This clinicopathologic case report examined how amyloid clearance after aducanumab treatment (30 doses, 280 mg/kg cumulative over 4.5 years) relates to downstream tau pathology and neurodegeneration at autopsy in a male TREM2 p.R47H variant carrier in his 50s with mild cognitive impairment, compared with 14 untreated age- or TREM2-matched controls.
Brain regions with low residual amyloid (preferentially gyral crests) showed less tau pathology and slower cortical atrophy on MRI (β = −0.50 [95% CI, −0.62 to −0.37]; P < .001), while high-amyloid regions (preferentially sulcal depths) had tau burden similar to untreated controls.
Single-patient case report severely limits generalizability; the TREM2 p.R47H variant may alter amyloid biology and treatment response in ways not typical of most Alzheimer disease patients; four-year gap between last dose and autopsy makes it difficult to attribute findings solely to aducanumab.
Extensive, not partial, amyloid clearance may be required to achieve meaningful downstream protection against tau pathology and neurodegeneration. Clinicians should note that patchy clearance—particularly sparing sulcal depths—may leave regions vulnerable to ongoing neurodegeneration despite treatment.
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