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Symptomatic and supportive therapy

TL;DR — Cholinesterase inhibitors produce a mean improvement of −2.7 ADAS-Cog points (95% CI −3.0 to −2.3) on a 70-point scale over 6–12 months, with no evidence of a difference between donepezil, galantamine and rivastigmine, and with 29% versus 18% of participants withdrawing for adverse events (Birks 2006, PMID 16437532). Whether that constitutes worthwhile benefit has been contested since AD2000, which found donepezil better than placebo by 0.8 MMSE points (95% CI 0.5–1.2) and 1.0 BADLS points (0.5–1.6) over two years but with no difference in institutionalisation (42% vs 44% at 3 years, P=0.4) or disability progression, concluding the drug was not cost-effective (Courtney 2004, PMID 15220031). DOMINO-AD partly rehabilitated it: in moderate-to-severe disease, continuing donepezil beat stopping it by 1.9 SMMSE points (95% CI 1.3–2.5) and 3.0 BADLS points (1.8–4.3), the cognitive effect exceeding the trial's prespecified 1.4-point MCID, and stopping donepezil doubled the risk of nursing-home placement in the following year (HR 2.09, 95% CI 1.29–3.39) (Howard 2012, PMID 22397651; Howard 2015, PMID 26515660). Memantine has a small benefit in moderate-to-severe AD (3.11 SIB points, 95% CI 2.42–3.92) and probably none in mild AD (Cochrane; McShane 2019, PMID 30891742). Among non-drug approaches, cognitive stimulation has the best evidence (SMD 0.40, 95% CI 0.25–0.55 for cognition; 1.99 MMSE points, 1.24–2.74), while a well-powered pragmatic exercise trial found no cognitive benefit and a small worse ADAS-Cog result in the exercise arm (Woods 2023, PMID 39804128; Lamb 2018, PMID 29769247).

Cholinesterase inhibitors

Effect size

The Cochrane synthesis of 13 randomised, double-blind, placebo-controlled trials found that donepezil, galantamine or rivastigmine at recommended doses over 6 or 12 months improved cognition by a mean −2.7 ADAS-Cog points (95% CI −3.0 to −2.3), with more positive blinded global-state ratings and benefits also on activities of daily living and behaviour. The review states plainly: "None of these treatment effects are large." There was nothing to suggest smaller effects in severe or mild dementia, though evidence outside mild-to-moderate disease was sparse, and no evidence of efficacy differences between the three drugs; donepezil appeared better tolerated than rivastigmine and simpler to titrate (Birks 2006, PMID 16437532).

Subsequent single-drug Cochrane reviews, which pool more trials and report GRADE certainty, keep that class conclusion but make the per-drug numbers and harms explicit:

Drug Design Cognitive/functional effect (24–26 weeks vs placebo) Harms Source
Donepezil 10 mg/day 30 RCTs, 8,257 participants; main analysis 13 studies / 3,396 participants at 24–26 weeks ADAS-Cog MD −2.67 (95% CI −3.31 to −2.02); MMSE +1.05 (0.73–1.37); SIB +5.92 (4.53–7.31); ADCS-ADL-sev +1.03 (0.21–1.85); clinician-rated global improvement OR 1.92 (1.54–2.39). No NPI difference (−1.62, −3.43 to 0.19) and no QoL difference Withdrawal 24% vs 20% (OR 1.25, 1.05–1.50); any AE 72% vs 65% (OR 1.59, 1.31–1.95). 23 mg/day no more efficacious than 10 mg; 10 mg marginally more efficacious than 5 mg but with more withdrawals Birks 2018, PMID 29923184; moderate-certainty evidence
Galantamine 16–24 mg/day 21 RCTs, 10,990 participants (19 with data); 6-month ADAS-cog from 6 studies / 3,049 participants ADAS-cog MD −2.86 (−3.29 to −2.43); the authors judge this within the 2.6–4-point MCID they apply. Functional disability (DAD MD 2.12, 0.75–3.49) and behaviour (NPI MD −1.63, −3.07 to −0.20) also improved with high certainty; global function only may improve (CIBIC-plus OR 1.58, 1.36–1.84; low certainty). No evidence of benefit in MCI (expanded ADAS-cog MD −0.21, −0.78 to 0.37) GI events dominate. In AD, death was lower on galantamine (OR 0.56, 0.33–0.96). In MCI, premature discontinuation 40.7% vs 28.6% (OR 1.71, 1.42–2.05) and nausea 29.4% vs 10.7% (OR 3.49, 2.75–4.44) Lim 2024, PMID 39498781; high-certainty for AD cognition
Rivastigmine 6–12 mg oral or 9.5 mg transdermal 7 trials contributing 3,450 patients at 26 weeks ADAS-Cog MD −1.79 (−2.21 to −1.37); MMSE +0.74 (0.52–0.97); ADL SMD 0.20 (0.13–0.27); less "no change or deterioration" on global impression (OR 0.68, 0.58–0.80). No behavioural or caregiver-distress difference Withdrawal OR 2.01 (1.71–2.37); any AE OR 2.16 (1.82–2.57). Patch may have fewer side effects than capsules at comparable efficacy Birks 2015, PMID 25858345; moderate-certainty, all industry-funded

For calibration, published MCIDs for ADAS-Cog are +2 to +3 points in MCI and +3 in mild AD (Muir 2024, PMID 38561021). Donepezil (−2.67) and galantamine (−2.86) both fall just short of the +3 mild-AD threshold while exceeding the lower bound of the +2 to +3 MCI band; rivastigmine (−1.79) falls below both. The AAN MCI guideline takes the operational consequence: clinicians may choose not to offer cholinesterase inhibitors in MCI (Level B) and, if offering, must first discuss the lack of evidence (Level A) (Petersen 2018, PMID 29282327) — consistent with the galantamine MCI null and with CCCDTD5's advice to deprescribe if the original indication was MCI (Herrmann 2022, PMID 35128025).

The long-term outcomes that matter

Trial Design Cognitive/functional result Hard outcomes
AD2000 (Courtney 2004, PMID 15220031) 565 community patients, mild-moderate AD, double-blind donepezil vs placebo continuing "as long as judged appropriate" MMSE +0.8 points (95% CI 0.5–1.2, P<0.0001) and BADLS +1.0 points (0.5–1.6, P<0.0001) over 2 years Institutionalisation 42% vs 44% at 3 years (P=0.4); disability progression 58% vs 59% (P=0.4); RR of institutional care 0.97 (0.72–1.30); no differences in behavioural symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths; no 5 mg vs 10 mg difference. Authors: "Donepezil is not cost effective, with benefits below minimally relevant thresholds"
DOMINO-AD (Howard 2012, PMID 22397651) 295 community patients, moderate-severe AD (SMMSE 5–13), already on donepezil ≥3 months, randomised 2×2 to continue/discontinue donepezil and start/not start memantine, 52 weeks Continue vs discontinue donepezil: SMMSE +1.9 (95% CI 1.3–2.5) and BADLS −3.0 (1.8–4.3), both P<0.001, cognitive effect above the prespecified 1.4-point MCID. Memantine vs placebo: SMMSE +1.2 (0.6–1.8, P<0.001), BADLS −1.5 (0.3–2.8, P=0.02). No significant benefit of the combination over donepezil alone See below
DOMINO-AD placement analysis (Howard 2015, PMID 26515660) Same cohort, residence tracked to 4 years — 162/295 (55%) entered nursing homes within 4 years, similar across arms. Significant heterogeneity of treatment effect over time (P=0.010): donepezil discontinuation increased placement in year 1 (HR 2.09, 95% CI 1.29–3.39) with no difference over the next 3 years (0.89, 0.58–1.35). Memantine had no effect in year 1 (0.92, 0.58–1.45) or thereafter (1.23, 0.81–1.87)

The two trials are usually presented as contradictory; they are better read as answering different questions. AD2000 asked whether starting donepezil in mild-moderate disease changes long-term outcomes (it did not, on institutionalisation or disability). DOMINO asked whether stopping it in moderate-severe disease is harmful (it was, transiently). The practical synthesis the DOMINO authors themselves draw is that decisions to stop should be informed by the risks of withdrawal "even if the perceived benefits of continued treatment are not clear" (PMID 26515660).

A meta-analysis of five ChEI-discontinuation RCTs (321 continued, 332 discontinued; follow-up 1.5–24 months) found the same direction as DOMINO: discontinuation worsened cognition (standardised MMSE difference −0.29, 95% CI −0.45 to −0.13) and neuropsychiatric symptoms (standardised NPI difference −0.32, −0.51 to −0.12) and raised dropout (RR 1.33, 1.11–1.59), with no difference in adverse events (RR 1.01, 0.85–1.20) (O'Regan 2015, PMID 26646039). The DOMINO placement effect is therefore not an isolated finding; the open question is duration, not direction.

High-dose donepezil

Donepezil 23 mg/day versus 10 mg/day in 1,467 randomised patients with moderate-to-severe AD produced a Severe Impairment Battery difference of 2.2 points (+2.6 vs +0.4, P<0.001) but no significant difference on the CIBIC+ global measure (4.23 vs 4.29). Withdrawal was 30.2% versus 17.9%, and treatment-emergent adverse events 73.7% versus 63.7%, with nausea, vomiting and diarrhoea substantially more common at the higher dose (Farlow 2010, PMID 20678673). A cognitive gain on one scale without a global-impression gain, bought with nearly double the withdrawal rate, is a poor trade in most patients.

Harms that are easy to miss

In a population-based cohort of 19,803 community-dwelling older adults with dementia prescribed cholinesterase inhibitors versus 61,499 who were not (Gill 2009, PMID 19433698):

Event ChEI Control Adjusted HR (95% CI)
Hospital visit for syncope 31.5 / 1,000 py 18.6 / 1,000 py 1.76 (1.57–1.98)
Hospital visit for bradycardia 6.9 4.4 1.69 (1.32–2.15)
Permanent pacemaker insertion 4.7 3.3 1.49 (1.12–2.00)
Hip fracture 22.4 19.8 1.18 (1.04–1.34)

Results held after matching on baseline comorbidity and after propensity-score matching. These are observational data with residual confounding by indication as the main threat, but the effects are mechanistically coherent (vagotonic bradycardia → syncope → fall). The authors' framing is the operative one: these risks "must be weighed carefully against the drugs' generally modest benefits."

Memantine

The Cochrane review pooled data from nearly 10,000 participants in 44 trials, 29 of them (7,885 participants) in AD, with relevant data for almost half the studies obtained from unpublished sources (McShane 2019, PMID 30891742):

Population Outcome Effect (95% CI) Certainty
Moderate-to-severe AD, ± ChEI Clinical global rating 0.21 CIBIC+ points (0.14–0.30) High
" Cognition 3.11 SIB points (2.42–3.92) High
" ADL 1.09 ADL19 points (0.62–1.64) High
" Behaviour/mood 1.84 NPI points (1.05–2.76) High
" Discontinuation vs placebo RR 0.93 (0.83–1.04) —
Mild AD (MMSE 20–23) Cognition 0.21 ADAS-Cog points (−0.95 to 1.38) Moderate
" ADL −0.07 ADL23 points (−1.80 to 1.66) Moderate
" Behaviour/mood −0.29 NPI points (−2.16 to 1.58) Moderate
" Discontinuation for adverse events RR 2.12 (1.03–4.39) —
All dementias Any adverse event RR 1.03 (1.00–1.06) High
All dementias Dizziness 6.1% vs 3.9% (~1.6×) Moderate
All dementias Falls No difference High

Three points follow. Memantine works in moderate-to-severe AD regardless of concomitant ChEI use; it does not work in mild AD despite common off-label use there, and may increase adverse-event discontinuation in that group; and although fewer memantine-treated participants experienced agitation as an adverse event (RR 0.81, 95% CI 0.66–0.99), memantine is not effective as a treatment for agitation (CMAI benefit 0.50 points, 95% CI −3.71 to 4.71) — see neuropsychiatric symptoms.

The review's closing observation frames the whole page: clinical heterogeneity makes it unlikely that any single drug will have a large effect, so optimal treatment may involve multiple drugs each with an effect below the MCID (PMID 30891742).

Two combination trials disagree on whether adding memantine to a cholinesterase inhibitor is worth it. Tariot randomised 404 patients with moderate-to-severe AD (MMSE 5–14) already on stable donepezil to memantine 20 mg/day or placebo for 24 weeks: SIB change favoured memantine (0.9 vs −2.5, P<0.001), as did ADCS-ADL19 (−2.0 vs −3.4, P=0.03) and CIBIC-Plus (4.41 vs 4.66) (Tariot 2004, PMID 14734594). DOMINO, in a similar MMSE band, found no significant benefit of the combination over donepezil alone (Howard 2012, PMID 22397651). The difference is design: Tariot added memantine to ongoing donepezil versus continuing donepezil; DOMINO started memantine in people already on donepezil and crossed that with a discontinuation arm. Both can be true: adding memantine in moderate-to-severe disease produces a small 24-week gain that does not compound into a 52-week advantage over donepezil continued alone.

TEAM-AD tested a different add-on in mild-to-moderate AD already on a cholinesterase inhibitor: 613 VA patients randomised to vitamin E 2,000 IU/day, memantine 20 mg, both, or placebo, followed a mean 2.27 years. Alpha-tocopherol slowed ADCS-ADL decline by 3.15 units versus placebo (95% CI 0.92–5.39; adjusted P=0.03) — a 19% slower annual decline, or about 6.2 months of delayed progression — while memantine (1.98 units, −0.24 to 4.20; P=0.40) and the combination did not (Dysken 2014, PMID 24381967). Infections/infestations as serious adverse events were more frequent on memantine (31 events in 23 participants) and combination (44 in 31) than placebo (13 in 11). The Cochrane conclusion that memantine does not work in mild AD is therefore corroborated by an independent long-duration trial. The vitamin E result sits outside that review, and it is not the first at this dose: the ADCS trial of selegiline and alpha-tocopherol randomised 341 patients with moderately severe AD at 2,000 IU/day for two years and reported a delay in a composite of death, institutionalisation, loss of basic ADLs or CDR 3 (median 670 vs 440 days, P=0.001) — but only in analyses adjusted for a baseline MMSE imbalance, with no significant difference unadjusted (Sano 1997, PMID 9110909). Two positive results at 2,000 IU/day in different populations, on different primary endpoints, one of them covariate-dependent, is not the same as a replication.

Non-pharmacological therapy

Intervention Best evidence Effect Interpretation
Cognitive stimulation (group or individual, broad activities with a social element) 37 RCTs, 2,766 participants; meta-analysis of 36 studies / 2,704 participants (Woods 2023, PMID 39804128) Cognition SMD 0.40 (95% CI 0.25–0.55), moderate quality; MMSE difference 1.99 points (1.24–2.74) across 25 studies/1,893 participants; self-reported QoL SMD 0.25 (0.07–0.42); communication and social interaction SMD 0.53 (0.36–0.70), high quality; slight benefits in iADL, self-reported depressed mood, anxiety and general behaviour; no negative effects reported; little or no effect on caregiver mood or anxiety Larger cognitive effects with ≥2 sessions weekly and with mild rather than moderate dementia (exploratory subgroups). Only 8 of 37 studies reported follow-up, so durability is largely unknown
Cognitive training (structured, targeted practice) 33 RCTs, 12 countries (Bahar-Fuchs 2019, PMID 30909318) vs control: global cognition SMD 0.42 (0.23–0.62), moderate quality; verbal semantic fluency SMD 0.52 (0.23–0.81), high quality, retained 3–12 months. vs alternative treatments: SMD 0.21 (−0.23 to 0.64), low quality Effects relative to passive/active controls, not relative to other active therapies; moderately confident there were no gains in mood, behavioural symptoms or ADLs
Reminiscence therapy 22 RCTs, 1,972 participants (Woods 2018, PMID 29493789) QoL overall SMD 0.11 (−0.12 to 0.33) — probably no important effect; care homes SMD 0.46 (0.18–0.75); cognition SMD 0.11 (0.00–0.23), "very small… of doubtful clinical importance"; MMSE 1.87 points (0.54–3.20); communication SMD −0.51 (−0.97 to −0.05) at end of treatment; individual RT probably slightly benefits depression (SMD −0.41, −0.76 to −0.06); no harmful effects on people with dementia; a possible small increase in carer anxiety at longer follow-up where carers joined groups Effects are inconsistent and setting- and modality-dependent
Structured exercise DAPA, 494 participants, 2:1 randomisation, 4 months supervised aerobic + strength training, pragmatic, investigator-masked (Lamb 2018, PMID 29769247) ADAS-Cog at 12 months 25.2 (SD 12.3) exercise vs 23.8 (10.4) usual care; adjusted difference −1.4 (95% CI −2.6 to −0.2, P=0.03) favouring usual care; no differences in ADLs, neuropsychiatric symptoms, health-related QoL, or carer QoL/burden; >65% attended more than three-quarters of sessions; 6-minute walk improved by 18.1 m (11.6–24.6) over 6 weeks Exercise improved fitness and did not improve cognition; the small point estimate favouring usual care is of uncertain clinical relevance but rules out a meaningful cognitive benefit at this dose and stage
Community occupational therapy 135 patient–caregiver couples, 10 sessions over 5 weeks vs no intervention (Graff 2007, PMID 17895439) Patient Dqol overall +0.8 (effect size 1.3; the PubMed record prints this interval as "0.6-.1", an internally impossible bound, so no upper limit is reproduced here); caregiver Dqol +0.7 (95% CI 0.5–0.9, effect size 1.2); mood and health-status scores also improved; effects persisted at 12 weeks The largest non-drug effect sizes on this page, on quality of life rather than cognition, in both members of the dyad. The control arm received no intervention, so participants could not be blinded
Music-based therapeutic interventions Cochrane: 30 RCTs, 1,720 randomised, 28 studies / 1,366 in meta-analysis (van der Steen 2025, PMID 40049590) vs usual care, end of treatment: depressive symptoms SMD −0.23 (−0.42 to −0.04; moderate certainty); overall behavioural problems SMD −0.31 (−0.60 to −0.02; low certainty); agitation/aggression SMD −0.05 (−0.27 to 0.17) — no effect. vs other activities: social behaviour SMD 0.52 (0.08–0.96). No demonstrated long-term effects ≥4 weeks after treatment ended The best-supported effect is on depressive symptoms (moderate certainty); the social-behaviour advantage over other activities rests on low-certainty evidence from 4 studies and 84 participants. Agitation is likely unaffected (moderate certainty), and cognition was not improved (SMD 0.19, −0.02 to 0.41)

The pattern across these is instructive: interventions with a strong social and communicative component (cognitive stimulation, group reminiscence, occupational therapy, music versus other activities) produce their most reliable effects on communication, quality of life and social interaction — outcomes that matter to people and are rarely primary endpoints — while interventions targeting cognition directly (cognitive training, exercise) produce either narrow or absent transfer. Exercise in dementia remains justified for fitness, falls and cardiovascular health; the DAPA result is that it should not be prescribed for cognition in established dementia. Prevention-stage exercise is a different question, on risk reduction and prevention. A multinutrient medical-food drink (Fortasyn Connect) in prodromal AD missed its 24-month NTB primary (difference 0.098, 95% CI −0.041 to 0.237, P=0.166) and then, among the 81 participants with 36-month efficacy data, reported a 60% reduction in NTB decline (difference 0.212, 0.044–0.380, P=0.014) with small-to-medium effect sizes (Cohen's d 0.25–0.31) (Soininen 2017, PMID 29097166; Soininen 2021, PMID 32920957). That 36-month result is a selected completer analysis after a negative primary, and it is not a treatment for established dementia.

Effect sizes beyond the licensing trials

A 30-trial meta-analysis (7,567 participants) estimated memantine versus placebo effects of SMD −0.24 (95% CI −0.34 to −0.15) for cognition and −0.16 (−0.29 to −0.04) for behavioural disturbance, with no difference in all-cause discontinuation. Adding memantine to a cholinesterase inhibitor improved behaviour by SMD −0.20 (−0.36 to −0.03), but heterogeneity was 77%; restricting to double-blind placebo-controlled studies reduced the estimate to −0.11 (−0.21 to −0.01) (Kishi 2017, PMID 28922160). A GRADE guideline based on four combination trials (n=1,549) found global-clinical SMD −0.20, cognition −0.27 and behaviour −0.19, yet issued only a weak recommendation because certainty was moderate for cognition/global impression and low for activities of daily living (Schmidt 2015, PMID 25808982). Statistical benefit and recommendation strength are not synonyms.

Non-drug evidence is likewise mixed rather than uniformly positive. Cognitive stimulation across 44 trials (2,444 participants) produced global-cognition Hedges g=0.49 immediately after treatment, corresponding to 2.41 ADAS-Cog points after removal of one outlier—borderline against a 3–4-point clinical threshold—with no significant global-cognition effect at 1–10 months and widespread blinding/control limitations (Cafferata 2021, PMID 34292011). Exercise meta-analysis found improvements in Barthel Index (MD 8.36, 95% CI 0.63–16.09), six-minute walk distance (84 m, 44–133) and NPI (−4.4, −8.42 to −0.38), but substantial heterogeneity and only 147–369 participants per outcome (López-Ortiz 2021, PMID 34601135). In a 96-person trial, cycling and stretching did not differ on ADAS-Cog at six months (P=0.386) or 12 months (P=0.856) (Yu 2021, PMID 33523004). The appropriate conclusion is modest multidomain benefit with uncertain cognitive specificity, not disease modification.

What this adds up to

  1. Start a cholinesterase inhibitor in mild-to-moderate AD expecting a small, group-level effect that cannot be predicted for an individual (PMID 16437532), and monitor for bradycardia, syncope and falls (PMID 19433698).
  2. Do not expect delayed institutionalisation from initiating treatment (PMID 15220031), but recognise that stopping in moderate-to-severe disease carries a real short-term risk (PMID 26515660).
  3. Add memantine in moderate-to-severe disease; do not use it in mild AD (PMID 30891742).
  4. Do not use combination therapy expecting more than donepezil alone in moderate-to-severe disease (PMID 22397651).
  5. Offer cognitive stimulation, which has the largest and most consistent non-drug evidence base and no reported harms (PMID 39804128); occupational therapy targeting the dyad has the largest QoL effect sizes in a single trial (PMID 17895439).
  6. Do not expect galantamine, or by extension the class, to treat MCI (PMID 39498781; PMID 29282327).

None of this is disease-modifying; that evidence is on anti-amyloid immunotherapy.

Open questions

  • Can responders to cholinesterase inhibitors be identified before treatment? The Cochrane review states explicitly that they cannot (Birks 2006, PMID 16437532).
  • Does the benefit of continued donepezil persist beyond 12 months in moderate-to-severe disease? DOMINO's design cannot answer it, and the placement effect was confined to year 1 (Howard 2012, PMID 22397651; Howard 2015, PMID 26515660).
  • Would starting memantine earlier be beneficial over the long term? The Cochrane authors call for a definitive long-duration trial in mild AD and note current evidence is against the widespread practice (McShane 2019, PMID 30891742).
  • Are the AD2000 and DOMINO results reconcilable, or does disease stage genuinely change the direction of the treatment decision (PMID 15220031; PMID 22397651)?
  • How durable are cognitive-stimulation effects? Only 8 of 37 trials reported any follow-up (Woods 2023, PMID 39804128).
  • Does cognitive training outperform any alternative active therapy, given that its advantage over alternatives was SMD 0.21 (−0.23 to 0.64) (Bahar-Fuchs 2019, PMID 30909318)?
  • Why did DAPA's exercise arm score slightly worse on ADAS-Cog, and is this noise, a dose effect, or a real signal (Lamb 2018, PMID 29769247)?
  • What is the interaction between symptomatic therapy and anti-amyloid therapy — should ChEIs be continued during antibody treatment, and does continuing one change ARIA risk? A 2026 real-world cohort compared 240 monoclonal-antibody-treated patients with propensity-matched patients on non-monoclonal treatment (donepezil, memantine, rivastigmine) and found a higher cumulative ARIA hazard with antibodies (HR 4.65, 95% CI 3.77–5.73), with concurrent antithrombotic use (1.87, 1.48–2.37), prior stroke (1.59, 1.21–2.10) and hyperlipidaemia (1.41, 1.09–1.84) also raising it (Dangpiaei 2026, PMID 41885326). That compares treatment cohorts rather than concomitant use: as of the 2026-08-31 search, no retrieved study reports whether continuing a cholinesterase inhibitor during anti-amyloid therapy changes ARIA risk or clinical outcome.
  • Does the TEAM-AD vitamin E functional benefit (3.15 ADCS-ADL units over 2.27 years) replicate outside a VA population, and does it justify a 2,000 IU/day dose given the infection signal on memantine combination (Dysken 2014, PMID 24381967)?
  • Is the LipiDiDiet 36-month completer analysis a delayed effect or a selected-survivor artefact of a negative 24-month primary (Soininen 2017, PMID 29097166; Soininen 2021, PMID 32920957)?

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