The Future of Alzheimer's Disease Drug Development

For drug developers across the neuroscience landscape, the Society for Neuroscience (SfN) annual meeting has become one of the most consequential scientific events of the year. Although SfN spans the full breadth of brain and nervous system research, for the purpose of this analysis I focus specifically on Alzheimer’s Disease (AD), which remains one of pharma’s highest-priority therapeutic areas, driven by demographic pressure, massive unmet need, and a market large enough to support multiple parallel mechanisms. Yet despite this prioritisation, the field has struggled for decades to convert mechanistic hypotheses into durable clinical benefit. What makes SfN uniquely valuable in this context is its immediacy. Unlike peer-reviewed literature or late-stage conferences, SfN surfaces the earliest mechanistic signals, unpublished, predominantly preliminary, and consistently predictive of where the science, and therefore industry portfolios, are heading.

This year, the tone was encouragingly optimistic. In her keynote session, Tara Spires-Jones captured a sentiment that threaded through the meeting: “I think for the first time in 25 years in the field, I can say it’s hopeful… I think we will in our lifetimes see at least better disease-modifying drugs.” That optimism is notable given the contentious backdrop, accelerated approvals for anti-amyloid antibodies, modest effect sizes, risk-benefit disputes, payer reluctance, and a regulatory landscape still divided over how to weigh biomarker shifts against clinical outcomes. Yet precisely because the limitations of amyloid-centric approaches have become so clear, the field is undergoing a rapid expansion toward non-amyloid targets, circuit-level biology, and systems-level mechanisms that better reflect the complexity of Alzheimer’s Disease.

SfN is where these shifts become visible first. Not to mention industry release of early preclinical insights based on patent-backed active programs, as well as key clinical data updates. This year, the meeting revealed three major currents likely to define the next wave of Alzheimer’s drug development: a reframing of AD biology around multi-system interactions; a surge in novel targets beyond amyloid and tau; and a biomarker landscape undergoing a structural transformation, especially around synaptic and immune-derived indicators.

A shift from linear cascades to interacting cellular systems

One of the clearest biological signals at SfN was the continued move away from a linear amyloid → tau → neurodegeneration model toward a view of Alzheimer’s as a disorder of interacting cellular systems. Neuroinflammation, microglial phenotype switching, astrocytic engagement, synapse-glia interactions, and immune-brain crosstalk were presented not as secondary modifiers but as central nodes in disease initiation and progression.

This shift was reinforced in Spires-Jones’ keynote, particularly the evidence that glia, microglia and astrocytes, actively engulf synapses near plaques in human postmortem tissue. Synaptic proteins appear inside glia far more frequently near plaques than in distal tissue (Tzioras et al., 2023 Cell Rep), indicating that synaptic elimination is not simply a downstream correlate of pathology but a mechanistically important event. Evidence from both human tissue and animal models suggests that glia remove synapses from viable neurons, not only from apoptotic or dying neurons, supporting the idea of direct synaptic attrition (Tzioras et al., 2023 Nature Reviews Neurology). As she summarized it, “We think that Aβ likely is contributing to synapse loss indirectly via glial interactions.” The conclusion is consistent across animal models and post-mortem human tissue: amyloid contributes to synaptic failure both directly, by binding hyperactive synapses, and indirectly, by recruiting glia to phagocytose vulnerable ones (Pickett et al., 2019 Cell Rep, Tzioras et al., 2023 Cell Rep).

This raises a new translational question, one with industry implications. If anti-amyloid antibodies bind synaptic Aβ, are they also tagging those synapses for Fc receptor–mediated clearance? That could be beneficial if it removes dysfunctional, hyperactive synapses, or harmful if it accelerates loss of functional ones. The field does not yet know. But the presence of this uncertainty underscores the importance of synaptic-level biomarkers and outcome measures for next-generation therapeutics.

Synaptic dysfunction as the actionable early phenotype

Across dozens of posters, synaptic dysfunction, not neuronal death, emerged as the earliest and most actionable pathological event. Soluble oligomeric Aβ and tau consistently appeared as the toxic species, in line with foundational work from Klein and Selkoe (Lambert et al., 1998 PNAS; Shankar et al., 2008 Nature Medicine). Hyperexcitability, loss of inhibitory synapses around plaques, and activity-dependent vulnerability were repeated themes. The implication for drug development is straightforward. Therapies stabilizing synaptic homeostasis, limiting oligomer toxicity, or preserving inhibitory/excitatory balance may have more impact if deployed early in the disease course.

Tau biology: propagation, synaptic accumulation, and trans-synaptic spread

Tau pathways have accelerated rapidly. Spires-Jones emphasized that tau sits closer than amyloid to cognitive decline and synapse loss, making it an appealing therapeutic axis. But her message was not that tau replaces amyloid, rather, it complements a more holistic view of the disease, one that will eventually demand combination approaches. She highlighted emerging evidence that tau spreads trans-synaptically, accumulates in synapses in both mice and human AD tissue, and interacts with potential molecular partners such as BIN1 (de Calignon et al., 2012 Neuron, Liu et al., 2012 PLoS ONE, Davies et al., 2023 Brain and Neuroscience Advances, Crotti et al., 2019 Scientific Rep). Her lab’s use of FRET to show tau–BIN1 proximity in synapses suggests that protein-protein interactions may mediate tau release and propagation, opening the door to novel target classes beyond aggregation inhibitors.

Other mechanistic contributors: lipid metabolism, APOE biology, mitochondrial energetics, vascular dysfunction

Beyond amyloid and tau, SfN showcased extensive work on APOE signalling, lipid metabolism, mitochondrial stress, and cerebrovascular integrity. These pathways appeared frequently across poster sessions, highlighting a field moving toward multi-factorial disease models. Mitochondrial energetics and metabolic vulnerability, particularly sex-specific ones, appeared repeatedly. Vascular impairment and BBB/BCSFB dysfunction were discussed as both upstream and downstream contributors to synaptic failure.

A new dimension: the brain–immune ecosystem and systemic immune decline

A defining addition to this year’s mechanistic picture came from Michal Schwartz’s talk on the brain–immune ecosystem. Her work challenges the long-held assumption of immune privilege, showing that the brain relies on peripheral immune cells for maintenance and repair, particularly monocyte-derived macrophages and T-regulatory cells. These cells access the CNS through the blood-CSF barrier and meninges, not the BBB, and are required for resolving chronic neuroinflammation (Baruch et al., 2014 Science). Crucially, in both mouse models and early human data, immune dysfunction appears before cognitive symptoms, suggesting that systemic immune exhaustion is a driver, rather than a consequence, of Alzheimer’s pathology (Baruch et al., 2014 Science, Baruch et al., 2020 Nature Aging).

This reframes neuroinflammation. Suppressing systemic immunity with anti-inflammatory drugs may paradoxically prevent the recruitment of immune cells needed to resolve CNS inflammation. In Schwartz’s words, “When you treat systemically with anti-inflammatory drugs, you suppress the immune system that you need to recruit to the brain to reduce inflammation… it’s almost paradoxical.” Her work provides a mechanistic rationale for immune-rejuvenation strategies, including PD-1/PD-L1 blockade, which appears to recruit monocyte-derived macrophages with disease-resolving activity, clear senescent microglia, and exert sustained benefit despite transient drug exposure.

For industry, this marks a major conceptual shift: Alzheimer’s may be as much a systemic immunological disorder as a brain-centric one.

Microglial modulation remained dominant, TREM2 activation, CSF1R tuning, and APOE-related pathways were common themes. But new target categories are emerging.

Synaptic opsonins and “eat-me” signals

One set of targets likely to grow rapidly is synaptic opsonin pathways, particularly MFGE8, which tags synapses via externalized phosphatidylserine and drives glial engulfment. Spires-Jones highlighted this as one of the most promising mechanistic directions, noting that multiple groups (and at least one stealth-mode company) are pursuing related pathways. These systems offer a direct way to tune synaptic pruning, either blocking maladaptive clearance or enhancing pathological synapse removal.

Tau propagation machinery: BIN1 and protein–protein interaction targets

With tau propagation now viewed as a key mechanism of disease spread, protein-protein interaction inhibitors, historically difficult but increasingly tractable, may represent a new domain for AD drug discovery.

Immune-rejuvenation targets: PD-1/PD-L1 and monocyte recruitment axes

The most conceptually novel category came from Schwartz’s work. Immune checkpoint pathways, PD-1, PD-L1, PD-L2, appear to regulate the recruitment of beneficial macrophages and Tregs to the brain. Her group’s preclinical data show that:

• Anti-PD-1/PD-L1 treatment improves cognition in amyloid and tau models (Baruch et al., 2016 Nature Medicine, Rosenzweig et al., 2019 Nature Communications).
• Efficacy requires monocyte-derived macrophages and depends on CCR2-mediated recruitment (Rosenzweig et al., 2019 Nature Communications, Dvir‑Szternfeld et al., 2022 Nature Aging).
• Treatment appears to clear senescent microglia and may bypass TREM2-related genetic deficiencies (Dvir‑Szternfeld et al., 2022 Nature Aging).
• A transient exposure produces long-lasting benefit (Baruch et al., 2016 Nature Medicine).

This represents a mechanistically refreshing approach, neither amyloid nor tau removal, but immune ecosystem recalibration.

Beyond conceptual advances, several exploratory programs are beginning to translate these immune-rejuvenation ideas into early-stage interventions. Examples include approaches aligned with Schwartz’s mechanistic insights.

Figure 1: Repurposing Momentum: Alzheimer’s at the Centre

Beyond novel targets, SfN abstracts reveal a striking trend, drug repurposing across multiple disease indications. Our analysis shows that compounds originally developed for oncology, immunology, and metabolic disorders are increasingly being explored for neurodegenerative conditions. Among these, Alzheimer’s Disease dominates repurposing efforts, reflecting both unmet need and mechanistic overlap with systemic pathways such as immune modulation and metabolic resilience.

The biomarker landscape may be the most transformative area for industry. Synaptic biomarkers in particular appear poised to enter clinical-stage utility.

SV2A PET imaging and the emergence of synaptic density as a quantifiable biomarker

Spires-Jones reviewed a series of converging datasets validating SV2A PET as a measure of synaptic density. The key point is that declines in SV2A PET likely reflect true synapse loss, not loss of SV2A protein in remaining synapses. Evidence includes correlations with synaptophysin across multiple regions, peptide-level mass spectrometry quantification, immunogold EM showing preserved SV2A per synapse, and high-resolution imaging in human brain homogenates (Tzioras et al., 2023 Cell Rep). The first antemortem/postmortem comparison is already underway, potentially a decisive moment for synaptic biomarkers.

If validated, synaptic density could become a major inclusion criterion, staging tool, and early efficacy endpoint across future AD trials, complementing Amyloid PET and plasma tau.

Immune-derived biomarkers

Schwartz’s work suggests that systemic immune exhaustion markers: PD-1 expression, leukocyte trafficking defects at the choroid plexus; circulating suppressor cell signatures, may emerge as early indicators of disease trajectory or treatment response. For immunomodulatory therapies, these biomarkers could provide stratification tools unavailable in current amyloid-focused paradigms.

Overall, the 2024–2025 wave of mechanistic work presented at SfN seems to signal a gradual redefinition of Alzheimer’s biology. The field appears to be moving away from an amyloid-exclusive framework. For drug developers, several themes could shape near-term strategy.

First, glial-modifying and immune-rejuvenation therapies may gain momentum, particularly those engaging microglial activation states, monocyte recruitment pathways, or immune checkpoint modulation. Second, synapse-centric approaches could become increasingly important, either as standalone strategies or in combination with amyloid or tau-directed agents. Third, combination therapies may emerge more prominently, as the field acknowledges that no single mechanism fully captures the disease’s complexity. Fourth, biomarker strategies are likely to evolve toward synaptic, immune, and circuit-level measures that align with early pathophysiology and offer greater sensitivity for detecting treatment effects.

For pharma, the high-risk/high-reward category might include immune checkpoint modulation, synaptic opsonin blockade, tau propagation interruption, and microglial senolytic approaches. These mechanisms are scientifically compelling but remain operationally early-stage, suggesting areas of competitive white space rather than guaranteed success.

The central message is increasingly clear: Alzheimer’s is not a single-pathway disease but an ecosystem disorder spanning brain and periphery. As therapeutic approaches expand to match this complexity, companies that succeed will likely be those able to integrate synaptic biology, immune-brain interactions, and circuit-level readouts into coherent, mechanistically informed development programs. The next 12 months may reveal which of these signals gain traction and which begin to shape the therapeutic strategies of the next decade.