Therapeutic Strategies for Alzheimer’s Disease

Therapeutic approaches for Alzheimer’s disease (AD) are guided by four disease characteristics: amyloid plaques, neurofibrillar tangles (NFT), neurodegeneration, and dementia. Amyloid plaques are composed largely of 4 kDa β-amyloid (Aβ) peptides, with the more amyloidogenic, 42 amino acid form (Aβ42) as the primary species. Because multiple, rare mutations that cause early-onset, familial AD lead to increased production or aggregation of Aβ42, amyloid therapeutics aim to reduce the amount of toxic Aβ42 aggregates. Amyloid-based therapies include γ-secretase inhibitors and modulators, BACE inhibitors, aggregation blockers, catabolism inducers, and anti-Aβ biologics. Tangles are composed of paired helical filaments of hyperphosphorylated tau protein. Tau-based therapeutics include kinase inhibitors, microtubule stabilizers, and catabolism inducers. Therapeutic strategies for neurodegeneration target multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative damage, and inflammation or stimulation of neuronal viability. Although not disease modifying, cognition enhancers are important to treat the symptom of dementia. Strategies for cognition enhancement include cholinesterase inhibitors, and other approaches to enhance the signaling of cholinergic and glutamatergic neurons. In summary, plaques, tangles, neurodegeneration and dementia guide the development of multiple therapeutic approaches for AD and are the subject of this review.