Monday, September 29, 2025

Rapid Advances in Alzheimer's Disease: A Quintuplet of Articles

There's an interesting quintuplet of articles on Alzheimer's disease in recent weeks.  The message is: this field is updating fast.

  • At STAT-PLUS, Karlawish (U Penn) summarizes recent changes here.
  • At Alz Dis Rel Disord, Palmqvist and colleagues provide a new 2025 guideline for blood-based Alzheimer diagnostics here. 
  • At Lancet, see a three-part open-access series on Alzheimer's:
    • Frisoni, new diagnostics here.
    • Fox, new therapies here.
    • Firsoni, new challenges here.
While the focus here is on Alzheimer's disease, advances in Parkinson's are significant too.   
  • In JAMA Neurology,  Starr et al. report long-term favorable five year outcomes for PD patients treated with subthalamic deep brain stimulators. Multiple clinical axes of benefit.  Here.
  • Also in JAMA Neurology, Bronte-Steward et al. report favorable outcomes for "adaptive" deep brain stimulation in PD.  Here.
  • Multiple groups report high accuracy of alpha-synunclein seed assays in PD diagnosis, including differentiating related disorders.  E.g. Orru et al. Lancet Neurol 2025 here.  Ma et al (in multi-system atrophy) here.   Siderowf in Lancet Neurol 2023 here.

###

AI CORNER

I've taken the Alzheimer articles listed above, given them to Chat GPT 5, and asked for a summary.

###
The field of Alzheimer’s disease is undergoing its most significant transformation since the discovery of amyloid and tau pathology. For the first time, widely accessible blood-based biomarkers (BBMs) have achieved diagnostic performance sufficient to guide clinical decision-making, while disease-modifying anti-amyloid therapies—though still of modest effect and with notable safety and cost concerns—have entered routine practice in multiple countries. This simultaneous advance in diagnostics and therapeutics is reshaping clinical pathways, reimbursement policies, and the culture of dementia care. Understanding this inflection point requires integrating insights from the new Alzheimer’s Association guideline for BBM use, the Lancet three-part Series that frames the evolving landscape of diagnosis, treatment, and ongoing controversies, and the STAT keynote commentary by Karlawish, which highlights the profound societal and policy implications. Together, these sources chart how Alzheimer’s medicine is moving from late-stage recognition and largely supportive care toward an earlier, biology-driven, and potentially preventive model—a shift that demands attention from neurologists, health-system leaders, and policymakers alike.

###
###

Here is a comprehensive postgraduate-level synthesis of the five requested sources—the Alzheimer’s Association 2025 Clinical Practice Guideline on Blood-Based Biomarkers (Palmqvist et al.), the Lancet three-part Series on the new landscape of Alzheimer’s disease (diagnosis – Frisoni et al.; treatment – Fox et al.; controversies & future directions – Frisoni et al.), and the STAT “Neurotransmissions” keynote essay by Karlawish.

The summary is tailored for clinicians, neuroscientists, and policy leaders in dementia and Alzheimer’s care.

1. New Blood-Based Diagnostic Guideline (Palmqvist et al., Alzheimer’s & Dementia 2025)

Scope and rationale
The guideline responds to the clinical and policy need for widely accessible, less-invasive diagnostic tools as disease-modifying therapies now require biomarker confirmation of β-amyloid pathology for eligibility. Traditional methods—amyloid-PET and CSF assays—remain expensive or logistically limited.

Methodology
An Alzheimer’s Association-convened panel applied a GRADE-based systematic review of diagnostic-test-accuracy studies comparing plasma p-tau isoforms (p-tau217, p-tau181, p-tau231), Aβ42/40 ratios, or derived indices against PET, CSF, or neuropathology.

Key performance-linked recommendations

  • Triaging role: BBMs with ≥90 % sensitivity and ≥75 % specificity can be used to identify patients with cognitive impairment in specialty memory clinics who should proceed to confirmatory CSF/PET testing.

  • Substitution role: BBMs with ≥90 % sensitivity and specificity may replace CSF or PET in specialized-care diagnostic work-ups.

  • Clinical integration: BBMs are adjuncts, not stand-alone tests; interpretation must consider pre-test probability, comorbidities, and local assay performance.

  • Variability and evidence gaps: Many commercial assays do not yet meet thresholds across diverse populations; ongoing living-guideline updates will track new evidence and multiplex approaches (eg ratios, multi-threshold algorithms).

Policy significance
The guideline is brand-agnostic and performance-based, enabling payers, regulators, and health-system leaders to align coverage decisions with objective accuracy benchmarks and with equitable access goals.

2. Lancet Series, Part 1 – Diagnosis in the New Era (Frisoni et al., Lancet 2025)

Paradigm shift
Alzheimer’s diagnosis is moving from clinical-syndromic to clinical-biological: cognitive impairment plus biomarker evidence of β-amyloid and tau is now required both for diagnostic certainty and for eligibility for anti-amyloid monoclonals.

Impact of biomarkers

  • Traditional clinical assessment alone had ~60–70 % accuracy; adding PET/CSF raises it to ~90–95 %, with earlier detection.

  • The arrival of scalable blood biomarkers is anticipated to be a “diagnostic revolution,” enabling earlier, broader, and more equitable case-finding across health-care systems.

  • Revised 2024 Alzheimer’s Association criteria propose an integrated bio-clinical staging framework—recognizing that pathology and symptoms evolve asynchronously, affecting clinical trial design and care planning.

Clinical pathway
A typical patient journey in memory clinics still begins with clinical and neuropsychological evaluation and structural imaging; biomarker confirmation (traditionally CSF/PET, increasingly plasma) now plays a decisive role for prognosis, counseling, and treatment access.

3. Lancet Series, Part 2 – Treatment Landscape (Fox et al., Lancet 2025)

Background therapies

  • Cholinesterase inhibitors and memantine—long-standing symptomatic agents—remain standard but have modest and context-dependent benefits and variable reimbursement across countries.

  • Non-pharmacologic strategies for behavioural & psychological symptoms of dementia (BPSD)—eg personalized activity, caregiver training, environmental adaptation—have demonstrated benefit but are under-implemented in real-world care due to workforce and resource barriers.

Disease-modifying agents

  • Anti-β-amyloid monoclonal antibodies (lecanemab, donanemab) now have regulatory approval in the US, EU, UK, China, Japan, and others, representing the first class to slow cognitive-functional decline (by ~27–39 % over 18 months in phase-3 trials).

  • Integration with routine care remains challenging because of eligibility constraints (confirmed β-amyloid positivity), infusion logistics, ARIA risk monitoring, costs, and health-system fragmentation.

Care priorities
Guidelines emphasize first addressing social, somatic, and behavioural issues; cognitive-symptom and disease-modifying therapies should be delivered in the context of comprehensive, individualized care plans.

4. Lancet Series, Part 3 – Controversies and Next Steps (Frisoni et al., Lancet 2025)

Debate over benefit–risk and value

  • Early anti-amyloid experience with aducanumab bred skepticism; lecanemab/donanemab show replicable though modest slowing of decline, with treatment-related ARIA in 10–18 % and treatment-associated deaths in a small fraction, especially in patients receiving anticoagulants or thrombolytics.

  • Policy and expert communities remain split between “breakthrough” and “insufficient benefit-for-risk-and-cost” camps, unlike in oncology or multiple-sclerosis where similar-magnitude biologic effects were accepted.

Converging innovations

  • Blood-based biomarkers (p-tau217, Aβ42/40) now demonstrate PET-level accuracy and are already in clinical use in several countries; they lower barriers to biologic-therapy eligibility and to large-scale secondary-prevention trials.

  • Digital biomarkers and remote cognitive assessments promise more sensitive, scalable screening.

  • A long-term vision is precision, multi-target therapy (amyloid plus non-amyloid pathways) coupled with population-level risk-reduction and prevention programs.

Societal perspective
The paper highlights the interplay of science, economics, and culture—for decades Alzheimer’s care relied on low-tech tools; now the field faces expensive diagnostics and therapeutics, demanding new value frameworks and equitable resource allocation.

5. STAT “Neurotransmissions” Keynote – A Cultural & Policy Turning Point (Karlawish, STAT 2025)

Framing the challenge
Karlawish underscores that care follows diagnosis, yet historically ~40 % of US patients with documented dementia were not even told the diagnosis, and worldwide under-diagnosis approaches 60 %.
Cultural reluctance to name Alzheimer’s disease—linked to fear, stigma, and use of “dementia” as a political epithet—has impeded timely evaluation and planning.

Impending change

  • With accessible biomarker tests and available disease-modifying therapies, the “walls are coming down”: the field is entering a period when getting a diagnosis becomes an enabling, not a dooming, act.

  • Karlawish argues that society must now grapple with ethical, social, and policy challenges of living well with diagnosed cognitive disorders, including support for patients and caregivers and the equitable deployment of novel tools.

  • He calls this moment the dawn of a revolution in how we talk about, detect, and manage dementia.

Discussion.
Integrated Perspective for Neurology & Policy Leadership

  1. Convergence of Diagnostics and Therapeutics
     The simultaneous maturation of reliable plasma biomarkers and disease-modifying biologics re-defines the Alzheimer’s care pathway: from late-stage recognition to earlier biological detection and targeted intervention.

  2. Implementation Science & Health-System Readiness
     Scaling BBMs and biologics requires validated high-throughput assays, clinician education, diagnostic-therapeutic algorithms, infusion infrastructure, ARIA-monitoring capacity, coverage policies, and cost-effectiveness frameworks.

  3. Equity & Global Health Considerations
     Given the worldwide diagnosis gap and variation in access to symptomatic drugs and specialist care, the democratizing potential of BBMs is high but contingent on quality-assured assays, workforce training, and coverage policy—especially in LMICs.

  4. Evolving Policy & Regulatory Landscape
     Living-guideline models (as exemplified by the Alzheimer’s Association CPG) and adaptive payer policies will be crucial to keep pace with rapid evidence evolution and to balance access with value and safety oversight.

  5. Cultural & Ethical Dimension
     Normalization of biomarker-based diagnosis will challenge societies to destigmatize Alzheimer’s disease, address advance-care planning, and invest in long-term care and caregiver support infrastructures.

Bottom-Line

These five contributions collectively depict Alzheimer’s disease at an inflection point:

  • Biological diagnosis is becoming routine, led by blood-based biomarkers that can triage or substitute for invasive and expensive tests.

  • Disease-modifying therapy is clinically real but modest in effect and not without risk and cost, demanding nuanced risk–benefit assessment and system-level preparedness.

  • Policy, ethics, and culture now matter as much as molecular science—successful translation will hinge on equitable access, health-system adaptation, transparent communication, and sustained investment in supportive care and prevention.

Together, these sources argue that the management of Alzheimer’s disease is moving from a late-recognition, largely supportive paradigm to an early-detection, biology-informed, progressively preventive model—a shift with profound implications for neurology practice, health-policy strategy, and societal attitudes toward cognitive aging.

#

#

Prompt. You are writing at the medical postgraduate level and for experts in neurologic disease and policy for Alzheimer's. Summarize these articles, which include a new guideline for blood-based diagnostics in Alzheimer's. There is also a timely new set of 3 articles from Lancet on diagnostics, on therapies, and on controversies and next steps. Finally, there is a keynote op ed in STAT, discussing that we are on the brink of major changes in management of Alzheimer disease. Write an informative article summarizing the five sources.