Alzheimer’s Autopsy Study Raises Questions About Amyloid Clearance

Autopsy data from an Alzheimer’s patient revealed that brain regions with extensive amyloid clearance after treatment had less downstream tau accumulation and brain degeneration.

Amyloid clearance also appeared to preferentially occur in the gyral crests, reported Edward Lee, MD, PhD, of the University of Pennsylvania in Philadelphia, who discussed the findings at the Alzheimer’s Association International Conference.

The case report was published in JAMA. It helps connect amyloid clearance to downstream biological benefits, not just a lower amyloid PET signal, Lee noted.

“The study suggests that where and how completely amyloid is cleared matters,” Lee told MedPage Today. “Regions with near-complete amyloid clearance had less tau accumulation and slower atrophy, whereas regions with residual amyloid looked much more like untreated Alzheimer disease. It also suggests amyloid may clear more effectively from gyral crests than from sulcal depths,” he added.

“Although this is only a single-patient case report, it offers important proof-of-concept that extensive amyloid clearance may be necessary to achieve meaningful downstream effects on tau pathology and neurodegeneration,” Lee pointed out. “The findings also raise new questions about brain clearance pathways that could help improve future anti-amyloid therapies.”

The study involved a male patient in his 50s with mild cognitive impairment who carried the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer’s. He received aducanumab (Aduhelm) in a clinical trial. Lee and colleagues also included data from 14 untreated controls, matched by age or presence of the TREM2 variant, in their analysis.

Aducanumab received accelerated approval from the FDA in 2021; the anti-amyloid antibody was discontinued by the drug company in 2024. Two other amyloid-targeting therapies — lecanemab (Leqembi) and donanemab (Kisunla) — have received full FDA approval after successful phase III trials.

The patient received 30 doses of aducanumab over 4.5 years and experienced three separate incidents of amyloid-related imaging abnormalities (ARIA) with edema. He achieved partial amyloid clearance. His Mini-Mental State Examination (MMSE) score decreased from 26 to 20 and his functional impairment increased to mild-to-moderate dementia.

After treatment, the patient remained stable for about 2 years before developing worsening behavioral symptoms. He died 4 years after receiving his last aducanumab dose. At autopsy, his brain showed variable amyloid distribution, with high levels of amyloid in deep cortical layers and low amyloid levels in superficial layers.

Compared with untreated controls, the patient’s low levels of amyloid were preferentially found in the gyral crests and were associated with less tau pathology at autopsy and slower longitudinal atrophy on in vivo MRI. Regions with high amyloid burden were seen in the sulcal depths and had similar levels of tau pathology as untreated controls at autopsy.

The patient’s clinical course and exposure to aducanumab was complex, so it’s hard to make claims or draw conclusions about therapeutic benefits, noted David Knopman, MD, of the Mayo Clinic in Rochester, Minnesota, who wasn’t involved with the study.

Local reductions in tau burden in areas where amyloid was cleared both in superficial and deep cortical layers is a novel histopathological finding and supports the hypothesis that amyloid reduction has downstream benefits, Knopman pointed out.

“The corollary was that full clearance of amyloid regionally appeared to be prerequisite for affecting tau accumulation. Moreover, brain volume losses were less in regions with full amyloid clearance,” he wrote in an email to MedPage Today.

“To the best of my knowledge, the finding of a relationship with treatment between amyloid clearance, tau accumulation, and reduction in volume loss may be the first demonstration of a therapeutic interruption of the hypothesized sequence of elevated amyloid [pointing to] elevated tauopathy [pointing to] cortical volume loss,” Knopman added.

Although the report is based on a single case and its findings must be interpreted cautiously, it provides direct evidence that the antibody engaged its intended target and produced biologically meaningful effects, said Bart De Strooper, MD, PhD, of University College London, who also wasn’t part of the study.

“At the same time, plaque removal was incomplete and varied considerably across brain regions. Such incomplete and uneven target engagement may help to explain why the cognitive benefits observed with this class of treatment have so far been relatively modest,” De Strooper told MedPage Today.

“These findings are likely to strengthen efforts to improve the penetration and distribution of therapeutic antibodies throughout the brain,” he observed. “One promising approach is to equip antibodies with a blood-brain barrier shuttle, which may enhance transport into deeper brain regions and produce a more uniform therapeutic effect.” Some of these approaches also may reduce ARIA risk, although this will need to be established in clinical studies, De Strooper said.

The presence of a p.R47H TREM2 variant could alter relationships between amyloid and tau or treatment response, but untreated controls with the TREM2 variant did not show the same patterns as the patient, Lee and co-authors noted. No pre-treatment tau PET was available to assess longitudinal changes with aducanumab, they added.