Future Therapeutic Strategies for Alzheimer's Disease: Focus on Behavioral and Psychological Symptoms

Abstract

Alzheimer's disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer's disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

Keywords: Alzheimer’s disease; neuropsychiatric symptoms; pharmacotherapy; psychomotor symptoms; social function.

Figure 1

Behavioral and Psychological Symptoms in Alzheimer’s Disease [15,16,17].

Figure 2

Summary of mechanism of candidate drugs for NPS treatment of AD. M1/M4 Rc; M1M4 muscarinic acetylcholine receptor, α1 Rc; alpha-1 adrenergic receptor, α2 Rc; alpha-2 adrenergic receptor, σ1 Rc; sigma 1 receptor, α3β4 nAChR; α3β4 nicotinic acetylcholine receptor, NA Rc; noradrenergic receptor, DRD2 Rc; Dopamine receptor D2, DRD3 Rc; Dopamine receptor D3, 5-HT1A Rc; serotonin 1A receptor, 5-HT2A Rc; serotonin 2A rèceptor, 5-HT6 Rc; serotonin 6 receptor, OX2 Rc; orexin 2 receptor, DM; Dextromethorphan. Each color represents the targets for each candidate drug.