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.

For GLP-1 receptor agonists specifically: HR 0.95 (95% CI 0.87-1.04) against DPP4 inhibitors in the intention-to-treat analysis. Only the continuous-use analysis reached significance (HR 0.79).

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

Primary outcome null. One secondary cognitive measure (ADAS-Exec) favoured liraglutide on an unadjusted test; ADCS-ADL and CDR-SB did not.

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.

Designed around new diabetes diagnoses with a landmark analysis and a one-year lag, which removes the prevalent-user advantage that inflates metformin's apparent benefit in the pooled cohorts.

Comparator is other oral antidiabetic drugs, not no treatment.

The split inside this one paper is the finding: the 41 observational studies show large benefits (SGLT2i OR 0.56, GLP-1RA OR 0.58) while the 23 randomised trials show no difference. When design and result disagree this cleanly, the trials are the ones to believe.

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.

A descriptive transcriptional atlas: it maps expression changes, isoform usage, co-expression modules and disease subtypes in microglia from post-mortem brains and estimates no effect of an exposure.

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 trial did not meet its primary endpoint at any of three doses despite sustained target engagement (lower CSF soluble TREM2, higher osteopontin); the most frequent adverse events were MRI changes resembling ARIA.

A regulatory enforcement action, not a study. The SEC's order finds the reported Phase 2 biomarker data were manipulated by an unblinded consultant and its complaint alleges the full patient data "showed no measurable cognitive improvement in the patients' episodic memory"; it estimates no effect.

Retraction notices for five PLOS ONE papers by Wang and colleagues, two co-authored with a Cassava Sciences employee. They withdraw the papers over blot-image integrity and estimate no effect.

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

Not effective, and drug-related QT prolongation was observed. The randomised sample was smaller than planned.

A feasibility trial in 29 residents: designed to test whether the trial can be run, not powered for efficacy, and it reports no efficacy estimate.

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.

After the first year the data rule out more than a 3% change either way. Diagnoses were 46% higher in the first year, which the authors attribute to people being seen more often just after starting a statin. This sits against the Chicago cohort, which found benefit in APOE4 carriers.

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.

A mechanism study: it shows Arc packages tau into extracellular vesicles and that cell-to-cell tau transmission is almost absent in Arc knockout mice, with Arc levels correlating with phosphorylated tau in human AD brain vesicles. It tests no intervention and estimates no effect on an outcome.

Direction is for tau seeding activity: substantial hippocampal and neocortical seeding was present even without overt neocortical tangles and predicted region-specific cognitive performance and longitudinal decline; seeding and modification profiles tracked neuritic plaque density and separated AD from PART.

A model-building and screening study: it identifies over 500 genetic modifiers of tau propagation (including VPS29 and the UFMylation cascade) and shows UFMylation inhibition suppresses seeded propagation in vitro and in vivo. It estimates no effect on a clinical outcome.