Project Details

Description

Background
Alzheimer´s disease (AD) is predominately seen as a neurocognitive disorder, yet its clinical symptomatology goes beyond memory loss. Most affected individuals also develop psychiatric manifestations (e.g., depressive symptoms, anxiety, or apathy). While previously considered to be late occurring, there is now convincing literature reporting these symptoms already present in the earliest clinical stages of the disease. Sometimes, the psychiatric symptomatology even precedes the cognitive and constitutes the first clinical manifestation. Additionally, psychiatric manifestations have been frequently reported to be the most distressing and burdensome aspects of AD, with a lowered quality of life for the patient and its caregivers. Subsequently, AD patients with psychiatric symptoms face earlier institutionalization, which also means significant costs for society. Taken together, psychiatric manifestations of AD are clinically highly relevant.

Scientific advances have linked these psychiatric symptoms to key pathological AD hallmarks. For example, in previous BioFINDER studies we have learnt that amyloid-beta (Aβ) pathology longitudinally drives the development of increased apathy and anxiety levels in initially cognitively unimpaired older adults. Interestingly, the psychiatric manifestations were further shown to develop in parallel but still independent from the cognitive deficits. This suggests that these early symptoms do not develop as psychological reactions to a failing cognition but rather directly from brain AD pathology. In another paper, we reported an increased overall burden of psychiatric symptoms as a stronger predictor than subtle memory deficits of early tau deposits in hippocampus among cognitively unimpaired Aβ-positive individuals (e.g., possible AD).

Despite the mounting number of studies, a definite neurobiological signature of psychiatric manifestations in AD has not yet been established. For instance, it is still debated whether early psychiatric manifestations are predominately related to an accumulation of Aβ in the frontal brain areas or deposition of tau pathology in the limbic brain system (e.g., hippocampus or amygdala). Interestingly, while early increased anxiety or apathy levels in AD have quite consistently been reported as associated with key AD pathologies, reports on depressive symptoms have been much less convincing. Therefore, it can be hypothesized that distressing depressive symptoms in AD arise from other neuropathological mechanisms (e.g., inflammation, glial cell dysfunction, or endocrine abnormalities). These aspects have only rarely been studied. An increased understanding of the mechanisms behind the psychiatric symptoms in AD could potentially develop into better symptomatic intervention strategies.

Aims of the project
First, to disentangle the complex relationship between Aβ, tau, and psychiatric manifestations in the early stages of AD. Second, to investigate the role of, e.g., glial cell dysfunction, inflammation, neurotransmitter dysregulation, and endocrine dysfunction in the development of psychiatric manifestations (e.g., depression) in AD.

The project will apply a wide array of data acquired by methodologies such as Aβ- and tau-PET imaging, biofluid biomarkers, proteomics, genotyping, inflammation biomarkers, and endocrine measures already planned for in the Swedish BioFINDER study.

In short, longitudinal PET imaging allows us to explore the temporal and spatial distribution of Aβ and tau pathology in relation to the development of psychiatric symptoms (Aβ in the frontal cortex vs. tau in limbic structures).

The use of biomarkers for glial cell functioning, inflammation, and endocrine aspects, as well as proteomics and genotyping (with focus on neurotransmitter-, glia cell-, inflammation-, and endocrine-related genes or proteins), allow us to explore alternative or complemental pathophysiological underpinnings of the psychiatric symptoms in AD.
StatusFinished
Effective start/end date2023/12/012024/12/31

Funding

  • Familjen Rönströms stiftelse