ARIA-H common in ApoE 4/4 before amyloid treatment

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NF52
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ARIA-H common in ApoE 4/4 before amyloid treatment

Post by NF52 »

Much of the discussion around approval for lecanemab has been how to determine the risk of ARIA-H (Amyloid Related Imaging Abnormality-micro-Hemorrhage or macro-Hemorrhage) for those with ApoE 4/4.

The data below suggests that for people with ApoE 4/4, with a diagnosis of MCI or Mild AD, a drug such as ALZ-801 may a safe treatment options, since no cases of ARIA-H or deaths have been reported. Yet this also suggests that amyloid pathology in AD is often not confined to plaques, especially in ApoE 4/4, and may indicate a need to reduce amyloid in the brain to reduce deposits in the brain's blood vessels BEFORE diagnosis of MCI/mild AD,
Background: APOE4 carriers show increased risk of ARIA in AD trials with amyloid-clearing antibodies, the highest in APOE4/4 homozygotes, related to a high burden of aggregated beta amyloid in cerebral micro-vessels (cerebral amyloid angiopathy, CAA)[/b]...ALZ-801 (valiltramiprosate)...showed promising efficacy in APOE4 carriers with no observed ARIA-E (Abushakra 2016). Two ongoing trials with ALZ-801 focus on APOE4 carriers with Early AD: Phase 2 enrolled APOE3/4 or APOE4/4, and APOLLOE4 Phase 3 is enrolling only APOE4/4; both studies allow subjects with any number of MH [microhemorrhage] or siderosis.

Design/Methods:Baseline MRIs were from Phase 2 and 3 studies (MCI or Mild AD, MMSE ≥22), acquired from 1.5T or 3T scanners and centrally evaluated. We report the type and number of ARIA-E/H lesions as of August 2022.

Results: Baseline demographics of the two studies were similar (~50% female, age 69 years, MMSE 25–26). In 242 homozygotes (211 from Phase 3) there were no subjects with ARIA-E, 72 with any MH [microhemorrhage], 23 with >4 MHs, of whom 15 had >10 MHs, 2 had macrohemorrhages >1 cm....

Conclusions: APOE4/4 homozygotes show a high incidence and wide range of CAA-related lesions at the baseline of ALZ-801 studies.
Prevalence of Amyloid-Related Imaging Abnormalities in APOE4/4 Homozygotes with Early Alzheimer’s Disease: Baseline Findings from Ongoing Clinical Trials of Oral Anti-Amyloid Agent ALZ-801 (Valiltramiprosate) (P5-6.003)

In this cohort of relatively young and mildly affected people, 29.7% of all participants had at least one microhemorrhage; 9.5% of the total had more than 4 microhemorrhages (the cut-off for exclusion from lecanemab trials); 6.2% had more than 10; and two individuals had macro hemorrhaged (slightly less than 1% of the total).
4/4 and still an optimist!
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