Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease

Abstract

Introduction: We analyzed relationships among peripheral immunity markers, cognition, Alzheimer's disease (AD)-related biomarkers, and neuroimaging to understand peripheral immunity involvement in AD.

Methods: Peripheral immunity markers were assessed in AD, non-AD neurodegenerative disorders, and controls, examining their connections with cognition, AD-related biomarkers, and neuroimaging using multiple regression models.

Results: The study included 1579 participants. Higher levels of white blood cell, neutrophil, monocyte, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lower lymphocyte-to-monocyte ratio (LMR) were associated with cognitive decline and more severe anxiety and depression. The impact of lower LMR, lymphocyte count, and higher NLR on cognitive decline is mediated through cerebrospinal fluid amyloid beta (Aβ) levels. Additionally, increased PLR, NLR, and SII were associated with brain atrophy and hippocampal Aβ deposition (amyloid positron emission tomography).

Discussion: Peripheral immunity markers offer a non-invasive and cost-effective means of studying AD-related pathophysiological changes, providing valuable insights into its pathogenesis and treatment.

Highlights: Peripheral immunity markers linked to cognitive decline and anxiety/depression.Low LMR, LYM, and high NLR linked to reduced CSF Aβ, impacting cognition.High PLR, NLR, SII associated with brain atrophy and hippocampal Aβ deposition.

Keywords: Alzheimer's disease; amyloid beta; cerebrospinal fluid; cognition; neuroimage; peripheral immunity.

FIGURE 1

The flow diagram of the participants in this study. CSF, cerebrospinal fluid; FDG, 18F‐fluorodeoxyglucose; MRI, magnetic resonance imaging; PET positron emission tomography.

FIGURE 2

Distribution of peripheral immunity markers across diagnostic groups. AD, Alzheimer's disease (containing posterior cortical atrophy); CN, cognitively normal; MCI, mild cognitive impairment; SYN, synucleinopathies, including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies; TAU, tauopathies, including progressive supranuclear palsy and corticobasal degeneration; TDP, TAR DNA‐binding protein 43 proteinopathies, including frontotemporal dementia and amyotrophic lateral sclerosis; Other, including essential tremor, Huntington's disease, hereditary spastic paraplegia, normal pressure hydrocephalus, and spinocerebellar ataxia.

FIGURE 3

Associations of peripheral immunity markers with cognition and CSF/plasma biomarkers. A, Heat map shows associations of blood inflammation indicators with cognition and CSF/plasma biomarkers, with colors representing the association coefficients (β) of multiple linear regressions. The color bar represents the range of β values. Models were adjusted for age, sex, education, and BMI. Controlling for multiple comparisons was performed with the false discovery rate method of Benjamini and Hochberg. Significance:*P < 0.05, **P < 0.01, ***P < 0.001, ‐P ≥ 0.05. B, Results of mediation analyses. Aβ, amyloid beta; BMI, body mass index; BNT, Boston Naming Test; CSF, cerebrospinal fluid; DST, Digit Symbol Test; HAM‐A, Hamilton Anxiety Scale; HAM‐D, Hamilton Depression Scale; LMR, lymphocyte‐to‐monocyte ratio; LYM, lymphocytes; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; MNC, monocytes; NfL, neurofilament light chain; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; SII, systemic immune‐inflammation index; WBC, white blood cells.

FIGURE 4

Associations of peripheral immunity markers with volumes of the cortical and subcortical regions. The t value was generated from multivariable regression analyses after adjusting for age, sex, education, and BMI. Controlling for multiple comparisons was performed with the false discovery rate method of Benjamini and Hochberg. The color bar represents the range of t values. AV45 PET, 18F‐florbetapir positron emission tomography; BMI, body mass index; MRI, magnetic resonance imaging; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; SII, systemic immune‐inflammation index.