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.

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

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

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.

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.

Less decline than placebo, alongside infusion reactions and ARIA.

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

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.

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.

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.

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.

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.

Seven separate comparisons against seven other antidiabetic drugs, so the comparator is always another drug rather than no treatment.

Direction is for AAVrh.10 delivery of APOE2 with the Christchurch mutation in mice: both vectors suppressed amyloid, but only the Christchurch variant also suppressed tau tangles and glial activation in tau mice and outperformed plain APOE2 behaviourally. Mouse work with no human outcome.

Heterogeneity was near-total (I-squared 98.9%) and the estimate went to null in people newly diagnosed with diabetes (HR 1.01), which is where prevalent-user bias would be smallest.

Comparator is other oral antidiabetic drugs, not no treatment.

The exposure actually studied is STOPPING metformin early, which carried 21% higher dementia incidence than staying on it. Read as indirect support for metformin, not as a trial of it.

Direction is for peripheral cancer in AD mice: tumour-secreted cystatin-C bound amyloid oligomers and activated microglial TREM2, enabling degradation of existing plaques and rescuing cognition; the effect was abolished by microglial deletion or mutation of TREM2 or cystatin-C. Mouse work with no human outcome.

Direction is for lowering PU.1 in microglia, which reduced the severity of amyloid pathology in mice; microglia-specific CD28 deficiency did the opposite and increased plaque load. Mouse work with no human outcome.

Direction is for deleting TIM-3 in microglia: it increased phagocytic activity, shifted microglia to the disease-associated state, reduced amyloid pathology and improved cognitive impairment in 5xFAD mice. Mouse work with no human outcome.

Direction is for blocking the ZBP1-RIPK1 axis: genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, amyloid pathology and behavioural deficits in AD mice, after showing that amyloid-induced oxidised mitochondrial DNA forms Z-DNA sensed by ZBP1 in microglia. Mouse work with no human outcome.

Direction is for removing the granzyme K-producing CD103-negative CD8+ T cells: their ablation ameliorated cognitive decline and reduced neuropathology in 3xTg-AD mice, and granzyme K caused neuronal dysfunction and tau hyperphosphorylation via PAR-1. Mouse and cell work with no human outcome.

Direction is for inhibiting C1q, C3 or the microglial receptor CR3, which reduced phagocytic microglia and early synapse loss; C1q was necessary for soluble amyloid-beta oligomers to damage synapses. Mouse work with no human outcome.

Direction is for NLRP3 or caspase-1 deficiency, which largely protected the mice from spatial memory loss and reduced amyloid deposition; the human data are limited to raised active caspase-1 in post-mortem MCI and Alzheimer brains.

The NPI-C agitation/aggression measure did not reach significance (p=0.094).

The authors describe the reduction as small (-1.32 points).

A post hoc dementia subgroup of a randomised-withdrawal trial that was not designed or powered for it; 46 randomised responders. The authors say to read it cautiously.

Both doses beat placebo. Treatment-emergent adverse events were more common than placebo (84.6% at 2 mg, 76.8% at 1 mg, 73.8% placebo).

For SGLT2 inhibitors specifically: HR 0.86 (95% CI 0.79-0.94) against DPP4 inhibitors, and HR 0.70 in the as-treated analysis.

Benefit was confined to APOE4 carriers (HR 0.60) and absent in non-carriers (HR 0.96). Observational, and it disagrees with the larger target-trial emulation that found nothing.