Association of plasma placental growth factor with white matter hyperintensities in Alzheimer’s disease

Background The global prevalence of dementia, particularly Alzheimer’s disease (AD), is increasing. With the introduction of anti-β-amyloid (Aβ) antibody drugs, the accurate in vivo diagnosis of AD has become crucial. Autopsy studies have shown that AD often coexists with cerebrovascular injury, which may affect cognitive outcomes and the effectiveness of anti-Aβ drugs. Although white matter hyperintensity (WMH) on magnetic resonance imaging (MRI) is an established marker of cerebrovascular injury, no fluid biomarker has been identified.

This study investigated the association between WMH severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels.

The study included 242 patients from memory clinics, and MRI, CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF.

Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group.

Plasma PlGF is a promising marker of cerebrovascular injury in AD. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was supported by the MHLW Research on Dementia Program grant number JPMH24GB1001 (KK), and the Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 20K20497 (KK) and 23K18262 (IT). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Niigata University (Approval No. 2019-0239). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes