Investigating the association between a history of depression and biomarkers of Alzheimer's disease, cerebrovascular disease, and neurodegeneration in patients with dementia.

The association between depression and dementia, particularly Alzheimer's disease (AD) and cerebrovascular disease (CVD), remains an active area of research. This study aimed to investigate the relationship between a history of depression and biomarkers of AD and CVD in patients with dementia in a clinical setting. A total of 126 patients from the University Health Network (UHN) Memory Clinic with comprehensive clinical evaluations, including neuropsychological testing and medical examinations, were included. Lumbar puncture was performed to collect cerebrospinal fluid (CSF) for biomarker analysis, and brain magnetic resonance imaging (MRI) scans were obtained to assess white matter hyperintensity (WMH) burden. The presence of depression was determined through medical records. The study findings did not reveal significant differences between participants with and without a history of depression in terms of AD biomarkers, WMH burden, neurofilament light chain levels, cognitive scores, age of symptom onset, disease duration, or vascular risk scores. Logistic regression analysis did not indicate a meaningful predictive value of these variables for depression status. This clinical study contributes to our understanding regarding the association between depression and AD/CVD biomarkers in patients with cognitive impairment. Further research is needed to elucidate the complex relationship between depression and dementia and to explore the potential mechanisms linking depression, AD, and CVD.

Assessing the Role of Past Depression in Patients with Mild Cognitive Impairment, with and without Biomarkers for Alzheimer's Disease.

Major depressive disorder (MDD) is a risk factor for Alzheimer's disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n = 12), MCI with remitted MDD (MDD+MCI) (n = 12), and remitted MDD alone (MDD) (n = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in MCI patients with AD(-) biomarkers.

Sex and gender differences in dementia.

The dementia landscape has undergone a striking paradigm shift. The advances in understanding of neurodegeneration and proteinopathies has changed our approach to patients with cognitive impairment. Firstly, it has recently been shown that the various proteinopathies that are the cause of the dementia begin to build up long before the appearance of any obvious symptoms. This has cemented the idea that there is an urgency in diagnosis as it occurs very late in the pathophysiology of these diseases. Secondly, that accurate diagnosis is required to deliver targeted therapies, that is precision medicine. With this latter point, the realization that various factors of a person need to be considered as they may impact the presentation and progression of disease has risen to the forefront. Two of these factors aside from race and age are biological sex and gender (social construct), as both can have tremendous impact on manifestation of disease. This chapter will cover what is known and remains to be known on the interaction of sex and gender with some of the major causes of dementia.

Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice.

The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-ß (Aß) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aß levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aß and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.