A young-onset dementia case associated with PDGFRβ mutation

Abstract

We report a case of young-onset dementia (YOD) in a 40-year-old male with a heterozygous missense variant in the PDGFRβ gene. The patient exhibited progressive memory decline and disorientation. Brain MRI and cerebrospinal fluid biomarkers were consistent with Alzheimer's disease. Whole-exome sequencing identified a likely pathogenic PDGFRB c.1316G > A (p.Arg439Gln) variant. This report highlights a novel potential genetic contributor to vascular dysfunction and cognitive decline.

Introduction

Young-onset dementia (YOD), characterized by progressive cognitive and behavioral decline before the age of 65, represents a clinically and etiologically heterogeneous syndrome. The underlying causes of YOD range from early-onset variants of adult neurodegenerative diseases, such as Alzheimer's disease (AD), frontotemporal dementia, and vascular dementia, to late-onset presentations of childhood neurodegenerative disorders, as well as potentially reversible metabolic, infectious, or inflammatory conditions. ¹

Recent findings have highlighted the critical role of vascular dysfunction and blood–brain barrier (BBB) breakdown in the pathogenesis of AD. Platelet-derived growth factor receptor beta (PDGFRβ) regulates pericyte function and promotes neural repair, endothelial integrity, and vascular smooth muscle proliferation, thereby maintaining BBB homeostasis. ² Studies have shown that soluble PDGFRβ levels are significantly reduced in both pericytes and vascular smooth muscle cells in AD brains, correlating with increased amyloid burden and cognitive impairment. ² Similarly, retinal studies in AD have demonstrated pericyte loss and PDGFRβ deficiency accompanied by vascular amyloid accumulation, suggesting systemic neurovascular unit dysfunction and the possibility of early biomarkers detectable through non-invasive retinal imaging. ³

Case presentation

40-year-old right-handed male, formerly employed as a professional driver, who exhibited progressive memory impairment and disorientation over the past 2–3 years. His symptoms included difficulty performing routine tasks, confusion while navigating familiar routes, and impaired goal-directed behavior. There was no history of alcohol or substance use, systemic illness, or head trauma. Notably, his brother developed similar symptoms at the age of 45 and died without a definitive diagnosis, raising the possibility of a familial or genetic etiology. Other family members declined genetic testing.

Neurological examination was unremarkable. Routine blood tests and infection panels, including HIV and VDRL, were within normal limits except for a folate deficiency, which was treated. His Mini-Mental State Examination score was 18/30, and the Addenbrooke's Cognitive Examination-Revised revealed deficits in memory, executive function, visuospatial ability, and complex attention. Although he appeared clinically stressed, this was not reflected in psychometric assessments.

Brain MRI scans revealed Fazekas score 0, medial temporal atrophy score was 2 bilaterally, and Koedam score was 3. Cerebrospinal fluid analysis showed an AD-compatible biomarker profile with low Aβ_1–42 (384 pg/ml), elevated total tau (963 pg/ml), and phosphorylated tau (184 pg/ml). The neurofilament light chain level was 2.5 times above the age-adjusted upper limit (2047 pg/ml). The HTau/Aβ_1–42 ratio was calculated as 2.51.

Initial genetic testing for mutations in amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was negative. Whole-exome sequencing subsequently identified a heterozygous missense variant in the PDGFRβ gene on chromosome 5q32 (NM_002609: c.1316G > A; p.Arg439Gln). This variant has previously been associated with idiopathic basal ganglia calcification type 4, Kosaki overgrowth syndrome, and myeloproliferative disorders, although our patient displayed no clinical features consistent with these conditions. This observation raises the possibility of a novel, vascular-mediated neurodegenerative phenotype associated with PDGFRB dysfunction. ⁴

The patient was treated with escitalopram (10 mg/day) and donepezil (10 mg/day). At a one-year follow-up, his clinical condition remained stable, with no evidence of disease progression.

Discussion

The PDGFRB c.1316G > A (p.Arg439Gln) variant identified in our patient has not been previously reported in major genetic databases such as ClinVar and VarSome. In silico predictions (e.g., SIFT, PolyPhen-2) suggest a deleterious effect on protein function. Given that the affected residue is evolutionarily conserved and based on these computational predictions, the variant is classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria (PM2: absent in population databases; PP2: missense variant in a gene with low benign variation; PP3: multiple lines of computational evidence support a deleterious effect).^5,6

To our knowledge, this is the first report implicating a PDGFRβ mutation in a case of YOD, distinguishing it from other known genetic causes. Given PDGFRB's essential role in pericyte function and neurovascular integrity, this case provides valuable clinical insight into the genetic basis of vascular contributions to cognitive decline. ³ Further whole-genome analyses are warranted to elucidate the pathogenic relevance of this variant and to assess its potential as a therapeutic target.

Conclusion

This case illustrates a likely pathogenic PDGFRβ mutation associated with early-onset dementia and highlights the role of vascular dysfunction in neurodegeneration. Broader genetic testing may reveal underrecognized contributors to cognitive decline.