Loneliness and biomarkers of brain pathology in people with subjective cognitive decline

Introduction

The experience of subjective cognitive complaints (SCCs) endorsed by older people has gained attention in recent years. The self-reported perception of cognitive decline that cannot be detected on objective cognitive testing defines the clinical diagnosis of subjective cognitive decline (SCD)¹external link, opens in a new tab. SCD is thought to reflect the earliest signs of Alzheimer’s Disease (AD), with several studies showing that SCD is related to future development of dementia¹external link, opens in a new tab^–3external link, opens in a new tab. SCD has been associated with AD pathological changes, including amyloid-beta plaques, tau neurofibrillary tangles, and neurodegeneration⁴external link, opens in a new tab^–6external link, opens in a new tab. In addition, several studies have also demonstrated an association of SCD with cerebrovascular disease (CVD)⁶external link, opens in a new tab^–8external link, opens in a new tab. These findings suggest that SCD could be an early indicator of various brain pathologies that may be clinically detectable before the onset of objective cognitive impairment.

Recently, the focus has been on whether SCD not only reflects brain pathologies but also neuropsychiatric conditions such as depression. Indeed, SCD and depressive symptomatology often co-occur, most frequently later in life¹external link, opens in a new tab^,8external link, opens in a new tab^,9external link, opens in a new tab. Another neuropsychiatric symptom that is gaining attention is loneliness. Recent publications have suggested that loneliness increases during ageing and could be associated with a greater risk of dementia, adverse health outcomes, and mortality¹⁰external link, opens in a new tab^,11external link, opens in a new tab. Given that loneliness and depressive mood are closely related¹²external link, opens in a new tab^,13external link, opens in a new tab, some studies have investigated the role of loneliness in SCD, suggesting that memory complaints are more frequent in older people with loneliness¹⁴external link, opens in a new tab^–19external link, opens in a new tab. This finding highlights the role of loneliness in individuals at risk of dementia. Furthermore, it is estimated that around a third of people with dementia feel lonely²⁰external link, opens in a new tab. However, the literature for the association between loneliness and biomarkers of brain pathology is still limited. Two previous studies showed that loneliness is related to cortical amyloid burden and higher tau binding in positron emission tomography (PET) in brain areas of early tau accumulation in older adults²¹external link, opens in a new tab^,22external link, opens in a new tab.

Another common finding of aging, SCD, and dementia is the presence of cerebrovascular disease (CVD), which can be assessed on magnetic resonance imaging (MRI). An in-vivo longitudinal study showed an association between loneliness and increased volume of brain white matter signal abnormalities (WMSA)²³external link, opens in a new tab, an established MRI marker of CVD that is associated with an increased risk of cognitive impairment and dementia²⁴external link, opens in a new tab. However, a post-mortem study showed that ante-mortem feelings of loneliness were not related to CVD or AD pathology at autopsy²⁵external link, opens in a new tab. Therefore, it is important to elucidate the association of loneliness with SCD and biomarkers of AD and CVD, in-vivo.

The main goal of this study was to investigate loneliness in the context of SCD, depressive symptomatology, and biomarkers of AD and CVD in a population-based cohort of cognitively unimpaired individuals. Firstly, we investigated whether depressive symptomatology and biomarkers of AD and CVD were associated with loneliness. AD biomarkers were assessed through amyloid-beta and phosphorylated tau levels in the cerebrospinal fluid (CSF) and CVD was assessed through WMSA on MRI. We hypothesized that both depressive symptomatology and biomarkers of AD and CVD would be associated with loneliness¹²external link, opens in a new tab^,13external link, opens in a new tab^,21external link, opens in a new tab^–23external link, opens in a new tab. Secondly, we investigated whether loneliness, depressive symptomatology, and biomarkers of AD and CVD were associated with SCD. We pursued to ascertain whether the potential association between loneliness and SCD was independent of depressive symptomatology, due to the known association of depressive symptomatology with both loneliness and SCD⁸external link, opens in a new tab^,13external link, opens in a new tab. We hypothesized that both loneliness and AD and CVD biomarkers would be associated with SCD, independently of depressive symptomatology⁴external link, opens in a new tab^–7external link, opens in a new tab^,14external link, opens in a new tab. In addition, there is an emerging interest in describing the role of specific subjective cognitive complaints, e.g. memory vs. non-memory complaints²⁶external link, opens in a new tab^,27external link, opens in a new tab. Different cognitive complaints may reflect different syndromic and biomarker profiles²⁸external link, opens in a new tab^,29external link, opens in a new tab. Therefore, we investigated whether our findings would differ for memory and concentration complaints. We hypothesized that subjective memory complaints would be associated with AD pathology, as memory impairment is common in typical AD, while concentration complaints would be more associated with CVD pathology, because difficulties in concentration have been observed in people with CVD²⁷external link, opens in a new tab^,28external link, opens in a new tab.