofluorescent assay Ly6G labeled neutrophils were observed in the cortex and hippocampus
in AD mice.		 Confirmed
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Abbreviations: Aβ, β-amyloid; AD, Alzheimer’s disease; APP, amyloid precursor protein; ASL-MRI, arterial spin labeled magnetic resonance imaging; CAP37, cationic antimicrobial protein of 37 kDa; CBF, cerebral blood flow; ELISA, enzyme-linked immunosorbent assay; FPR1, N-formylpeptide receptor 1; Gr-1, granulocyte receptor 1; H3Cit, citrullinated histone H3; MPO, myeloperoxidase; NE, neutrophil elastase; NETs, neutrophil extracellular traps; NOR, novel object recognition; OR, object replacement; PET, positron emission tomography; RT-PCR, Real-time Polymerase Chain Reaction.

Some clinical studies have been performed to evaluate the importance of neutrophils and NETs in AD patients (Table 2) [24,26–30]. Although a cross-sectional study demonstrated non-significant difference in neutrophil counts between AD patients and healthy controls [29], the average neutrophil to lymphocyte ratio (NLR) in AD patients was significantly higher than that in elderly individuals with normal cognitive, and the NLR value of severe dementia patients was significantly higher than those of mild or moderate dementia patients [29]. In addition, emerging evidence suggests that the NLR in patients with AD showed significant correlations with core cerebrospinal fluid (CSF) biomarkers, including Aβ, total tau, and phosphorylated tau protein [30]. Therefore, the NLR may exhibit clinical correlations with the severity of AD, positioning it as a potential hematological biomarker to assist in diagnostic stratification and dynamic monitoring of disease progression. Besides, the level of neutrophil oxidative stress was significantly increased, but mitochondrial mass and activity of neutrophils were not changed in AD patients compared with controls [26].

Table 2.

Neutrophils and NETs in AD patients.

Author (year) Study design Patient Age Detection method of neutrophils and NETs Main results Association of AD and neutrophils and NETs
Vitte et al. (2004) [26] Cohort 19 AD patients vs. 40 healthy controls 77 ± 1 vs. 71 ± 2, 26 ± 1 Flow cytometry 1) There was a significantly higher DCF staining of resting neutrophils in AD patients.
2) There was no significant difference in the value of neutrophils stained with JC-1 between AD patients and controls.		 Confounding
Tzikas et al. (2014) [27] Cohort 28 AD patients vs. 27 healthy controls 72.9 ± 9.0 vs. 67.6 ± 9.7 ELISA 1) There was a significant increase in plasma MPO level in AD patients.
2) There was a significantly positive association between plasma MPO level and the presence of AD, stage, and plasma Aβ1-42 level and Aβ1-42/1-40 ratio.		 Confirmed
Smyth et al. (2022) [24] Case-control AD patients NA 1) Immunostaining
2) ELISA		 1) Positive staining of MPO, CD66B, and S100A8 was observed in brain tissue microarrays of middle temporal gyrus.
2) There was a significant increase in MPO, S100A8 and calprotectin in AD human brain tissue.
3) There was a significantly positive association between calprotectin, S100A8, and MPO abundance.
4) Colocalization of MPO, S100A8, and H3Cit was observed in brain tissue microarrays of middle temporal gyrus.
5) The localisation of MPO was observed in lectin‑positive vessels.
6) Sporadic deposition of MPO localised to amyloid plaques and tau tangles.		 Confirmed
Wright et al. (2022) [28] Cohort 32 AD patients vs. 49 healthy controls 77.62 ± 5.66 vs. 73.96 ± 10.86 ELISA There was a significant increase in plasma MPO levels in 84.4% AD patients at 1 month after CHEI treatment and a significant decrease at 6 months. Confirmed
Algul et al. (2024) [29] Cross-sectional 175 AD patients vs. 61 healthy controls 75.31 ± 9.62 vs. 73.87 ± 7.49 Automated hematology analyzer system 1) There was a no significant difference in neutrophil value between AD patients and controls.
2) There was a significant increase in NLR in AD patients.		 Confounding
Jacobs et al. (2024) [30] Cohort/Meta-analysis 111 ADNI, 190 NYU CU elderly people 73.79 ± 6.43, 61.53 ± 10.94 ELISA There was a significant association between NLR and CSF Aβ42 in the CU ADNI cohort and between NLR and CSF p-tau, t-tau in the CU NYU cohort. Confirmed
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Abbreviations: Aβ, β-amyloid; AD, Alzheimer’s disease; ADNI, Alzheimer’s Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; CHEI, cholinesterase inhibitor; CU, cognitively unimpaired; DCF, 2’,7’-dichlorodihydrofluorescin; ELISA, enzyme-linked immunosorbent assay; H3Cit, citrullinated histone H3; JC-1, 5,5′,6,6’-tetrachloro 1,1’,3,3′-tetraethylbenzimid azolocarbocyanine iodide; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; NLR, neutrophil-to-lymphocyte ratio; NYU, New York University.

Consequently, neutrophils may exacerbate the pathological process of AD through mediating vascular endothelial adhesion, blocking blood flow, infiltrating cerebra and accumulating at the site of Aβ deposition, and releasing NETs. To reduce neutrophil-derived MPO, deplete neutrophils, interfere with neutrophilic adhesion, or knock out STING/NLRP3/IL‐1β may improve cognitive function in AD (Figure 1). To study the relationship between neutrophils and AD holds significant potential for identifying novel biomarkers and developing immunomodulatory therapeutic strategies and offers valuable insights for advancing diagnostic and therapeutic innovations in AD.

Figure 1.

Figure 1.

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Neutrophils and NETs are involved in the pathology of AD.

Abbreviations: Aβ, β-amyloid peptide; MPO, myeloperoxidase; ROS, reactive oxygen species.

3. Association of RBCs with AD

RBCs are the most abundant cell population in the blood circulation. They are not only responsible for oxygen transport but also serve as pleiotropic cells that integrate circulatory, metabolic, and immune functions, playing an important role in the pathological process of AD.

Some studies have explored the relationship between AD and RBCs and their biomarkers in mice (Table 3) [31,32]. It has been observed that HGB was up-regulated and co-localized with Aβ in amyloid plaques of APP/PS1 mice, which suggest that HGB may directly participate in plaque formation or interact with Aβ, thereby promoting neurotoxic deposition [31]. Furthermore, blood oxygen saturation, hemoglobin (HGB) concentration, and RBCs counts were significantly reduced in APPswe/PS1ΔE9 mice, potentially leading to insufficient tissue oxygen delivery and exacerbating hypoxic neuronal damage [32]. In RBCs of APPswe/PS1ΔE9 mice, the expression of phosphorylated band 3 protein and levels of soluble Aβ40 and Aβ42 were markedly elevated. This elevation may disrupt the RBCs cytoskeleton, thereby causing RBCs deformation and impairing oxygen transport in the bloodstream, ultimately contributing to AD progression [32]. Besides, in cases of hemorrhagic events or erythrolysis, HGB and heme released entered the extracellular environment, where they contributed to the generation of ROS. This process induced oxidative stress and neuronal damage and degeneration, thereby increasing BBB permeability. Furthermore, HGB and heme gained access to the brain parenchyma, interacting with neuroimmune cells and pathological protein aggregates. These interactions further amplified pro-inflammatory signaling and the progression of [33].

Table 3.

RBCs parameters in AD mice.

Author (year) Type of mouse Age (months) Detection methods of RBCs Main results Association of AD and RBCs parameters
Chuang et al. (2012) [31] APP/PS1 <5 or >8 1) Immunohistochemistry
2) Western blotting analysis
3) Immunofluorescence
4) Zeiss fluorescent microscope		 1) There were the highest intensities of HGB-β+ signal and significant increase in HGB-α in APP/PS1 mice.
2) Colocalization of HGB-β+/Aβ+ amyloid plaques was observed in the cortex and hippocampus of the APP/PS1 mice.		 Confirmed
Wang et al. (2023) [32] APPswe/PS1ΔE9 3/6/9 1) Pulse oximeters
2) Automatic blood cell counter
3) Western blotting analysis
4) ELISA		 1) There was significant decrease in blood oxygen saturation, HGB concentration and RBCs count in AD mice.
2) There was significant increase in the expression of phosphorylated band 3 protein and levels of soluble Aβ40 and Aβ42 in the RBCs of AD mice.		 Confirmed
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Abbreviations: Aβ, β-amyloid; AD, Alzheimer’s disease; APP, amyloid precursor protein; ELISA, enzyme-linked immunosorbent assay; HGB, hemoglobin; RBCs, red blood cells.

Emerging clinical studies have further delineated the association between RBCs and AD pathology (Table 4) [34–42]. RBCs morphology abnormalities were commonly observed in AD patients, which might be related to the direct binding of Aβ fibers to RBCs and interference with their normal physiological functions [34,39]. Piezo1 channels were present on the RBCs membrane, where they regulate RBCs volume and facilitate RBCs transit through narrow capillaries, thereby supporting oxygen delivery [43]. Aβ in small concentration inhibited the proper function of Piezo1 channel, which might impair RBC-mediated oxygen supply and exacerbate the pathological progression of AD [44,45].

Table 4.

RBCs parameters in AD patients.

Author (year) Study design Patient Age Detection methods of RBCs Main results Association of AD and RBCs parameters
Mohanty et al. (2008) [34] Cross-sectional 6 AD patients vs. 10 healthy controls NA Olympus IX-70 microscope There was a significant increase in the number of RBCs with altered morphology in AD patients, and the percentage of elongated RBCs in samples from healthy individuals treated with either Aβ1-40 or Aβ1-42 fibrils. Confirmed
Ferrer et al. (2011) [35] Case-control 17 AD patients vs. 25 control cases 67–81 vs. 39–78 1) Double-labeling immunofluorescence
2) Confocal microscopy		 1) There was a significant decrease in HGB immunoreactivity in neurons with pre-tangles, NFT and hyperphosphorylated tau of AD patients.
2) HGB was observed in the core of amyloid of neuritic plaques and in the diffuse plaques in AD.		 Confirmed
Shah et al. (2011) [36] Cohort 881 older persons 80.6 ± 7.4 Beckman/Coulter LH750 automated processor 1) The incident AD hazard ratios increased with HGB levels lower or higher than 13.7 g/dL.
2) Participants with anemia or clinically high HGB had a more rapid cognitive decline compared with those with clinically normal HGB.		 Confirmed
Öztürk et al. (2013) [37] Cross-sectional 197 AD patients vs. 133 healthy controls 76.22 ± 6.92 vs. 71.68 ± 5.30 Beckman Coulter Gen-S automated analyzer 1) There was a significant increase in RDW and ESR values in AD patients.
2) A significant negative correlation was observed between MMSE scores and RDW levels.
3) There were no significant differences in HGB, ferritin, serum iron between AD patients and controls.		 Confounding
Faux et al. (2014) [38] Cross-sectional 211 AD patients vs. 768 healthy controls NA Clinicopathology test There was a significant decrease in iron, HGB, MCH, MCHC, red cell folate, PCV and a significant increase in ESR in AD patients. Confirmed
Lan et al. (2015) [39] Cross-sectional 50 AD patients vs. 50 healthy controls 69.70 ± 4.70 vs. 67.82 ± 3.76 1) Olympus IX-70 microscope
2) Immunofluorescence assay		 There were significant differences in morphology and size of RBCs between AD patients and controls, and a significant increase in the ratio of amyloid binding-positive peripheral RBCs in AD patients. Confirmed
Dong et al. (2019) [40] Cross-sectional 56 AD patients vs. 59 healthy controls 69.04 ± 9.05 vs. 68.12 ± 5.81 Automatic hematology analyzer There were no significant differences in RBCs count, MCV, MCH, RDW between AD patients and controls. Unconfirmed
Huang et al. (2022) [41] Meta-analysis 961 AD patients vs. 6224 healthy controls NA Calculate SMD 1) There were significant changes in HGB level in AD patients compared with controls.
2) There were no significant differences in RBCs count, MCV, RDW between AD patients and controls.		 Confounding
Qiang et al. (2023) [42] Cohort 313448 UK Biobank 60.38 ± 5.40 Hematology analyzer 1) There were positive association between dementia and RDW, MRV, and MSCV.
2) There were negative association between dementia and RBC count, HGB, MCHC, and IRF.		 Confirmed
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Abbreviations: Aβ, β-amyloid; AD, Alzheimer’s disease; ESR, erythrocyte sedimentation rate; HGB, hemoglobin; IRF, immature reticulocyte fraction; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MMSE, Mini-Mental State Examination; MSCV, mean sphered cell volume; MRV, mean reticulocyte volume; NFT, neurofibrillary tangles; PCV, packed cell volume; RBCs, red blood cells; RDW, red blood cell distribution width; SMD, standardized mean difference.

In addition, immunofluorescence and confocal microscopy demonstrated reduced neuronal HGB expression within neurons containing abnormal protein aggregates (such as pre-tangles, NFTs and hyperphosphorylated tau) in AD patients [35]. Some studies have found that patients with AD have changes in levels of RBC indices. Qiang et al. found that there was positive correlation between dementia and red blood cell distribution width (RDW), as well as mean reticulocyte volume, but an inverse correlation between dementia and mean corpuscular hemoglobin concentration, along with immature reticulocyte fraction [42]. However, another study found that there were no significant differences in RBCs count, mean corpuscular volume, mean corpuscular hemoglobin, RDW between AD patients and controls [40]. The reasons for this discrepancy might be significant methodological heterogeneities across studies, including variations in patient populations (e.g. disease stage, comorbidities) and differences in therapeutic interventions, compound these biological variances, ultimately leading to divergent findings in the studies.

Overall, the interactions between RBCs and Aβ, including the binding of Aβ to RBCs, the inhibition of Piezo1 channels on the RBCs membrane by Aβ, and the colocalization between Aβ and HGB and heme, may have implications for oxygen transport and could contribute to altered RBCs function, and promote Aβ deposition, thereby contributing to the pathological progression of AD (Figure 2). Therefore, targeting intervention in the interactions between Aβ and RBCs may significantly ameliorate AD-related symptoms.

Figure 2.

Figure 2.

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RBCs contribute to the pathology of AD.

Abbreviations: Aβ, β-amyloid peptide; HGB, hemoglobin; RBC, red blood cell; ROS, reactive oxygen species.

4. Association of platelets with AD

As a major source of peripheral amyloid precursor protein (APP) and Aβ, increased platelets promote the activation of platelets and contribute to Aβ deposition, eventually causing amyloid plaque deposition in the brain, leading to irreversible neuronal damage and ultimately AD.

Animal studies demonstrated that platelets might have exacerbated AD progression by disrupting BBB integrity, facilitating the translocation of peripherally derived Aβ into the brain, where it aggregated into pathological deposits (Table 5) [46–49]. Pharmacological inhibition of platelets activation (e.g. via aspirin) significantly ameliorated AD-related symptoms in mice models [46]. Notably, in 3xTg-AD mice, platelet counts, morphology, and expression levels of APP and glycoproteins remained comparable to wild-type controls. Both animal experiments and clinical studies revealed significant changes in platelet APP isoforms and secreted amyloid precursor protein beta, further implicating platelets dysfunction in AD pathogenesis [48]. Interestingly, platelets depletion in APP/PS1 mice exacerbated amyloid plaque expansion and hippocampal neuritic dystrophy, indicating that platelets might also have exerted neuroprotective effects by limiting plaque expansion and neuronal damage [49]. However, these AD mice exhibit markedly enhanced platelets adhesion and thrombus formation [47]. The hyperactivation of platelets contributed to increased generation of ROS, thereby inducing mitochondrial dysfunction and exacerbating oxidative stress. Furthermore, activated platelets carried several crucial enzymes, including monoamine oxidase-B, cyclooxygenase, and nitric oxide synthase. These enzymes were considered major enzymatic sources of ROS and might further aggravate oxidative stress-mediated neuronal damage and neurodegeneration in AD [50].

Table 5.

Platelet parameters in AD mice.

Author (year) Type of mouse Age (months) Detection methods of platelet Main results Association of AD and platelet parameters
Wu et al. (2021) [46] SAMP8, APP/PS1, C57BL/6 4/6/10, 3/6/10/15, 2/15 1) IF staining
2) ELISA		 1) There was a significant increase in platelets Aβ contents in mice with age.
2) There was a significant increase in platelets Aβ and tau proteins, learning and memory deficits in C57 mice injected with platelets from aged APP/PS1 mice.
3) There was a significant decrease in platelets Aβ and tau proteins and memory deficits were rescued in SAMP8 mice after inhibiting their platelet activation by aspirin.		 Confirmed
Canobbio et al. (2016) [47] 3 × Tg-AD 18 1) Fluorescence microscope
2) Western blot analysis
3) Transmission electron microscope		 1) There were no significant differences in the level of expression of APP and glycoprotein in platelets, platelet count and morphology between WT and 3xTg-AD mice.
2) Platelets adhere more avidly on matrices in 3xTg-AD mice compared with WT mice.
3) There was a significant increase in the phosphorylation of Pyk2, Akt, p38MAP kinase and MLC in response to collagen adhesion in 3xTg-AD platelets.
4) There was a significant increase in platelet adhesion and thrombus formation on collagen-coated surface in 3xTg-AD mice.		 Confounding
Plagg et al. (2015) [48] 3xTg-AD, APP_SweDI 7/14/20, 6/12 1) Western blot analysis
2) ELISA
3) Flow cytometry
4) HPLC		 1) There was a significant decrease in platelet APP isoform and sAPPβ in 3xTg-AD mice.
2) There was a significant increase in platelet apoptosis and necrosis, CD62P positive cells, and decrease in sAPPβ in APP_SweDI mice.
3) There were no significant differences in APP and serotonin between APP_SweDI and WT mice.		 Confounding
de Sousa et al. (2023) [49] APP-PS1 12–13 1) Fluorescence immunohistochemistry
2) Confocal laser scanning microscope		 There was a significant increase in neuritic dystrophy in the hippocampus, a significant change in the size distribution of amyloid plaque in APP-PS1 female mice after their platelets were depleted by anti-CD42b. Confirmed
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Abbreviations: Aβ, β-amyloid; AD, Alzheimer’s disease; APP, amyloid-precursor protein; ELISA, enzyme-linked immunosorbent assay; HPLC, high-performance liquid chromotography; IF, Immunofluorescence; MLC, myosin light chain; sAPPβ, secreted amyloid precursor protein beta.

Clinical studies have yielded controversial evidence regarding the potential relationship between platelets and associated biomarkers in the pathogenesis of AD (Table 6) [37,40, 48,51–56]. Zainaghi et al. found that the amyloid precursor protein ratio (APPr) in platelets was significantly reduced in AD patients, and this reduction was correlated with membrane fluidity and the cognitive decline, suggesting that there was abnormal APP processing in platelets in AD patients [51]. Furthermore, AD-specific alterations in peripheral platelet biomarkers, such as a marked decrease in platelet distribution width, indicated potential platelets activation and functional dysregulation during disease progression [52]. Mean platelet volume (MPV), which has also been extensively studied as an indicator of platelet activation and inflammation, showed a positive correlation with CSF T-tau [57] and an increase in AD patients. This increase was attributed to the AD-related inflammatory response, which promoted platelet activation and led to a state of platelet hyperactivity [53]. Conversely, inflammation could also result in substantial platelet consumption or impaired bone marrow function, contributing to reduced MPV [52,58]. In addition, emerging evidence indicated that significant structural and functional abnormalities in platelets were present in AD patients [59–61].

Table 6.

Platelet parameters in AD patients.

Author (year) Study design Patient Age Detection method of platelet Main results Association of AD and platelet parameters
Zainaghi et al. (2007) [51] Cross-sectional 23 AD patients vs. 29 healthy controls 74.4 ± 9.0 vs. 70 ± 5.8 1) Modified Lowry method
2) Western blotting analysis
3) PTI spectrofluorometer		 1) There was a significant decrease in APPr in platelets of AD patients.
2) Positive correlations between the APPr and DPH anisotropy, as well as the MMSE score, the CAMCOG score, and the score on the memory subscale of the CAMCOG were observed.		 Confirmed
Wang et al. (2013) [52] Cross-sectional 120 AD patients vs. 120 non-demented controls 72.8 ± 3.6 vs. 73.7 ± 4.2 Sysmex XE-2100 autoanalyzer 1) There was a significant decrease in MPV and PDW in AD patients.
2) A positive correlation was observed between MMSE and MPV and PDW.
3) There was no significant difference in platelet between AD patients and controls.		 Confounding
Öztürk et al. (2013) [37] Cross-sectional 197 AD patients vs. 133 healthy controls 76.22 ± 6.92 vs. 71.68 ± 5.30 Beckman Coulter Gen-S automated analyzer There was no significant difference in platelet between AD patients and controls. Unconfirmed
Koç et al. (2014) [53] Cross-sectional 109 AD patients vs. 81 healthy controls 76.74 ± 8.99 vs. 75.32 ± 8.42 CELL-DYN 3700 SL analyzer There was a significant increase in MPV, and a significant decrease in platelet count in AD patients. Confirmed
Plagg et al. (2015) [48] Cross-sectional 43 AD patients vs. 30 healthy controls 80 ± 1 vs. 77 ± 1 1) Western blotting analysis
2) ELISA
3) Flow cytometry		 1) There was a significant increase in total platelet APP and sAPPβ levels, and decrease in platelet APP isoforms and EGF levels in AD patients.
2) There was no significant difference in serotonin between AD patients and controls.		 Confounding
Bram et al. (2019) [54] Cross-sectional 20 AD patients vs. 20 healthy controls 76.2 ± 7.2 vs. 74.9 ± 4.5 1) Western blotting analysis
2) Modified Lowry method		 1) There was a significant decrease in ADAM10 and PSEN1 in platelet in AD patients.
2) There was no significant difference in BACE1 in platelet between AD patients and controls.		 Confounding
Dong et al. (2019) [40] Cross-sectional 56 AD patients vs. 59 healthy controls 69.04 ± 9.05 vs. 68.12 ± 5.81 Automatic hematology analyzer 1) There was a significant decrease in PDW in AD patients.
2) There were no significant differences in platelet count and MPV between AD patients and controls.		 Confounding
Dos Santos et al. (2020) [55] Cross-sectional 60 probable AD patients vs. 60 healthy controls NA vs. ≥ 60 Complete blood count There was a significant decrease in platelets in AD patients. Confirmed
Fu et al. (2023) [56] Meta-analysis 702 AD patients vs. 710 controls NA Calculate SMD 1) There was a significant decrease in APPr, ADAM10, and Na+-K+-ATPase in platelet, a significant increase in HMW/LMW tau, adenosine A2 receptor, MAO-B, NO production and ONOO− production in AD patients.
2) There were no significant differences in BACE1, PSEN-1, 5-HT, Ca2+, DPH, TMA-DPH between AD patients and controls.		 Confounding
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Abbreviations: AD, Alzheimer’s disease; ADAM10, A-disintegrin and metalloprotease 10; APP, amyloid-precursor protein; APPr, amyloid-precursor protein ratio; BACE1, Beta-site APP-cleaving enzyme 1; CAMCOG, Cambridge cognitive test; DPH, 1,6-diphenyl-1,3,5-hexatriene; EGF, epidermal growth factor; ELISA, enzyme-linked immunosorbent assay; HMW, high molecular weight; LMW, low molecular weight; MAO-B, monoamine oxidase B; MMSE, mini-mental state examination; MPV, mean platelet volume; PDW, platelet distribution width; PSEN1, presenilin-1; PTI, Photon Technology International; sAPPβ, secreted amyloid precursor protein beta; SMD, standardized mean difference; TMA-DPH, I-[4-(trimethylamino) phenyl]-6-phenyl-1,3,5, hexatriene; 5-HT, 5-hydroxytryptamine.

Thus, platelets in AD exhibit a dual functional role (Figure 3). On the one hand, platelets are recognized as a primary peripheral source of APP. Upon activation, they release substantial amounts of Aβ into the bloodstream. This peripherally derived Aβ is then thought to cross the BBB, contributing to cerebral amyloid deposition and thereby exacerbating the pathological cascade of AD. In addition, Aβ can further promote platelet activation and aggregation by activating the PI3K/AKT signaling pathway [62], leading to the release of more Aβ and forming a positive feedback loop that drives disease progression; on the other hand, platelets may exert neuroprotective effects by limiting amyloid plaque expansion and mitigating neuronal damage. Targeting the inhibition of PI3K/AKT pathway or preventing platelet depletion may represent a novel therapeutic avenue for mitigating the pathological progression of AD. Notably, platelets dysfunction was observed in AD patients and animal models, including reduced APPr, enhanced platelets adhesion, and heterogeneous alterations in platelets biomarkers, which underscores their dynamic and multifaceted involvement in the complex regulatory networks driving AD pathogenesis. Therefore, further study on the role of platelets in the pathology of AD may provide novel ideas for the development of targeted treatment strategies of AD.

Figure 3.

Figure 3.

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Platelets participate in the pathology of AD.

Abbreviations: Aβ, β-amyloid peptide; BBB, blood-brain barrier; ROS, reactive oxygen species.

5. Conclusion

In summary, the paradigm of neutrophils, RBCs, and platelets in AD has shifted from “bystanders” to “active participants” in disease pathogenesis. Accumulating evidence highlights that neutrophils, RBCs, and platelets participate in AD pathogenesis through multifaceted mechanisms. Neutrophils exacerbate AD progression through NETs-driven neuroinflammation, vascular endothelial adhesion, and thrombosis. RBCs indirectly accelerate neurodegenerative processes in the CNS through oxygen-carrying dysfunction, abnormal morphology and function. Platelets play a dual role in the pathology of AD, exacerbating cerebrovascular dysfunction by generating Aβ and exerting neuroprotective effects by limiting amyloid plaque expansion. Therefore, the development of peripheral blood-based biomarkers could revolutionize early diagnosis and therapeutic monitoring in AD. Utilizing their associated biomarkers for disease diagnosis and monitoring holds considerable clinical feasibility. Indicators such as neutrophil count, RBCs count, platelet count, NLR, MPV, RDW, and HGB are directly derived from blood routine examination, making them readily accessible in clinical practice. In contrast, novel NETs biomarkers currently require analysis in specialized laboratories. Before their integration into routine clinical use, key challenges such as analytical standardization and extensive clinical validation must be addressed. Nevertheless, the precise mechanisms underlying neutrophils, RBCs, and platelets involvement in AD remain incompletely elucidated. Future research should integrate advanced technologies such as single-cell sequencing, metabolomics, and live imaging to delineate phenotypic evolution of peripheral blood cells subpopulations across AD stages. Therapeutic strategies targeting peripheral blood components, including NETs inhibitors and RBC metabolic modulators, hold promise for novel AD interventions. Unlocking their translational potential will demand interdisciplinary collaboration to bridge mechanistic discoveries with clinical applications, ultimately advancing precision medicine in AD.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

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