Alzheimer Disease

Alzheimer disease is a progressive neurodegenerative disorder characterized by amyloid-beta plaques and neurofibrillary tau tangles; these brain changes may precede symptoms by 20 years or more. fda+1fdaJune 9, 2023 Peripheral and Central Nervous System ...fdaFDA issues guidance regarding drug development for early Alzheimer’s disease | FDA In a patient with objective cognitive and functional decline, the first management decision is whether an Alzheimer etiology is sufficiently likely that confirmation would affect prognosis, medication selection, or eligibility for anti-amyloid treatment.

A biomarker result is most actionable in mild cognitive impairment or early dementia with an Alzheimer-like phenotype, atypical presentations with competing etiologies, or cognitive impairment after traumatic brain injury or contact-sport exposure where Alzheimer copathology would alter use of Alzheimer-directed therapy. BMJ+1BMJRetired contact sports athletes with cognitive concerns: promoting lifelong brain health | Practical NeurologyNatureDesigning the next-generation clinical care pathway for Alzheimer’s disease | Nature Aging Do not use an isolated nonspecific neurodegeneration marker to label Alzheimer disease: plasma neurofilament light reflects axonal injury across several neurodegenerative disorders and has limited differential diagnostic specificity. BMJBMJBlood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances | Journal of Neurology, Neurosurgery & Psychiatry

Amyloid-negative testing should redirect the etiologic workup rather than trigger anti-amyloid treatment. In particular, chronic traumatic encephalopathy cannot currently be diagnosed with sufficient sensitivity or specificity by tau PET, and FDG-PET has no clear established clinical utility for CTE; amyloid PET or fluid biomarkers can instead identify coexisting Alzheimer pathology. BMJBMJRetired contact sports athletes with cognitive concerns: promoting lifelong brain health | Practical Neurology

Lecanemab and donanemab are FDA-approved anti-amyloid immunotherapies for Alzheimer disease. cellcellThe evolving landscape of Alzheimer’s disease therapy: From Aβ to tau Their use belongs in an early-disease, biomarker-guided pathway rather than empiric treatment of nonspecific cognitive decline, because amyloid-directed therapy addresses amyloid pathology and carries clinically important ARIA risk. fda+1fdaJune 9, 2023 Peripheral and Central Nervous System ...The LancetPreparing for disease-modifying therapies in Alzheimer's ...

For donanemab, FDA-reported trial outcomes showed less decline than placebo at week 76 on the Integrated Alzheimer’s Disease Rating Scale (difference 2.92), ADAS-Cog13 (difference -1.33), instrumental activities of daily living (difference 1.70), and CDR-Sum of Boxes (difference -0.70). fdafdaFDA approves treatment for adults with Alzheimer’s disease | FDA Across anti-beta-amyloid trials, reported slowing on composite measures has ranged approximately 25% to 40%, depending on the measure used. Oxford AcademicOxford AcademicEvaluating clinical meaningfulness of anti-β-amyloid therapies ... Present these outcomes as slowing of decline rather than recovery or cure.

Before treatment selection, discuss ARIA and establish an MRI monitoring plan. Lecanemab and donanemab have reported ARIA in about 21% of treated patients in a treatment-pathway review; when ARIA is detected, MRI every 30 days until resolution was proposed. The LancetThe LancetPreparing for disease-modifying therapies in Alzheimer's ... APOE ε4 genotype identifies substantially different ARIA-E risks: reported rates for lecanemab were 5.4% in noncarriers, 10.9% in heterozygotes, and 32.6% in homozygotes; corresponding reported donanemab rates were 15.7%, 22.8%, and 40.6%. NatureNatureXPro1595 in early Alzheimer’s disease with inflammation: results from the phase 2 MINDFuL trial | npj Dementia

FDA-recognized symptomatic Alzheimer therapies are the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, plus the N-methyl-D-aspartate receptor antagonist memantine. fdafdaJune 9, 2023 Peripheral and Central Nervous System ... These agents do not target the underlying amyloid or tau pathology, and expected benefit is modest and transitory. fdafdaJune 9, 2023 Peripheral and Central Nervous System ... They may remain clinically useful for symptomatic management while biomarker evaluation or anti-amyloid eligibility assessment proceeds.

Cholinesterase inhibitor adverse effects reflect enhanced muscarinic tone; nausea and vomiting have been reported in approximately one in four to one in seven treated patients. The LancetThe LancetTreatment for Alzheimer's disease Reassess tolerability after initiation or escalation and distinguish medication-related gastrointestinal symptoms from intercurrent illness before discontinuing a potentially beneficial agent.

Memantine is a noncompetitive antagonist at extrasynaptic NMDA receptors and has an approximately 60-hour half-life with once-daily administration described in a vascular cognitive impairment review. NatureNatureVascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future | Neuropsychopharmacology Its FDA-recognized role is Alzheimer symptomatic treatment, whereas vascular cognitive impairment has no FDA-approved therapy; do not extrapolate an Alzheimer drug label to pure vascular cognitive impairment without recognizing that distinction. fda+1fdaJune 9, 2023 Peripheral and Central Nervous System ...NatureVascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future | Neuropsychopharmacology

Vascular cognitive impairment and dementia has no FDA-approved treatment, whereas three cholinesterase inhibitors and memantine are FDA-approved Alzheimer symptomatic therapies and lecanemab and donanemab are FDA-approved anti-amyloid therapies for Alzheimer disease. NatureNatureVascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future | Neuropsychopharmacology In patients with cerebrovascular disease and cognitive impairment, establish whether Alzheimer pathology is also present before assigning an Alzheimer-specific treatment rationale.

Medication review is a direct management intervention in vascular cognitive impairment: stroke best-practice guidance advises attention to drugs that may increase cognitive fluctuations or cognitive decline. Wolters KluwerWolters KluwerCanadian Stroke Best Practice Recommendations This is especially important when interpreting short-interval cognitive worsening, because medication effects can confound estimation of neurodegenerative progression.

In retired contact-sport athletes, fluid biomarkers can identify neurodegeneration and Alzheimer co-pathology, but phosphorylated tau biomarkers are not thought to be elevated in CTE without Alzheimer co-pathology. BMJBMJRetired contact sports athletes with cognitive concerns: promoting lifelong brain health | Practical Neurology A positive p-tau181 or p-tau217 result in this setting therefore supports investigation for Alzheimer biology rather than a clinical diagnosis of CTE. BMJBMJRetired contact sports athletes with cognitive concerns: promoting lifelong brain health | Practical Neurology

For anti-amyloid therapy, separate clinical trajectory from ARIA monitoring. Cognitive and functional scales quantify change over time, whereas MRI detects treatment-related ARIA; an ARIA finding warrants repeat MRI approximately every 30 days until resolution. fda+1fdaFDA approves treatment for adults with Alzheimer’s disease | FDAThe LancetPreparing for disease-modifying therapies in Alzheimer's ... New neurologic symptoms during treatment should therefore trigger assessment for ARIA rather than being presumed to represent inevitable disease progression. The LancetThe LancetPreparing for disease-modifying therapies in Alzheimer's ...

Blood biomarkers may become useful longitudinal adjuncts, but their roles are not interchangeable. Longitudinal increases in plasma phosphorylated tau have been associated with brain atrophy and cognitive decline, particularly in Alzheimer disease, while NfL tracks axonal injury without Alzheimer specificity. BMJBMJBlood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances | Journal of Neurology, Neurosurgery & Psychiatry Use biomarker trends, when obtained, to complement rather than replace clinical and imaging-based evaluation.

Revisit goals of care as function changes. Alzheimer disease progressively affects memory, thinking, language, and eventually the ability to perform simple tasks. fdafdaFDA approves treatment for adults with Alzheimer’s disease | FDA At each follow-up, document changes in instrumental and basic activities, update caregiver capacity, and reassess whether the burden of infusion visits, MRI surveillance, and adverse-event risk remains proportionate to the patient’s goals.