Redesigning Alzheimer’s Modalities around Clearance

Redesigning Alzheimer’s Modalities around Clearance

Author: KJ Lavan 

The most radical shift in Alzheimer’s disease (AD) may not be what we target—but how we move things out of the brain.

For decades we’ve chased amyloid production. The emerging clearance science says: follow the flow.

⸻

1. From “amyloid problem” to “clearance problem”

New work visualizing how amyloid-β (Aβ) is cleared from the human brain adds weight to a simple but disruptive idea:

AD is as much a fluid-dynamics disorder as a proteinopathy.

The glymphatic–meningeal lymphatic system—glial-supported perivascular channels plus dural lymphatic vessels—acts as the brain’s waste-clearance network, moving cerebrospinal fluid (CSF) in, mixing with interstitial fluid, and exporting Aβ, tau, and other toxins to cervical lymph nodes. When this system falters, toxic proteins accumulate even if production hasn’t changed.  

Human imaging now directly tracks CSF–waste flow along these pathways in neurosurgical patients, confirming that clearance is not diffuse “soaking” but a highly organized channel architecture that can, in principle, be measured and modulated.  

In parallel, UK Biobank data show that MRI markers of impaired glymphatic flow—altered perivascular-space metrics, reduced DTI-ALPS index, enlarged choroid plexus, disrupted CSF–blood coupling—predict future dementia and tightly track vascular risk factors like hypertension and diabetes.  

Taken together, these findings reposition glymphatic/lymphatic clearance from an interesting side story to a central therapeutic axis for AD.

⸻

2. The clearance network as a therapeutic target

Recent reviews synthesize a rapidly converging picture:

• The glymphatic system, driven by arterial pulsation, respiration, aquaporin-4 (AQP4) water channels, and sleep-linked neuromodulators, is crucial for clearing Aβ and tau.  

• Meningeal lymphatic vessels (mLVs) form the brain’s final drainage step; their dysfunction accelerates amyloid deposition and cognitive decline in aging and AD models.  

• Glymphatic and lymphatic impairment is bidirectionally linked with pathology: reduced clearance promotes Aβ/tau buildup, and accumulating proteins further damage clearance pathways.  

This is more than mechanistic nuance. It implies that anti-amyloid antibodies are being deployed into a compromised plumbing system. If clearance pathways are narrow, stiff, or offline, we may lower plaque burden in PET-positive regions yet fail to restore network homeostasis or cognition.

The future of AD therapeutics likely lies in co-treating proteins and pipes.

⸻

3. Non-invasive “clearance neuromodulation” is already emerging

Three streams of preclinical work hint at how we might actively drive amyloid out of the brain:

1. 40 Hz gamma stimulation

Multisensory 40 Hz light–sound stimulation in 5xFAD mice enhances glymphatic influx and efflux, increases AQP4 polarization at astrocytic endfeet, dilates mLVs, and reduces amyloid burden. Blocking glymphatic clearance abolishes these benefits, indicating that the therapeutic effect runs through fluid dynamics, not just microglial activation.  

2. Transcranial photobiomodulation of lymphatics

Near-infrared light (≈808 nm) targeting meningeal lymphatics in aged and AD-model mice boosts CSF drainage to deep cervical lymph nodes, decreases Aβ deposition, dampens neuroinflammation, and improves cognition—without invasive surgery.  

3. Exercise as “lymphatic rehabilitation”

Long-term treadmill exercise in AD mice increases mLV diameter and drainage capacity, restores vessel junction architecture, reduces Aβ and gliosis in hippocampus and cortex, and improves memory. Mechanistically, exercise down-regulates an astrocyte EAF2–p53–TSP-1 axis that otherwise suppresses lymphatic plasticity.  

Layered atop these are proposals to pharmacologically modulate AQP4, vasomotion, and meningeal lymphangiogenesis to restore glymphatic throughput.  

These approaches point toward a new category: “clearance-enhancing neuromodulation” that sits alongside monoclonal antibodies, small molecules, and cell therapies rather than competing with them.

⸻

4. Redesigning Alzheimer’s modalities around clearance

If we take this clearance-centric view seriously, several future shifts in AD care become almost inevitable:

1. From single-target drugs to “flow-stacked” regimens

• Anti-amyloid or anti-tau biologics plus a clearance modality (gamma stimulation, photobiomodulation, structured exercise) optimized to open glymphatic and lymphatic channels during or after treatment windows.  

• Trial endpoints that combine PET or plasma Aβ/tau with imaging of glymphatic indices (DTI-ALPS, perivascular space metrics, meningeal lymphatic visibility) to see whether we are truly restoring dynamic clearance capacity, not just static plaque load.  

2. Sleep and cardiovascular health as precision-clearance medicine

• Human data now show that deep sleep increases glymphatic inflow and that acute sleep loss blunts CSF–to–blood clearance of AD biomarkers.  

• The UK Biobank findings tie hypertension, diabetes, and arterial stiffness directly to impaired glymphatic markers and dementia risk.  

In a clearance framework, “lifestyle” is no longer soft advice—it is systems-level neuromechanics: blood pressure control, sleep quality, and aerobic conditioning become active levers to preserve the brain’s waste-removal infrastructure.

3. Earlier, fluid-dynamic staging of Alzheimer’s

Reviews now integrate AT(N) biomarker staging with glymphatic impairment signatures—enlarged perivascular spaces, reduced ALPS index, altered choroid plexus volume, and mLV drainage deficits—suggesting that clearance decline may precede overt clinical symptoms in a large subset of patients.  

This opens the door to:

• Preclinical interventions that aim first to normalize clearance before plaque/tangle burden becomes entrenched.

• Risk stratification based on a “clearance phenotype,” not just genetics or cognitive scores.

4. Reframing prevention as maintaining hydraulic resilience

The OHSU study showing organized human glymphatic channels, combined with dementia-prediction data from population imaging, suggests a future where we routinely monitor brain-clearance health in midlife the way we track ejection fraction or glomerular filtration rate today.  

In that world, the question becomes:

Can we maintain glymphatic–lymphatic resilience across the lifespan so that classic AD pathologies never reach a critical threshold?

⸻

5. A thought to leave the field with

If amyloid plaques are the smoke, glymphatic failure may be the blocked chimney. Antibodies can dampen the fire, but unless we restore the chimney’s structure and airflow, the house continues to fill with toxins.

The new amyloid-clearance work doesn’t merely refine our understanding of plaque biology. It forces a deeper question:

What if the most powerful Alzheimer’s interventions of the next decade are not just those that bindamyloid—but those that restore the brain’s ability to wash it away?

Designing Alzheimer’s modalities around that premise could turn “disease modification” from a statistical nuance into something patients and families can actually feel.

⸻

References (selected)

• Anderson, P. (2025). Brain’s waste clearance system implicated in dementia. Medscape Medical News. Reporting on Markus et al., Alzheimer’s & Dementia.  

• Chen, Y., Cai, J., She, Y., et al. (2025). Long-term exercise enhances meningeal lymphatic vessel plasticity and drainage in a mouse model of Alzheimer’s disease. Translational Neurodegeneration, 14, 37.  

• He, Z., & Sun, J. (2025). Clearance mechanisms of the glymphatic/lymphatic system in the brain: new therapeutic perspectives for cognitive impairment. Cognitive Neurodynamics, 19, 111.  

• Kopeć, K., et al. (2025). The therapeutic potential of glymphatic system activity to reduce the pathogenic accumulation of cytotoxic proteins in Alzheimer’s disease. International Journal of Molecular Sciences, 26(15), 7552.  

• Murdock, M. H., Yang, C.-Y., Sun, N., et al. (2024). Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature, 627, 149–156.  

• Oregon Health & Science University. (2024). Brain’s waste-clearance pathways revealed for the first time. OHSU News, summarizing Piantino et al., PNAS.  

• Wang, M., Yan, C., Li, X., et al. (2024). Non-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice. Nature Communications, 15, 1453.  

• Zhao, D., et al. (2025). Targeting the glymphatic system: Aβ accumulation and phototherapy strategies across different stages of Alzheimer’s disease. Translational Neurodegeneration.