Brain Volume Loss in Lecanemab and Donanemab Therapy
Direct Answer
Brain volume loss observed with lecanemab and donanemab therapy likely represents "pseudoatrophy"—a phenomenon where anti-inflammatory treatment causes resolution of pre-existing brain inflammation and edema, resulting in apparent volume reduction that does not reflect true neurodegeneration. 1
Mechanism of Pseudoatrophy
The brain volume loss seen with anti-amyloid monoclonal antibodies parallels what has been documented with anti-inflammatory therapies in other neurological conditions:
Anti-inflammatory drugs characteristically produce excessive brain volume decrease within the first 6 months to 1 year of treatment, followed by stabilization during the second year. 1
This pseudoatrophy phenomenon is directly associated with resolution of ongoing white matter inflammation induced at the time of treatment initiation. 1
The mechanism involves reduction of pre-existing vasogenic edema and inflammatory tissue swelling rather than actual loss of neurons or axons. 1
Evidence from Anti-Amyloid Therapy Trials
The accelerated brain volume loss observed with lecanemab and donanemab raises important questions about tissue effects:
Treatment with these antibodies shows accelerated loss of brain volume in treated patients compared to placebo patients. 2
The "removal" of amyloid, based on reduced accumulation of amyloid-PET tracer, most likely also reflects therapy-related tissue damage, which would correlate with the accelerated brain volume loss observed. 2
Donanemab achieves rapid and robust amyloid reduction of 60-85 Centiloid units, with some patients showing complete amyloid clearance within 24-36 weeks. 3, 4
Alternative Interpretation: True Tissue Damage
There is concerning evidence that the volume loss may not be entirely benign pseudoatrophy:
The minimal clinical effect of these antibodies, combined with increased frequency of ARIA and accelerated brain volume loss, suggests the possibility of actual therapy-related tissue damage rather than purely inflammatory resolution. 2
ARIA-E (edema) occurs in 12.6% of lecanemab patients and up to 35-36% with other anti-amyloid antibodies, representing inflammatory vascular permeability changes that could contribute to tissue injury. 1, 5
ARIA is theorized to result from an inflammatory response to monoclonal antibody treatment against amyloid, causing increased vascular permeability leading to edema and extravasation of blood products. 1
Clinical Monitoring Implications
To distinguish pseudoatrophy from pathological volume loss:
Brain volume should be measured every 3-6 months during the first year of treatment to identify the pseudoatrophy pattern of early rapid loss followed by stabilization. 1
Mandatory MRI monitoring before the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) is required to assess for ARIA and monitor volume changes. 6, 5
3T MRI provides greater sensitivity for detection of microhemorrhages and subtle tissue changes compared to 1.5T imaging. 5
Important Caveats
Multiple confounding factors complicate interpretation of brain volume changes:
Lifestyle-related factors (alcohol consumption, smoking, dehydration, BMI), genetics (APOE ε4 allele), and comorbid conditions (diabetes, cardiovascular risk factors) can all affect brain volume independent of treatment effects. 1
Differences in MRI hardware quality and software packages used for analysis can generate notable variability in brain atrophy assessments. 1
The use of longitudinal brain volume assessment as a marker of disease progression in individual patients cannot be considered reliable at present, requiring caution when interpreting apparent changes in brain volume loss rates. 1
Unresolved Questions
The field lacks definitive answers about the nature of this volume loss:
Whether the volume loss represents benign resolution of inflammation (pseudoatrophy) versus actual tissue damage from antibody-mediated effects remains incompletely understood and requires further investigation before concluding these therapies are safe. 2
The correlation between amyloid removal, brain volume loss, and the modest clinical benefits (approximately 30% slowing of decline) suggests the relationship between these parameters is complex and not fully elucidated. 3, 7