Depressive and Biopsychosocial Frailty Phenotypes: Impact on Late-life Cognitive Disorders

Abstract

In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer’s disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality.

Understanding exogenous factors and biological mechanisms for cognitive frailty: a multidisciplinary scoping review

“…Panza et al discussed a potential link with cognition via increased cortisol levels associated with long term stress, and referred to the interplay between vascular depression, cognition, frailty and vascular burden. Panza et al, (2023) referred to a depressive frailty phenotype whereby underlying biological and physiological mechanisms overlapped in the trajectory of cognitive decline.…”

Increased Risk of Dementia after Transient Global Amnesia: A Nationwide Population-Based, Longitudinal Follow-Up Study in South Korea

“…with age, female sex, diabetes, stroke, depression, anxiety, and rural residence, which have been reported to be risk factors for dementia [26][27][28][29][30][31][32].…”

The Relationship Between Social Isolation and Cognitive Frailty Among Community-Dwelling Older Adults: The Mediating Role of Depressive Symptoms

“…50 Additionally, excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevated cortisol levels, decreased levels of insulin-like growth factor-1 (IGF-1), and testosterone, potentially serving as an endocrine mechanism underlying depression and cognitive frailty. 51 Finally, mitochondrial dysfunction can be observed in many neurodegenerative diseases and depression, which may be an important pathway in the pathophysiology of both depression and cognitive frailty. 19 This study provides a new direction for the prevention and management of cognitive frailty.…”