ALSP is a progressive neurodegenerative disease caused by CSF1R mutations, representing a prototypical primary brain microgliopathy. The disease typically presents in middle adulthood with cognitive decline, motor symptoms, and psychiatric manifestations. While no disease-modifying therapy is currently approved, emerging treatments targeting TREM2 and hematopoietic stem cell transplantation offer potential therapeutic strategies. Early diagnosis through genetic testing and characteristic MRI findings is essential for appropriate management and family counseling. Ongoing research continues to elucidate disease mechanisms and develop targeted therapies for this rare but devastating condition.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive neurodegenerative disorder primarily affecting the cerebral white matter. ALSP is caused by heterozygous loss-of-function mutations in the CSF1R (colony stimulating factor 1 receptor) gene, making it the prototypical primary brain microgliopathy—a disease driven by microglial dysfunction.
ALSP is a progressive neurodegenerative disease caused by CSF1R mutations, representing a prototypical primary brain microgliopathy. The disease typically presents in middle adulthood with cognitive decline, motor symptoms, and psychiatric manifestations. While no disease-modifying therapy is currently approved, emerging treatments targeting TREM2 and hematopoietic stem cell transplantation offer potential therapeutic strategies. Early diagnosis through genetic testing and characteristic MRI findings is essential for appropriate management and family counseling. Ongoing research continues to elucidate disease mechanisms and develop targeted therapies for this rare but devastating condition.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive neurodegenerative disorder primarily affecting the cerebral white matter. ALSP is caused by heterozygous loss-of-function mutations in the CSF1R (colony stimulating factor 1 receptor) gene, making it the prototypical primary brain microgliopathy—a disease driven by microglial dysfunction.
Previously described as two separate entities — hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) — these conditions were unified under the ALSP designation when CSF1R mutations were identified as the shared genetic cause in 2012.[@r2017] ALSP typically manifests in the fourth to fifth decade of life (mean onset ~43 years) and progresses to severe disability and death within 5-10 years of symptom onset. Women appear to have a significantly younger age of onset than men (40 vs. 47 years).
The estimated prevalence is approximately 1 in 100,000, though ALSP is likely underdiagnosed due to clinical overlap with more common conditions including Alzheimer's disease, frontotemporal dementia, multiple sclerosis, and vascular dementia.
ALSP represents a unique category of neurodegenerative disease characterized by:
ALSP is a rare disease with an estimated prevalence of approximately 1 in 100,000 to 1 in 1,000,000, though it is likely underdiagnosed due to clinical overlap with more common conditions including [Alzheimer's disease](/diseases/alzheimers-disease), [frontotemporal dementia](/diseases/frontotemporal-dementia), [multiple sclerosis](/diseases/multiple-sclerosis), and vascular dementia[^1].
The disease typically manifests in the fourth to fifth decade of life, with a mean age of onset around 43 years. Women tend to present significantly earlier than men (mean age 40 vs. 47 years)[^2]. The disease shows autosomal dominant inheritance with high penetrance, though de novo mutations account for approximately 20-40% of cases. There is no clear gender predilection, and cases have been reported across multiple ethnic backgrounds.
The CSF1R gene, located on chromosome 5q32, encodes a 108 kDa type III receptor tyrosine kinase (RTK) that belongs to the platelet-derived growth factor receptor family. CSF1R is the receptor for two ligands: colony stimulating factor 1 (CSF-1/M-CSF) and interleukin-34 (IL-34). The receptor plays a pivotal role in regulating the survival, differentiation, proliferation, and activation of mononuclear phagocytic cells, including microglia in the central nervous system[^3].[@v2020]
Over 100 pathogenic variants in CSF1R have been identified in ALSP patients, with the majority affecting the tyrosine kinase domain. The mutation spectrum includes:
Under normal conditions, ligand binding triggers CSF1R dimerization and autophosphorylation, activating downstream pathways including:
ALSP is fundamentally a disease of microglial homeostasis. CSF1R haploinsufficiency leads to:
The most common initial presentation (approximately 55% of cases) involves cognitive decline resembling Frontotemporal Dementia or early-onset Alzheimer's Disease[^6]:
Depression and anxiety are frequently reported (30-40% of patients), often preceding the recognition of cognitive decline by months to years[^9]. Psychotic symptoms including visual or auditory hallucinations may also occur, particularly in later disease stages.
Characteristic neuroimaging findings on MRI are essential for diagnosis and help distinguish ALSP from other white matter disorders[^10]:
Definitive diagnosis requires identification of a pathogenic variant in CSF1R through sequencing of exons 12-22 (tyrosine kinase domain) or whole-gene analysis. Genetic testing should be considered in any adult presenting with progressive white matter disease and cognitive decline, particularly when MRI features are suggestive. Testing should include both targeted CSF1R sequencing and comprehensive panel testing for leukodystrophies.
In the pre-genetic testing era, brain biopsy was often required for diagnosis. Histopathological findings include axonal spheroids (on neurofilament immunostaining), pigmented macrophages (PAS-positive, autofluorescent), and white matter loss with gliosis. Biopsy is now rarely necessary when genetic testing is available, but may still be considered in atypical cases.
ALSP must be distinguished from several more common conditions[^11]:
| Condition | Key Distinguishing Features |
|-----------|----------------------------|
| Multiple Sclerosis | Presence of oligoclonal bands in CSF, enhancing lesions, spinal cord involvement, and periventricular lesions perpendicular to the lateral ventricles |
| Frontotemporal Dementia | Predominant frontotemporal atrophy on MRI without significant white matter changes favors FTD; white matter involvement on MRI suggests ALSP |
| CADASIL | Notch3 mutation testing and characteristic temporal pole involvement (white matter hyperintensities) distinguish CADASIL |
| Vascular Dementia | Vascular risk factors, lacunar infarcts, and stepwise progression favor vascular disease; ALSP shows more confluent, symmetric white matter changes |
| Metachromatic Leukodystrophy | ARSA enzyme activity deficiency and childhood/young adult onset distinguish MLD; adult-onset MLD is rare |
| Adult Polyglucosan Body Disease | GBE1 mutation, characteristic periodic acid-Schiff-positive polyglucosan bodies in nerve/brain biopsy |
| Hereditary Cerebral Amyloid Angiopathy | CAA-related hemorrhages and cortical/subcortical microbleeds on MRI |
No disease-modifying therapy is currently approved for ALSP. Management is symptomatic:
Case reports have described stabilization or improvement following allogeneic HSCT, particularly when performed early in the disease course. Donor-derived microglia can repopulate the brain, potentially restoring CSF1R-dependent microglial functions. However, HSCT carries significant morbidity and mortality risks, and prospective controlled trial data are lacking.
Iluzanebart is a human monoclonal IgG1 agonist antibody targeting TREM2, developed by Vigil Neuroscience for ALSP treatment. The rationale is that trem2 activation can compensate for CSF1R dysfunction by activating overlapping downstream signaling pathways.
ALSP is invariably progressive, with median disease duration from symptom onset to death of approximately 6.8 years (range 2-29 years). Rapid cognitive decline, early motor involvement, and younger age at onset are associated with faster progression. The cause of death is most commonly aspiration pneumonia, followed by status epilepticus and general debilitation.
ALSP is a progressive neurodegenerative disease caused by CSF1R mutations, representing a prototypical primary brain microgliopathy. The disease typically presents in middle adulthood with cognitive decline, motor symptoms, and psychiatric manifestations. While no disease-modifying therapy is currently approved, emerging treatments targeting TREM2 and hematopoietic stem cell transplantation offer potential therapeutic strategies. Early diagnosis through genetic testing and characteristic MRI findings is essential for appropriate management and family counseling. Ongoing research continues to elucidate disease mechanisms and develop targeted therapies for this rare but devastating condition.
The study of Adult Onset Leukoencephalopathy With Axonal Spheroids And Pigmented Glia (Alsp) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Recent advances in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) have focused on understanding disease mechanisms, identifying biomarkers, and developing novel therapeutic approaches. Key developments include: