The associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by APOE genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive impairment (MCI).
Objective
To investigate the association between CSF biomarkers and agitation in cognitively impaired individuals, with a focus on the potential moderating role of APOE ε4 status.
Methods
We analyzed 491 cognitively impaired individuals (359 MCI and 132 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available CSF biomarker data. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI), focusing on agitation.
Results
Among APOE ε4 carriers, agitation was significantly associated with higher CSF GAP-43 (OR = 1.584, 95% CI: 1.159–2.195, p = 0.005) and p-tau levels (OR = 1.49, 95% CI: 1.073–2.101, p = 0.02). These associations were not observed in non-carriers. In addition, APOE ε4 carriers with agitation showed a higher risk of progression to dementia compared with other groups (HR = 4.422, 95% CI: 2.542–7.692, p < 0.001).
Conclusions
CSF GAP-43 and p-tau levels are associated with agitation in APOE ε4 carriers. Agitation in this subgroup is also associated with an increased risk of progression to dementia, suggesting that it may reflect underlying disease-related processes.
GedaYERobertsROMielkeMM, et al.Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study. Am J Psychiatry2014; 171: 572–581.
2.
DonovanNJAmariglioREZollerAS, et al.Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease. Am J Geriatr Psychiatry2014; 22: 1642–1651.
3.
ArenareGMancaRCaffarraP, et al.Associations between neuropsychiatric symptoms and Alzheimer’s disease biomarkers in people with mild cognitive impairment. Brain Sci2023; 13: 1195.
4.
Van der MusseleSLe BastardNSaerensJ, et al.Agitation-associated behavioral symptoms in mild cognitive impairment and Alzheimer’s dementia. Aging Ment Health2015; 19: 247–257.
5.
GrossbergGUrganusAScheinJ, et al.A real-world assessment of healthcare costs associated with agitation in Alzheimer’s dementia. J Med Econ2024; 27: 99–108.
6.
BlonieckiVAarslandDCummingsJ, et al.Agitation in dementia: relation to core cerebrospinal fluid biomarker levels. Dement Geriatr Cogn Dis Extra2014; 4: 335–343.
7.
Krell-RoeschJRakusaMSyrjanenJA, et al.Association between CSF biomarkers of Alzheimer’s disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging. Alzheimers Dement2023; 19: 4498–4506.
8.
BanningLCPRamakersIKöhlerS, et al.The association between biomarkers and neuropsychiatric symptoms across the Alzheimer’s disease spectrum. Am J Geriatr Psychiatry2020; 28: 735–744.
9.
ChenYFuAKYIpNY. Synaptic dysfunction in Alzheimer’s disease: mechanisms and therapeutic strategies. Pharmacol Ther2019; 195: 186–198.
TerryRDMasliahESalmonDP, et al.Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol1991; 30: 572–580.
12.
SteinackerPWernerLTarabukoA, et al.Evidence for reduced synaptic protein SNAP-25 in cerebrospinal fluid in major depressive disorder and schizophrenia. BMJ Ment Health2025; 28: e301752.
13.
WangJChenHSLiHH, et al.Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice. Brain Behav Immun2023; 109: 23–36.
14.
OsimoEFBeckKReis MarquesT, et al.Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry2019; 24: 549–561.
15.
LanGLiALiuZ, et al.Presynaptic membrane protein dysfunction occurs prior to neurodegeneration and predicts faster cognitive decline. Alzheimers Dement2023; 19: 2408–2419.
16.
ÖhrfeltABenedetALAshtonNJ, et al.Association of CSF GAP-43 with the rate of cognitive decline and progression to dementia in amyloid-positive individuals. Neurology2023; 100: e275–e285.
17.
FranzmeierNDehsarviAStewardA, et al.Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease. Nat Commun2024; 15: 202.
18.
SandeliusÅPorteliusEKällénÅ, et al.Elevated CSF GAP-43 is Alzheimer’s disease specific and associated with tau and amyloid pathology. Alzheimers Dement2019; 15: 55–64.
19.
WingoTSLiuYGerasimovES, et al.Shared mechanisms across the major psychiatric and neurodegenerative diseases. Nat Commun2022; 13: 4314.
20.
RisacherSLKimSNhoK, et al.APOE Effect on Alzheimer’s disease biomarkers in older adults with significant memory concern. Alzheimers Dement2015; 11: 1417–1429.
21.
Serrano-PozoADasSHymanBT. APOE And Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol2021; 20: 68–80.
22.
VattathilSMBlosteinFMiller-FlemingTW, et al.GWAS Links APOE to neuropsychiatric symptoms in mild cognitive impairment and dementia. Alzheimers Dement2025; 21: e70329.
23.
von ElmEAltmanDGEggerM, et al.The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med2007; 147: 573–577.
LiYLiuWWangX, et al.Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer’s disease pathology. Alzheimers Dement2025; 21: e70946.
26.
SaykinAJShenLYaoX, et al.Genetic studies of quantitative MCI and AD phenotypes in ADNI: progress, opportunities, and plans. Alzheimers Dement2015; 11: 792–814.
27.
SoaresCBellaverBFerreiraPCL, et al.CSF Total tau as a proxy of synaptic degeneration. Nat Commun2025; 16: 8076.
28.
HanssonOSeibylJStomrudE, et al.CSF Biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement2018; 14: 1470–1481.
29.
SennikSSchweizerTAFischerCE, et al.Risk factors and pathological substrates associated with agitation/aggression in Alzheimer’s disease: a preliminary study using NACC data. J Alzheimers Dis2017; 55: 1519–1528.
30.
GuadagnaSEsiriMMWilliamsRJ, et al.Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia. Neurobiol Aging2012; 33: 2798–2806.
31.
TekinSMegaMSMastermanDM, et al.Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol2001; 49: 355–361.
32.
LiuCCLiuCCKanekiyoT, et al.Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol2013; 9: 106–118.
33.
YasunoFKimuraYOgataA, et al.Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer’s disease: an in vivo positron emission tomography study. Psychogeriatrics2023; 23: 126–135.
34.
Schaffer AguzzoliCFerreiraPCLPovalaG, et al.Neuropsychiatric symptoms and microglial activation in patients with Alzheimer disease. JAMA Netw Open2023; 6: e2345175.
35.
LanGChenXYangJ, et al.Microglial reactivity correlates with presynaptic loss independent of β-amyloid and tau. Ann Neurol2024; 95: 917–928.
36.
RohdenFFerreiraPCLBellaverB, et al.Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease. Nat Commun2025; 16: 5653.
37.
RuthirakuhanMHerrmannNAndreazzaAC, et al.Agitation, oxidative stress, and cytokines in Alzheimer disease: biomarker analyses from a clinical trial with nabilone for agitation. J Geriatr Psychiatry Neurol2020; 33: 175–184.
38.
RotUSandeliusÅEmeršičA, et al.Cerebrospinal fluid GAP-43 in early multiple sclerosis. Mult Scler J Exp Transl Clin2018; 4: 2055217318792931.
39.
ZengQWangYWangS, et al.Cerebrospinal fluid amyloid-β and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients. Alzheimers Res Ther2024; 16: 69.
40.
LiDSunYDingL, et al.Associations of growth-associated protein 43 with cerebral microbleeds: a longitudinal study. J Alzheimers Dis2024; 97: 1913–1922.
41.
HooverBRReedMNSuJ, et al.Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron2010; 68: 1067–1081.
42.
LanGDuJChenX, et al.Association of APOE-ε4 and GAP-43-related presynaptic loss with β-amyloid, tau, neurodegeneration, and cognitive decline. Neurobiol Aging2023; 132: 209–219.
43.
BlonieckiVZetterbergHAarslandD, et al.Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?Alzheimers Res Ther2020; 12: 153.
44.
BurkeSLMaramaldiPCadetT, et al.Neuropsychiatric symptoms and Apolipoprotein E: associations with eventual Alzheimer’s disease development. Arch Gerontol Geriatr2016; 65: 231–238.
45.
PinkAStokinGBBartleyMM, et al.Neuropsychiatric symptoms, APOE ε4, and the risk of incident dementia: a population-based study. Neurology2015; 84: 935–943.
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