image: Potential disease-modifying targets of Alzheimer’s disease include (but not limited to) amyloid (A), tau (T), neurodegeneration (N), inflammation (I), vascular injury (V), and α-synuclein (S).
Credit: ©Science China Press
Advances in medicine and economic development have extended life expectancy, accelerating population aging and increasing the prevalence of age-related diseases such as Alzheimer’s disease (AD). AD is the primary cause of dementia and ranks as the seventh leading cause of death globally. Current AD treatments predominantly address symptoms and do not reverse underlying pathology or substantially slow disease progression. In contrast, disease-modifying therapies (DMTs) target the underlying pathophysiology of AD, potentially slowing or halting disease progression.
In 2024, the Alzheimer’s Association introduced the ATNIVS framework, encompassing Amyloid-beta (Aβ), tau pathology (T), neurodegeneration (N), neuroinflammation (I), vascular injury (V), and α‑synuclein (S). This framework integrates AD-specific, non-specific, and non-AD co-pathologies into a unified system, enabling precision therapeutics across heterogeneous patient populations.
The review summarizes advances in DMTs addressing each pathological domain:
Targeting Aβ: strategies include inhibiting production (e.g., Verubecestat and Lanabecestat), promoting clearance (e.g., Aducanumab, Lecanemab, and Donanemab), and inhibiting aggregation (e.g., ALZ‑801).
Targeting tau: approaches include inhibiting expression (e.g., BIIB080), inhibiting aggregation (e.g., LMTM), stabilizing microtubules (e.g., TPI‑287), and attenuating aberrant post‑translational modifications (e.g., Nicotinamide) to reduce neurofibrillary tangle formation.
Targeting neurodegeneration: strategies include stem cell therapy and neuroprotective agents (e.g., Simufilam, Edaravone, and Levetiracetam) to repair and preserve neuronal function.
Targeting neuroinflammation: TREM2 receptor agonists (e.g., AL002), immunomodulators (e.g., Masitinib), and GLP‑1 receptor agonists (e.g., Semaglutide).
Targeting cerebrovascular injury: agents such as Cilostazol, Rapamycin, and the Chinese herbal compound Yangxue Qingnao Wan aim to promote cerebral blood flow, and modulate endothelial or metabolic function.
Targeting α‑synuclein: examples include Nilotinib and Ambroxol.
The team further notes that, despite substantial evidence from preclinical studies supporting the mechanisms of these therapeutic targets and their promising effects, very few candidate drugs have demonstrated significant efficacy in halting or slowing disease progression in clinical trials. This likely reflects the multifactorial etiopathogenesis and pathophysiology of AD; beyond Aβ and tau, comorbid processes contribute to disease advancement, rendering single‑target strategies insufficient.
Future directions include multi‑target combination therapy and biomarker‑driven precision stratification. Applying the ATNIVS framework to AD DMT development may accelerate the implementation of mechanism‑matched interventions. This approach can also facilitate precision therapeutics across diverse patient subgroups.