Over the past three decades, AD drug development has largely centered on the Aβ cascade hypothesis, with strategies designed to reduce Aβ production, inhibit aggregation, or promote clearance. Although early anti-Aβ strategies failed to yield significant cognitive benefits in clinical trials, continuous mechanistic optimization ultimately led to the development of anti-Aβ monoclonal antibodies. Aducanumab, Lecanemab, and Donanemab have reduced amyloid plaque burden and modestly slowed clinical progression in early AD, providing the first evidence that disease-modifying effects can be achieved in this disorder^[3].

Clinical experience with Aβ-targeted therapy has also clarified the limitations of single-target strategies. First, Aβ deposition typically begins more than a decade before symptom onset, whereas cognitive decline is more closely associated with tau spread, synaptic dysfunction, and neuronal loss. Clearing Aβ alone is therefore unlikely to reverse an established neurodegenerative process. Second, AD is not driven by a single molecular abnormality, but by interactions among Aβ, tau, neuroinflammation, vascular dysfunction, and metabolic alterations. Although anti-Aβ therapy can reduce a major pathological burden, it does not directly address parallel or downstream processes, which may help explain its limited clinical benefits. Thus, the success of Aβ clearance both validates the targeting of key pathological nodes and points toward a broader strategy: coordinated modulation of multiple disease-driving networks. Rather than disproving the amyloid hypothesis, these findings suggest that amyloid removal alone may be insufficient once downstream pathological cascades become self-sustaining.

For many years, APOE ε4 has been recognized as a major genetic risk factor for sporadic AD. More recent research has positioned APOE as a pathogenic network hub linking Aβ, tau, neuroinflammation, and cerebrovascular dysfunction. APOE4 not only impairs Aβ clearance but also promotes tau aggregation and propagation and sustains microglial activation by altering cholesterol metabolism, lysosomal function, and blood-brain barrier integrity. APOE therefore acts across multiple stages of disease progression, extending beyond its established role in amyloid deposition. Mechanistic studies further indicate that APOE3 Christchurch modulates microglial responses and suppresses Aβ-induced tau seeding and propagation, providing strong human genetic evidence that APOE functions upstream of several interconnected pathological pathways rather than solely through amyloid metabolism.

These findings have stimulated the development of APOE-targeted therapies. For instance, LX1001 (AAV-mediated APOE2 gene replacement) and antisense oligonucleotides (ASOs) targeting APOE4 have entered preclinical and early clinical investigation. These approaches aim to reduce toxic APOE4-associated effects or restore the protective functions of APOE2, with the potential to influence Aβ deposition, neuroinflammation, and neuronal injury rather than a single pathological marker. Recent work also suggests that interventions may need to account for cell-type-specific APOE4 functions in astrocytes, microglia, and neurons, moving the field from a general risk gene framework toward more precisely defined combination strategies.

Neuroinflammation is increasingly recognized as a key contributor to AD progression. Aβ deposition can activate microglia and induce chronic inflammatory signaling through pathways involving TREM2, the NLRP3 inflammasome, and the complement system, thereby promoting aberrant tau phosphorylation, synaptic loss, and neuronal injury. Genetic studies have further shown that loss-of-function variants in TREM2 increase AD risk. TREM2 regulates not only microglial phagocytosis and Aβ clearance but also lipid metabolism and cellular energy homeostasis, making it an important link among Aβ pathology, neuroinflammation, and neurodegeneration. The NLRP3 inflammasome serve as an amplifier of inflammatory signaling by promoting the release of cytokines such as IL-1β and facilitating tau propagation. Clinical experience, however, underscores the complexity of immune modulation. Despite encouraging preclinical findings, the phase II trial of the TREM2 agonist AL002 failed to achieve its primary endpoint, suggesting that response may depend on disease stage, immune status, and patient stratification. These observations have shifted attention from generalized immune activation toward context-dependent modulation of neuroimmune responses^[6].

A notable recent advance is the identification of clonally expanded CD8⁺ T cells in the AD brain. Studies have detected antigen-specific CD8⁺ T cell clones associated with tau pathology, with clonal expansion occurring after CXCL16-CXCR6-mediated trafficking to the cerebrospinal fluid^[7].

cDC1 cells can take up and present tau-related antigens, activate CD8⁺ T cells, and support their sustained expansion, thereby intensifying intracerebral inflammation and tau pathology. Conversely, genetic deletion or pharmacological inhibition of cDC1 has been reported to reduce tau deposition, attenuate neuroinflammation, and limit neuronal injury. Together, these findings support a mechanistic framework involving a cDC1-CD8⁺ T-cell axis in AD and broaden the study of neuroinflammation from microglia-centered innate immunity to interactions between innate and adaptive immune responses.

As disease-modifying therapies enter clinical practice, AD treatment strategies are shifting from diagnosed-based decisions toward biomarker-guided stratification. Plasma p-tau217 has emerged as a key biomarker for identifying AD pathology and predicting Aβ-PET positivity, supporting early detection, participant stratification, and assessment of eligibility for anti-Aβ therapy. MTBR-tau243 provides a more direct measure of neurofibrillary tangle burden. Plasma and CSF MTBR-tau243 levels increase in Aβ-positive mild cognitive impairment (MCI) and AD dementia, showing high consistency with tau-PET, with reported AUC values of 0.92-0.95. These findings support its potential role as a "T" biomarker within the A/T/(N) framework. Importantly, MTBR-tau243 may help identify individuals with relatively low tau burden, providing more refined enrollment criteria for trials combining anti-Aβ and anti-tau approaches^[11].

Clinical trial findings support this stratification framework. In TRAILBLAZER-ALZ 2, patients with low or intermediate tau burden showed greater slowing of clinical decline with donanemab than those with high tau burden, suggesting that pathological staging may predict treatment response more effectively than clinical staging alone. These results support earlier intervention, more precise stratification, and biomarker-informed evaluation of combined approaches.