# Video research-update insert: Amyloid-beta as the Primary Upstream Cause of Alzheimer's Disease

Editorial script and storyboard insert, 5 October 2026. No rendered video. Read alongside the original review; no new grade is announced.

## Narration

Genetics, biomarker ordering and treatment trials support an upstream amyloid contribution in defined settings. Benefit after plaque removal varies across trials, and a universal amyloid-to-tau-to-neurodegeneration chain remains a separate question.

In the 1991 study, aPP missense variation segregated with familial Alzheimer disease. A specific inherited route does not establish the initiating cause of all sporadic disease. [P1671712]

In the 2019 study, an APOE3 Christchurch homozygote had delayed impairment despite extensive amyloid. A single case bounds simple sufficiency but cannot estimate prevalence. [P31686034]

In the 2025 study, long exposure suggested possible delay, while short or partial removal lacked significant clinical effects. External controls and extension selection prevent treating this as a fresh randomized prevention result. [P40120616]

The next discriminating question is: Does early amyloid removal prevent sporadic clinical onset? Late symptomatic benefit may reflect contribution after initiation, while tau or other injury becomes self-sustaining. Long-duration prevention randomization in biomarker-defined presymptomatic groups; prespecify clinical onset, clearance, tau trajectory and adverse events.

The timeline shows selected changes in evidence, not inevitable progress or proof of a single cause. The review’s archived grade remains unchanged; the depth of source reading is documented in the update.

## Storyboard and source locks

| Insert | Visual | Narration anchor | Sources |
|---|---|---|---|
| Opening | Claim and bounded update statement | First paragraph | Review claim and source ledger |
| Timeline 1991 | Dated study card with design, result and limit | APP missense variation segregated with familial Alzheimer disease. | [P1671712](https://pubmed.ncbi.nlm.nih.gov/1671712/) |
| Timeline 2019 | Dated study card with design, result and limit | An APOE3 Christchurch homozygote had delayed impairment despite extensive amyloid. | [P31686034](https://pubmed.ncbi.nlm.nih.gov/31686034/) |
| Timeline 2025 | Dated study card with design, result and limit | Long exposure suggested possible delay, while short or partial removal lacked significant clinical effects. | [P40120616](https://pubmed.ncbi.nlm.nih.gov/40120616/) |
| G1 | Question → competing explanation → discriminating test | Does early amyloid removal prevent sporadic clinical onset? | [P36449413](https://pubmed.ncbi.nlm.nih.gov/36449413/), [P37459141](https://pubmed.ncbi.nlm.nih.gov/37459141/), [P38381674](https://pubmed.ncbi.nlm.nih.gov/38381674/), [P40120616](https://pubmed.ncbi.nlm.nih.gov/40120616/) |
| G2 | Question → competing explanation → discriminating test | Does tau change mediate clinical benefit? | [P17478722](https://pubmed.ncbi.nlm.nih.gov/17478722/), [P37459141](https://pubmed.ncbi.nlm.nih.gov/37459141/), [P37966285](https://pubmed.ncbi.nlm.nih.gov/37966285/) |
| G3 | Question → competing explanation → discriminating test | Which clearance, species and exposure matter? | [P36449413](https://pubmed.ncbi.nlm.nih.gov/36449413/), [P37459141](https://pubmed.ncbi.nlm.nih.gov/37459141/), [P37966285](https://pubmed.ncbi.nlm.nih.gov/37966285/), [P40120616](https://pubmed.ncbi.nlm.nih.gov/40120616/) |
| G4 | Question → competing explanation → discriminating test | Where does amyloid fail to be sufficient? | [P1671712](https://pubmed.ncbi.nlm.nih.gov/1671712/), [P16369530](https://pubmed.ncbi.nlm.nih.gov/16369530/), [P31686034](https://pubmed.ncbi.nlm.nih.gov/31686034/) |

## Editorial constraints

- Use the primary-source links shown above and keep the inference limit on screen with each milestone.
- Do not narrate an abstract check as complete-paper examination, a model result as human proof, or an unresolved inference as absence of all research.
- Preserve trial endpoint hierarchy, cohort reuse, correction notices and online/issue dates.
- Use original graphics made from this ledger. Publisher figure imagery has not been cleared or supplied for video reuse.
- Confirm any change in verdict through a separate documented HSEF review; this insert makes none.