Every row of the evidence table

Direction is for antisense oligonucleotides lowering APP in neurons derived from people with an APP duplication or trisomy 21: reduced APP, rescued endolysosome and autophagy dysfunction and fewer intracellular and extracellular amyloid-β aggregates. Cell-culture work with no human outcome.

A retraction notice. It withdraws the 2006 Nature paper on Aβ*56 over figures showing "signs of excessive manipulation, including splicing, duplication and the use of an eraser tool", and reports no effect estimate.

An investigative news feature reporting signs of image fabrication in papers on the Aβ*56 amyloid oligomer. It is not a study of an outcome and reports no effect estimate.

A perspective review of arguments for and against the amyloid hypothesis, concluding that amyloid-beta is likely necessary but not sufficient and acts early as a trigger of tau-mediated neurodegeneration. It reports no effect estimate.

Phase 1 target-engagement result in 19 people; no clinical outcome measured.

The review's subject is the harm itself: brain swelling and microbleeds caused by the drugs.

Prespecified and post hoc re-analyses of a trial already reported elsewhere, so this is not independent evidence.

A statistically detectable but very small cognitive effect (ADAS-Cog SMD -0.11) alongside 107 more cases of ARIA-E per 1,000. The reviewers' own conclusion is that removing amyloid does not seem to produce clinically meaningful effects — the sharpest disagreement in this table with how the individual trials were reported.

Mechanistic multi-omic profiling of blood from three ARIA-positive patients and three matched controls on lecanemab. It describes a clonally expanded cytotoxic CD8+ T-cell signature and estimates no clinical effect.

Direction is for lecanemab in mice: it significantly reduced amyloid pathology and neuritic damage, an effect absent with Fc-silenced antibody or without microglia despite intact plaque binding. Mouse work with no human outcome.

An initial negative opinion was reversed on re-examination, with use restricted to APOE4 heterozygotes and non-carriers. The EPAR describes ARIA as affecting more than 1 in 10 people without giving a percentage.

Phase Ib/IIa biomarker result in 13 people; no cognitive outcome measured.

Against placebo: ARIA-E 24.4% vs 1.9%. Risk tracks APOE4 status and baseline imaging.

Direction is for the slower titration schedule against standard dosing, on the drug's own side effect. Amyloid reduction was comparable.

An open-label extension: after 18 months everyone is on the drug, so the comparison is early-start versus delayed-start, not drug versus placebo.

A single-clinic safety series with no comparison group. It reports how often ARIA and infusion reactions happened in practice, which is useful, but it cannot estimate an effect of the drug in either direction.

A mechanistic tissue study describing which microglial states accompany amyloid removal (TREM2 and APOE upregulation correlating with antibody response and clearance; complement signalling contributing). It estimates no effect of immunisation on a clinical outcome.

Corporate announcement discontinuing a product and terminating its confirmatory trial. It reports no clinical outcome, so no direction exists to record.

CHMP refused the drug, then on re-examination recommended it only for people with one or no APOE4 copy, where the ARIA rates are lower. Benefit on cognition and harm from ARIA in the same document, with the restriction as the regulator's way of balancing them.

Benefits were statistically present but every one fell below the minimum clinically important difference, against a number needed to harm of 9 for ARIA-oedema. Agrees with the Cochrane review and not with the trial reports.

Approved on amyloid reduction (surrogate) while reporting higher ARIA rates than placebo; the notice reports no cognitive outcome.

Less decline than placebo, alongside infusion reactions and ARIA.

Phase 1 dose-finding. The outcome is amyloid clearance; no cognitive outcome was measured.

Two identically designed trials disagreed: EMERGE met its primary endpoint, ENGAGE did not.

A coverage determination. It sets the conditions under which Medicare pays and reports no effect estimate.

Benefit is on the surrogate marker only: the approval rested on amyloid reduction, not on confirmed clinical benefit, and the confirmatory trial was later terminated.

Co-primary endpoints were not met at 52 weeks. The comparator was a low dose of the same drug rather than placebo, which the authors say masked any separation; they report separation in the MCI subgroup only at 78 and 104 weeks.

The primary endpoint was not met: the low dose showed no clinically meaningful benefit and the 3 mg dose showed 32% greater progression than placebo, with more serious adverse events. Less whole-brain volume loss on MRI is a surrogate finding.

The primary clinical endpoint (CDR-SB) was not met in the overall population. The tau figures are a biomarker outcome, not a clinical one.

ADAS-Cog11 showed slower decline, but the co-primary functional endpoint (ADCS-ADL) did not differ and the authors classify the study as negative.

Phase 1b safety and target-engagement result: adverse events were all mild or moderate with no serious events on MAPTRx, and CSF total tau fell dose-dependently by more than 50% in the two highest-dose groups. No clinical outcome was measured.

Antihypertensive treatment improved cognitive scores by a small amount (SMD 0.06, moderate certainty) but the reduction in dementia incidence was not statistically significant (OR 0.89, low certainty). The drug-class rankings rest on one trial per class and are described as highly uncertain.

Significant for MCI and for the MCI-or-dementia composite; not significant for probable dementia alone (HR 0.86, 95% CI 0.72-1.02).

A large drop in blood pressure (22/9 mmHg) and fewer serious adverse events in the intervention villages.

Antihypertensive use tracked lower Alzheimer's risk but not lower non-Alzheimer dementia risk, where treated and untreated hypertension looked the same. A single baseline blood pressure reading predicted neither.

Individual participant data from five double-blind placebo-controlled trials, which is the strongest design in this table for this exposure.

Consistent across 14 trials (I-squared 0%) but small in absolute terms: 0.39 percentage points over about 4 years.

Direction is for STOPPING the antipsychotic: discontinuers were hospitalised less than matched continuers.

Direction is for discontinuation: tapering after 12 weeks lowered the 24-month absolute risk of delirium and fracture versus continuing, with no difference in stroke, pneumonia or death. Results were similar for abrupt discontinuation and after 24 weeks.

Wider range of harms than regulatory alerts had flagged, with the highest risks soon after starting. No increase in ventricular arrhythmia.

Direction is for valacyclovir: cognition worsened more on the drug than on placebo on the primary outcome (between-group difference 3.93 ADAS-Cog points, P = .01); function, amyloid PET and tau PET did not differ. The authors conclude it is not recommended.

No difference from placebo on the primary agitation outcome or other main behavioural outcomes. As-needed psychotropic use was lower during the active period, and no serious drug-related adverse events occurred.

Observational: 80% of residents were on no anti-dementia drug, so who gets prescribed and who does not may itself track prognosis.

Cholinesterase inhibitors, not memantine: -0.39 MMSE points a year against -2.50 with no treatment. The mortality benefit held only in the first year. Registry data with weighting, not a trial.

The authors state the data are compatible with anything from a 39% decrease to a 5% increase in risk, against DPP-4 inhibitors rather than no treatment.