title: An increased neutrophil-lymphocyte ratio in Alzheimer's disease is a function of age and is weakly correlated with neocortical amyloid accumulation.
abstract: Inflammation is a hallmark of Alzheimer's disease (AD). Whether directly involved in the pathogenesis, or a downstream consequence of neuronal death, the blood neutrophil-lymphocyte ratio (NLR) is reported to be a putative, non-invasive peripheral biomarker for AD. The aim of this study was to re-evaluate the diagnostic utility of longitudinal measures of the NLR. The NLR was stable across all time-points and weakly correlated with neocortical amyloid burden (R=0.21 at baseline, 0.27 at 18 months, 0.20 at 36 months and 0.10 at 54 months). Cross-sectionally, the NLR was significantly elevated in AD participants as compared to HC participants at baseline (p<0.0001), 18 months (p<0.0001), 36 months (p=0.002) and at 54 months (p=0.007), however only prior to adjustment for age, sex and APOEε4 allele status (p>0.05 at all time-points except for 18 months; p<0.0001). Longitudinally, the NLR was not significantly different between HC and AD participants (p>0.05) adjusted for age, sex and APOEε4 allele status. Comparing the NLR between cognitive transition groups over time (transition towards an AD type dementia), there was no significant difference in the NLR levels between those participants, who did not transition and those participants who did transition, or those in the stable AD group after adjusting for age, sex and APOEε4 allele status (p>0.05). Despite inflammation being a hallmark in AD and previous reports showing that the NLR can discriminate HC from AD patients, our results suggest that the sensitivity of the NLR itself is not robust enough for diagnostic utility. We identified significant relationships cross sectionally (p<0.05 at baseline, 18 months and 36 months) between the NLR and neocortical amyloid burden, but this relationship was lost after longitudinal analyses (p>0.5). The NLR also had limited association with cognitive decline, although in our cohort, the number of participants transitioning was relatively small. In conclusion, the NLR may reflect AD-related inflammatory processes in the periphery, but age and sex are dominant covariates which need to be controlled for in population-based screening.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Rembach
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Watt
authors.affiliation: CSIRO Computational Informatics/Australian e-Health Research Centre, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Wilson
authors.affiliation: Sir James McCusker Alzheimer's Disease Research Unit, Health Department of WA, Perth, WA 6009, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rainey-Smith
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia; Department of Psychiatry, St George's Hospital, University of Melbourne, Victoria 3101, Australia; National Ageing Research Institute, Parkville, Victoria 3050, Australia.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Ellis
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.affiliation: CSIRO Preventative Health Flagship, Parkville, Victoria 3010, Australia.
authors.forename: S Lance
authors.initials: SL
authors.lastname: Macaulay
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Sir James McCusker Alzheimer's Disease Research Unit, Health Department of WA, Perth, WA 6009, Australia.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: National Ageing Research Institute, Parkville, Victoria 3050, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: CSIRO Computational Informatics/Australian e-Health Research Centre, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D053327:Apolipoprotein E4 / Q000235:genetics; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D061212:Memory, Episodic; D019579:Neocortex / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology*; D011569:Psychiatric Status Rating Scales; D011877:Radionuclide Imaging; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D053327:Apolipoprotein E4; D013844:Thiazoles
keywords: Alzheimer's disease; Diagnosis; Haematology; Neocortical amyloid burden; Neuroinflammation