As the global population ages, Alzheimer’s disease (AD) continues to be a formidable challenge, not only due to its hallmark cognitive decline but also because of the complex neuropsychiatric symptoms that accompany its progression. Among these, anxious–depressive symptoms and sleep disturbances emerge as pervasive issues that significantly impact patients’ quality of life and may hold critical clues about the disease’s underlying mechanisms. Recent research advances have begun to unravel the intricate relationships between these neuropsychiatric manifestations, AD biomarkers, and cognitive deterioration, opening new avenues for understanding and potentially intervening in this devastating condition.
Alzheimer’s disease has long been characterized primarily by progressive memory loss and cognitive dysfunction, with amyloid-β plaques and tau neurofibrillary tangles standing as the neuropathological hallmarks. Yet, the clinical presentation of AD is not restricted to cognitive impairment alone. Neuropsychiatric symptoms such as anxiety, depression, and disturbances in sleep architecture frequently precede or accompany the cognitive changes, sometimes manifesting years before definitive diagnosis. This temporal emergence raises critical questions regarding whether these symptoms are merely epiphenomena of neurodegeneration or active contributors to the pathological cascade.
To delve into this complex dynamic, researchers have been investigating the associations between anxious–depressive symptoms, sleep disturbances, and classical AD biomarkers at various stages of the disease spectrum—from preclinical phases to mild cognitive impairment (MCI) and full-blown dementia. These biomarkers include amyloid-β deposition, tau pathology, and neurodegeneration quantifiable via neuroimaging and cerebrospinal fluid analyses. Understanding how these neuropsychiatric symptoms correlate with biological markers and cognitive deficits can illuminate whether they serve as risk factors, early indicators, or downstream effects of AD.
One pivotal line of inquiry examines the bidirectional relationships between anxious–depressive symptoms and AD pathology. Chronic anxiety and depression are known to exert deleterious effects on neuroplasticity, hypothalamic-pituitary-adrenal (HPA) axis regulation, and inflammatory processes. These factors, in turn, may exacerbate amyloid and tau accumulation or accelerate neuronal loss. Conversely, emerging pathology in brain regions implicated in mood regulation—such as the hippocampus, amygdala, and prefrontal cortex—might precipitate anxious–depressive symptoms. Disentangling cause from consequence, however, requires longitudinal studies employing sensitive biomarker assessments alongside detailed neuropsychiatric evaluations.
Sleep disturbances present another compelling piece of the puzzle. Sleep plays a critical role in brain homeostasis, including the glymphatic clearance of neurotoxic metabolites like amyloid-β. Disrupted sleep patterns, including insomnia, fragmented sleep, and altered sleep architecture, have been associated with increased amyloid burden and tau pathology in both animal models and humans. The mechanistic basis for this association may lie in impaired clearance mechanisms, heightened neuroinflammation, and altered circadian rhythms, all of which can potentiate neurodegenerative processes. Importantly, sleep disturbances are prevalent throughout the AD continuum and are linked to faster cognitive decline.
Evaluating the interplay between these symptoms and biomarkers, researchers propose integrative models that conceptualize anxious–depressive symptoms and sleep disturbances not just as byproducts of neurodegeneration but as interactive components in disease propagation. These models suggest that mood and sleep disruptions may exacerbate AD pathology and cognitive impairment via chronic stress pathways, neuroinflammation, synaptic dysfunction, and dysregulation of neural circuits. At the same time, AD-related neuropathology may disrupt neural substrates governing mood and sleep, creating a vicious cycle that accelerates disease progression.
Recent studies utilizing advanced neuroimaging techniques—such as positron emission tomography (PET) scans targeting amyloid and tau proteins—and fluid biomarkers reinforce the associations between neuropsychiatric symptoms and specific pathological signatures. For example, increased tau deposition within medial temporal lobe structures correlates with higher depression scores, while amyloid accumulation is linked with both anxiety and impaired sleep quality. These findings emphasize regional vulnerability patterns and support a network-based understanding of AD symptomatology.
From a clinical perspective, recognizing anxious–depressive symptoms and sleep disturbances as potential modifiable risk factors offers promising therapeutic implications. Interventions targeting mood disorders and improving sleep quality may not only alleviate patient suffering but also slow down or alter the trajectory of cognitive decline. Behavioral therapies, pharmacological approaches, and emerging neuromodulatory techniques present avenues for integrated treatment strategies that address these often-overlooked symptoms.
Moreover, incorporating assessments of mood and sleep disturbances into routine clinical evaluations and research protocols could enhance early detection of individuals at high risk for progression to AD dementia. These symptoms, especially when emerging alongside biomarker evidence of amyloid or tau pathology, could serve as valuable indicators prompting timely intervention. The multidimensional nature of AD necessitates a holistic framework that considers cognitive, emotional, and physiological domains in concert.
Scientific evaluation is also advancing into genetic and molecular underpinnings linking mood and sleep regulation with AD pathology. Investigations into gene variants affecting neurotransmitter systems, circadian rhythm genes, and stress response pathways are uncovering biological substrates that may predispose individuals to both neuropsychiatric symptoms and neurodegeneration. Integrating these molecular insights with clinical and biomarker data will refine models of AD etiology and progression.
The societal burden of AD, compounded by comorbid neuropsychiatric symptoms, underscores the urgency of addressing these intertwined aspects. Sleep disturbances and depressive symptoms contribute to caregiver stress, increased healthcare utilization, and diminished quality of life, amplifying the human and economic toll of dementia. Targeted interventions have the potential to mitigate these effects, enhancing patient well-being and potentially delaying institutionalization.
Looking toward the future, interdisciplinary research combining neurology, psychiatry, sleep medicine, and neuroimaging will be essential to unraveling the complex web connecting anxious–depressive symptoms, sleep disturbances, and AD pathology. Large-scale longitudinal studies with diverse populations and multimodal biomarker assessments will clarify causal relationships and identify critical windows for intervention.
Ultimately, the emerging narrative portrays anxious–depressive symptoms and sleep disturbances as integral components of Alzheimer’s disease rather than peripheral symptoms. Their interactive roles with AD biomarkers highlight mechanistic pathways that can be harnessed for diagnostic and therapeutic gains. By reframing these neuropsychiatric manifestations within the broader disease model, researchers and clinicians step closer to comprehensive management strategies that address both mind and brain in Alzheimer’s disease.
The challenge now lies in translating these scientific insights into clinical practice, developing interventions that can effectively target mood and sleep disturbances in the context of evolving AD pathology. Personalized medicine approaches, informed by biomarker profiles and symptomatology, could optimize patient outcomes, delaying progression and improving quality of life. As research continues to illuminate these multifaceted connections, the hope is that the silent suffering associated with anxious–depressive symptoms and sleep disruption in Alzheimer’s disease will be met with effective remedies grounded in deep scientific understanding.
In this rapidly evolving field, the integration of biological, clinical, and psychosocial dimensions of Alzheimer’s disease promises to revolutionize how the scientific community approaches neuropsychiatric symptoms within neurodegenerative contexts. Decoding the language of mood and sleep disturbances in AD not only enriches our understanding of pathophysiology but also empowers the design of innovative treatment paradigms with the potential to alter disease trajectories fundamentally.
Subject of Research: Neuropsychiatric manifestations (anxious–depressive symptoms and sleep disturbances) and their interactions with Alzheimer’s disease biomarkers and cognitive decline.
Article Title: Anxious–depressive symptoms and sleep disturbances across the Alzheimer disease spectrum.
Article References:
Chai, Y., Shokri-Kojori, E., Saykin, A.J. et al. Anxious–depressive symptoms and sleep disturbances across the Alzheimer disease spectrum. Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00416-4
Image Credits: AI Generated
