What are the new biologics for Alzheimer's disease (AD) and is there evidence for using lithium orotate?

New Biologics for Alzheimer's Disease and Evidence for Lithium Orotate

The most promising new biologics for Alzheimer's disease are monoclonal antibodies targeting amyloid pathology, while there is insufficient high-quality evidence supporting lithium orotate use for AD treatment or prevention.

Current Biologics for Alzheimer's Disease

Monoclonal Antibodies Targeting Amyloid Pathology

Recent FDA approvals have focused on monoclonal antibodies that target amyloid beta plaques:

• Aducanumab (Aduhelm): First anti-amyloid antibody approved under accelerated pathway
• Lecanemab (Leqembi): Targets soluble and insoluble forms of amyloid beta
• Donanemab: Recently showed positive results in clinical trials

These biologics work by binding to and removing amyloid beta plaques from the brain, potentially slowing cognitive and functional decline in early stages of Alzheimer's disease 1.

Patient Selection for Biologic Therapies

Appropriate patient selection is critical and requires:

1. Confirmation of amyloid pathology: Either through:

   • CSF biomarkers (Aβ42/Aβ40 ratio)
   • Amyloid PET imaging
   • Emerging blood-based biomarkers (plasma Aβ42/Aβ40, p-tau181, p-tau217) 2

2. Disease stage: Most effective in early stages (MCI or mild dementia) 1

3. Exclusion criteria: Patients with significant cerebrovascular disease or those on anticoagulation therapy due to risk of ARIA (Amyloid-Related Imaging Abnormalities)

Emerging Blood-Based Biomarkers

Blood-based biomarkers are revolutionizing AD diagnosis and treatment monitoring:

• Amyloid markers: Plasma Aβ42/Aβ40 ratio (though with smaller effect size than CSF) 2
• Tau markers: Phosphorylated tau species (p-tau181, p-tau217, p-tau231) - currently the most accurate blood biomarkers 2
• Neurodegeneration markers: Neurofilament light (NfL) and brain-derived tau 1
• Astrogliosis marker: Glial fibrillary acidic protein (GFAP) - shows promise as an early marker of amyloid pathology 1

These biomarkers are increasingly being used as pre-screening tools for clinical trials and may soon help determine eligibility for biologic therapies in clinical practice 1.

Evidence for Lithium in Alzheimer's Disease

Preclinical Evidence

Lithium has shown several potentially beneficial mechanisms in preclinical studies:

• Reduces amyloid and tau pathology
• Inhibits glycogen synthase kinase-3 beta (GSK3B), a key enzyme in tau hyperphosphorylation
• Stabilizes calcium homeostasis
• Enhances synaptic plasticity
• Increases brain-derived neurotrophic factor (BDNF)
• Provides neuroprotective effects 3, 4

Clinical Evidence

Despite promising preclinical data, clinical evidence for lithium in AD is limited:

• A small placebo-controlled trial in patients with amnestic mild cognitive impairment showed that long-term lithium treatment may slow progression of cognitive deficits and attenuate tau hyperphosphorylation 4
• A study of low-dose lithium for agitation in AD patients found no significant change in BDNF levels or improvement in cognitive function 5

Lithium Orotate Specifically

There is a notable absence of high-quality clinical studies specifically examining lithium orotate (as opposed to prescription lithium carbonate or citrate) for AD in the current evidence base. Key considerations:

• Lithium orotate is available as a dietary supplement but is not FDA-approved for AD treatment
• No clinical trials have established its efficacy, optimal dosing, or safety profile for AD
• It lacks standardized formulations and quality control compared to prescription lithium

Clinical Implications and Recommendations

1. For diagnosis and treatment planning:

   • Comprehensive cognitive assessment remains essential
   • Consider biomarker confirmation of AD pathology before initiating biologic therapies
   • Blood-based biomarkers may soon provide a less invasive screening option before more expensive or invasive testing 2

2. Regarding lithium:

   • Current evidence does not support the routine use of any lithium formulation, including lithium orotate, for AD treatment or prevention
   • Patients interested in lithium should be directed toward clinical trials rather than self-medication with supplements
   • If considering lithium, prescription formulations with established pharmacokinetics and safety monitoring would be preferable to unregulated supplements

3. Future directions:

   • Combination therapies targeting multiple pathological mechanisms may prove more effective than single-target approaches 6
   • Additional well-designed long-term trials are needed to establish lithium's efficacy and safety in AD prevention or treatment 6

Cautions and Limitations

• Biologic therapies for AD are extremely expensive and may not be covered by insurance
• These treatments slow but do not reverse disease progression
• ARIA is a significant adverse effect of anti-amyloid antibodies requiring MRI monitoring
• Lithium has a narrow therapeutic window and potential toxicity, requiring careful monitoring if used clinically
• Supplement forms of lithium lack standardization and regulatory oversight

The field of AD therapeutics is rapidly evolving, with biomarker-guided treatment selection becoming increasingly important for optimizing outcomes and minimizing risks.