Alzheimer's disease (AD) continues to be a pressing global health concern, with cases projected to reach 153 million by 2050. This article critically examines current and emerging therapeutic approaches, highlighting both their limitations and potential.

Understanding AD and Current Treatment Challenges

AD manifests as a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and hallmark pathological features such as beta-amyloid (Aβ) plaques and tau tangles. While familial AD (FAD) accounts for only 1% of cases, most patients present with sporadic AD (SAD), driven by complex risk factors including genetics, age, and lifestyle.

Currently approved treatments focus on symptomatic relief rather than disease modification. Acetylcholinesterase inhibitors like donepezil and rivastigmine provide modest cognitive improvements (e.g., a -2.67 point ADAS-Cog difference with donepezil over 26 weeks) but fail to halt disease progression. Similarly, memantine, with small effect sizes (SMD = −0.09 to −0.27), offers limited benefits in moderate to severe AD. These drugs often come with side effects or limited accessibility due to high costs.

Monoclonal Antibodies: Limited Gains, Significant Risks

Monoclonal antibodies targeting Aβ, including lecanemab and donanemab, have recently gained FDA approval. However, their clinical impact remains modest, with improvements of only 0.45 and 0.7 points on the CDR-SOB scale compared to placebo. Moreover, these therapies carry substantial risks, with 23–57% of patients experiencing amyloid-related imaging abnormalities, such as cerebral edema and hemorrhage.

Beyond Aβ: Alternative Pathways to Target Neurodegeneration

The limited success of Aβ-focused therapies has prompted exploration of alternative mechanisms:

Inflammation and Oxidative Stress: Chronic neuroinflammation and oxidative stress are prevalent in both FAD and SAD. Cytokines like TNFα and IL-1β, released by activated astrocytes and microglia, exacerbate neuronal damage. While TNFα inhibitors and MAPK p38 inhibitors show promise in other inflammatory conditions, their application in AD is hampered by poor brain penetration and side effects.

Rosiglitazone: Initially tested for its role in mitigating AD risk associated with diabetes, this PPARγ agonist failed in clinical trials when administered to patients with established dementia, underscoring the importance of early intervention.

Ladostigil: A Promising Multi-Mechanistic Agent

Ladostigil, a small molecule with neuroprotective and anti-inflammatory properties, has emerged as a potential therapeutic candidate. By crossing the blood-brain barrier, ladostigil reduces oxidative stress, suppresses pro-inflammatory cytokine release, and prevents memory decline and brain atrophy in preclinical models.

A phase 2 trial in patients with mild cognitive impairment (MCI) demonstrated:

• A slower decline in cognitive function and brain volume, particularly in ApoE4 non-carriers, where progression rates were halved compared to placebo (p = 0.028).
• Reduced atrophy in the hippocampus and whole brain.
• A safety profile comparable to placebo, with no significant adverse effects.

Notably, the conversion rate to dementia in the placebo group (7% per year) was lower than the historical estimate of 15%, possibly due to the trial's focus on early-stage patients.

Clinical Implications and Future Directions

The findings highlight the need for earlier intervention in AD, particularly at the MCI stage, where therapies like ladostigil may be most effective. Future trials should incorporate:

• More sensitive cognitive assessments.
• Biomarkers for inflammation and oxidative stress.
• Stratification based on genetic risk factors, such as ApoE4 status.

While current treatments provide limited benefits, emerging agents like ladostigil represent a shift toward multi-mechanistic approaches, offering new hope for AD patients and their families.

Conclusion

For physicians, this critical appraisal underscores the evolving landscape of AD therapeutics. While challenges remain, innovative strategies targeting inflammation, oxidative stress, and neuroprotection could redefine treatment paradigms, particularly for early-stage disease. Early identification and intervention remain paramount in optimizing outcomes for patients with AD.