Late-onset dementia with leukoencephalopathy and a COL4A2 gene variant, causal link or fortuitous association: a case report

Topic: Brain proteins, microglia and lab models

Cerebral small vessel disease can manifest as vascular dementia, typically associated with vascular risk factors or cerebral amyloid angiopathy, and more rarely associated with hereditary conditions. We present a case of late-onset dementia, associated with a likely pathogenic COL4A2 variant. A 74-year-old woman presented with cognitive decline and behavioral changes, without personal history of cerebral infarcts or intracerebral hemorrhage. Brain MRI revealed an extensive leukoencephalopathy affecting periventricular and deep white matter, including subcortical white matter in the anterior temporal lobes and the orbitofrontal regions. Genetic analysis identified a heterozygous glycine substitution within the triple-helical domain of COL4A2 , as commonly observed in patients with COL4A1/A2 collagenopathy. COL4A2 pathogenic variants have been associated with various neurological and extraneurological phenotypes and an incomplete penetrance. The diffuse vascular leukoencephalopathy detectable on this patient’s MRI is consistent with the ones observed in COL4A1/COL4A2 mutated patients. However, the clinical phenotype of this patient, limited to cognitive decline and behavioral changes occurring in the absence of any overt stroke, is unusual. These data suggest that this phenotype is either caused by the COL4A2 variant or is fortuitously associated with this variant or is the result of another cause for which this COL4A2 variant acts as a modifier. Memory clinic physicians should consider genetic analyses in the diagnostic workup of vascular leukoencephalopathies, but they should also interpret cautiously the causality between clinico-radiological phenotypes and molecular pathogenic variants, specifically when dealing with variants with possible incomplete penetrance.

@article{garniercrussard2025-41312509,
  author  = {Garnier‐Crussard, Antoine and Sadr, Alexandre Bani and Quadrio, Isabelle and Formaglio, Maïté and Desestret, Virginie and Tournier‐Lasserve, Elisabeth and Coste, Thibault},
  title   = {{Late-onset dementia with leukoencephalopathy and a COL4A2 gene variant, causal link or fortuitous association: a case report}},
  journal = {Cerebral Circulation - Cognition and Behavior},
  year    = {2025},
  doi     = {10.1016/j.cccb.2025.100518},
  pmid    = {41312509},
  url     = {https://doi.org/10.1016/j.cccb.2025.100518}
}

Key findings

• Cerebral small vessel disease can manifest as vascular dementia, typically associated with vascular risk factors or cerebral amyloid angiopathy, and more rarely associated with hereditary conditions.
• We present a case of late-onset dementia, associated with a likely pathogenic COL4A2 variant.
• Brain MRI revealed an extensive leukoencephalopathy affecting periventricular and deep white matter, including subcortical white matter in the anterior temporal lobes and the orbitofrontal regions.
• COL4A2 pathogenic variants have been associated with various neurological and extraneurological phenotypes and an incomplete penetrance.
• These data suggest that this phenotype is either caused by the COL4A2 variant or is fortuitously associated with this variant or is the result of another cause for which this COL4A2 variant acts as a modifier.

Why it matters

This single case describes a woman with late-onset dementia and a variant in the COL4A2 gene, along with widespread white matter changes on brain imaging. The authors state it is unclear whether the gene variant caused her dementia or was an unrelated finding, so no conclusions about cause or treatment can be drawn.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.cccb.2025.100518
• PubMed: 41312509
• Original source →
• Free full text: Cerebral Circulation - Cognition and Behavior →

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Studies this one cites

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• Impact of multiple pathologies on the threshold for clinically overt dementia Acta neuropathologica · 2017-05-09 · usefulness score 66/100 · Getting a diagnosis
• Small vessel disease: mechanisms and clinical implications The Lancet. Neurology · 2019-05-13 · usefulness score 60/100 · Lewy body dementia
• Vascular dementia Lancet (London, England) · 2015-10-01 · usefulness score 59/100 · Lewy body dementia

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