Preparing for disease-modifying therapies in Alzheimer's disease

The long-awaited era of disease-modifying therapy for Alzheimer's disease has finally arrived and will substantially impact how the is perceived managed, although these new treatments pose challenges equitable access. drugs closest to widespread clinical implementation are lecanemab donanemab—intravenous monoclonal antibodies that remove β-amyloid plaques from brain can slow cognitive functional decline. Lecanemab was granted accelerated approval by United States Food Drug Administration (FDA) in January 2023, traditional July 2023; marketing authorisation applications have been made European Medicines Agency Healthcare products Regulatory UK. For donanemab, initial FDA approval, based on phase 2 trial results, declined but a further application announced results 3 (due be published 17, 2023). No national health-care system ready deliver more than fraction patients who might eligible. UK not alone having fragmented dementia services, which inadequately resourced staffed, mainly community-based. Multidisciplinary teams facilities needed administer therapies safely, their delivery require an accurate molecular diagnosis disease. Yet, UK, only about 60% people with receive even dementia. Despite guidance our National Institute Heath Care Excellence recommending structural imaging, unless well established subtype clear, there wide variation imaging use between centres. An audit memory services England showed proportion receiving scan and, those did, majority had CT scan, 26% MRI. Less 2% confirmation using CSF biomarkers (also included NICE guidance) or amyloid PET (which not). guidelines available investigation management mild impairment, key target group treatment. advent provides opportunity change. Licensing immune modulators thrombolysis led radical changes treatment paradigms multiple sclerosis stroke, respectively, including development pathways, rapid assessment units, upscaling multidisciplinary nurse specialists. These improved outcomes all patients, just eligible specific treatment, provided infrastructure allow adoption as they became available. availability bring influx into services: disease, other dementias, individuals concerned risk developing Clear referral criteria pathways primary care specialist required. Access must limited living near centres, health systems also ensure access minorities alone. Much slogan “time brain” adopted means diagnostic delays adversely affect outcomes—if progression slowed, then initiating early possible result maximal benefit; if evidence supports could progress past point eligibility whilst awaiting appointments tests. Careful communication expectations many fulfil either due too advanced impairment non-Alzheimer's pathology, presence comorbidities (eg, cerebrovascular microbleeds); alternative patients. dementia, arises promote prevention addressing modifiable factors. will, at least initially, likely resemble methodology used trials (table). Greater tests required, demand MRI major bottleneck. It scanners needed, efficient existing scanners, shorter, focussed protocols; neuroradiological expertise interpretation, detection amyloid-related abnormalities (ARIA). donanemab side-effects, notably ARIA 21% 39% respectively. While usually asymptomatic transient, requires close monitoring. Symptoms signs non-specific, blurred vision, headaches, unsteadiness, include focal deficits such dysphasia. However, re-dosed safely after period off treatment.TableOverview design investigating donanemabLecanemab*Based Clarity AD, 3, 18-month placebo-controlled randomised N=1795 .Donanemab†Based TRAILBLAZER-ALZ, 2, N=257 TRAILBLAZER-ALZ N=1736, whose yet unpublished.Inclusion criteriaDiagnosis diseaseMMSE ≥22Study partnerScreening exclude concomitant pathologyAmyloid positivity (PET CSF)Diagnosis 20–28Study (PET)Tau (PET)Drug deliveryTwo-weekly intravenous infusionMonthly infusionMonitoringClinical every monthsMRI week 9, months first 6 until completionIf detected, performed 30 days resolvedClinical weeks 4 12, 12 repeated 4–6 resolvedAmyloid done 24, 52 76Duration dosingThroughout studyStopped once negativeMMSE= Mini-Mental State Examination. ARIA= abnormalities.* Based .† unpublished. Open table tab MMSE= abnormalities. number potentially infusions two-weekly monthly basis dwarf similar neurological disorders. Infrastructure staff infusion suites pharmacies need expanded built sites convenient carers. Again, shown pathway shifts put place thrombectomy this shift insurmountable. In course, home feasible, subcutaneously administered become Blood pathology—in fact, plasma p-tau217 already entry-criterion study—although, present, rely examination. modalities advantages disadvantages terms cost, access, acceptability. Upscaling testing cost-effective provide both tau pathology; lumbar puncture capacity trained nursing medical staff, laboratory equipment analysis interpretation. Amyloid scanner tracer availability, nuclear medicine physicians, expensive. substantial, insurmountable: protocols train specialists do punctures, FDG-PET cancer monitoring demonstrates scanning 18F radiotracers feasible scale. trials, flortaucipir tau-PET determine pathology. Flortaucipir approved reimbursed USA, countries. unclear whether replaced examination, biomarkers, careful staging. APOE-ε4 factor hence, genetic given potential implications family members, involvement counsellors necessary. certain factors—such APOE ε4 status, microbleeds, anticoagulation therapies—help predict symptoms typically emerge soon initiation, it develop severe complications. Current mandate frequent but, real-world experience gained, tailored focussed. There guidelines, patient carer education, increased awareness amongst range healthcare professionals appropriate recognition symptoms, avoid harmful thrombolysis). When medications should stopped, how, unanswered questions. dosing stopped amyloid-PET levels dropped below pre-specified level, known long fast, remission, re-accumulates; therefore, re-dosing Some achieve clearance continue clinically, so no longer appropriate, burden administration outweigh its benefit. caregivers needed. long-term safety unknown, ascertained through post-market surveillance registries ALZ-NET, Association USA. involved preparing timely substantial. introduced accessible costs innovative funding models akin Risk Sharing Scheme pharmaceutical industry government Political vital. Effective change cooperation stakeholders, professionals, industry, charities, governments, undoubtedly challenge, unprecedented way perceived, improve pave next generation