Basic Science and Pathogenesis.

Background: Vascular cognitive impairment/dementia (VD) is the second most prevalent cause of dementia following Alzheimer's disease (AD). VD is characterized by the progression of white matter hyperintensity burden (WMH) and associated neurodegeneration. GFAP, a biomarker for reactive astrogliosis, is associated with Aβ pathology and mediates tau-pathology in preclinical AD.

Basic Science and Pathogenesis.

Background: We recently demonstrated that large extracellular vesicles (EVs) released by Aβ-loaded microglia and carrying Aβ (Aβ-EVs) propagate synaptic dysfunction in the mouse brain by moving at the axon surface (Gabrielli et al., Brain, 2022; Falcicchia et al., Brain Commun, 2023).

Basic Science and Pathogenesis.

Background: The J20 mouse is an established model of amyloid pathology, exhibiting neuropathological and behavioural symptoms reflective of human Alzheimer's disease (AD). Previous work, conducted by Castanho et al (2020), revealed transcriptomic change in the hippocampus of J20 mice to be associated with the accumulation of amyloid pathology. Here, we investigated the spatial distribution of such transcriptomic changes using novel spatial transcriptomic technology.

Basic Science and Pathogenesis.

Background: Post-mortem neuropathological examinations following the first active immunotherapy strategy (AN-1792, Elan Pharmaceuticals, 2000) for Alzheimer's disease (AD) have evidenced amyloid-β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.

Method: DNA and RNA was isolated from post-mortem prefrontal cortex tissue of immunised cases (n = 14) who received varying doses (ug) and number of doses during the trial period.

Basic Science and Pathogenesis.

Background: Evaluating sex differences in modifiable risk factors for Alzheimer's disease could provide valuable information regarding the mechanisms by which these factors confer risk. Physical activity is a risk factor that has been shown to positively impact both telomere length, a marker of cellular age, and cognition. The goal of this study was to evaluate whether telomere length mediates the association between physical activity and cognition differently by sex.

Basic Science and Pathogenesis.

Background: Knowledge of the chemical composition of amyloid plaques and tau tangles at the earlier stages of Alzheimer's disease (AD) pathology is sparse. This is due to limited access to human brain during life and at the earlier stages of AD pathophysiology and technical limitations in quantifying amyloid and tau species at a subcellular level. Understanding the chemical composition of plaques and tangles, how rapidly they grow and what factors drive growth is important for developing and refining therapeutics.

Basic Science and Pathogenesis.

Background: The neuroimmune response, characterised by the proliferation and activation of microglial cells, is a driver of Alzheimer's disease (AD). However, the extent of immune cell infiltration and interactions in the human AD brain are yet to be established in detail. While microglial cells are at the centre of this neuroimmune response, recent research has explored the possibility of peripheral immune cell involvement, typically focusing on T-cell infiltration.

Basic Science and Pathogenesis.

Alzheimer's disease (AD) is a multi-factorial and complex disease, with the risk of developing disease still largely unknown despite numerous genetic and epidemiological studies over recent years. Several genetic and modifiable lifestyle risk factors are known to contribute to disease etiology, and epigenetic mechanisms are suggested to also contribute my mediating their interaction. It is now ten years since we published the first cross-tissue epigenome-wide association study (EWAS) of DNA methylation in AD post-mortem brain samples, with subsequent studies nominating robust and reproducible alterations in genes such as ANK1, HOXA3 and RHBDF2.

Basic Science and Pathogenesis.

Background: Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD), a devastating neurodegenerative disorder involving the intracellular aggregation of hyperphosphorylated tau.

Method: We used whole transcriptome and targeted long-read cDNA sequencing to profile transcript diversity in the entorhinal cortex of wild-type (WT) and transgenic (TG) mice harbouring a mutant form of human tau.

Result: Whole transcriptome profiling showed that previously reported gene-level expression differences between WT and TG mice reflect changes in the abundance of specific transcripts.

Basic Science and Pathogenesis.

Background: P-tau217 has emerged as a compelling alternative to long-established p-tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer's disease (AD). Understanding the specificity and significance of p-tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.

Methods: We measured p-tau217 phosphorylation by mass spectrometry.

Basic Science and Pathogenesis.

Background: The genetic association between 17q21.31 and increased risk for tauopathies, such as Progressive Supranuclear Palsy, is well established. However, the mechanisms driving the differential disease risks between two major haplotypes, H1 and H2 are unclear.

Basic Science and Pathogenesis.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, hereditary cerebrovascular disease which causes stroke, complex migraine, and cognitive impairment. Given its monogenic nature, CADASIL is considered a 'pure' model of small vessel disease and vascular dementia. CADASIL is caused by NOTCH3 pathogenic variants with a broad resulting phenotypic spectrum.

Basic Science and Pathogenesis.

Background: Millions of people suffer from traumatic brain injury (TBI) annually and many subsequently develop AD-like characteristics, but the processes occurring in the brain and the reasons for the acquisition of AD-like dementia are unknown. TBI is the leading cause of mortality in young adults and causes a huge socioeconomic burden. Improving outcomes in these patients would be a significant public health benefit.

Basic Science and Pathogenesis.

Background: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.

Method: We investigated the protein expression, morphological differences of Ng and correlated Ng to hyperphosphorylated tau in the postmortem brains of 17 AD cases and 17 age and sex-matched controls.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease research lacks a suitable model to match the sporadic version of Alzheimer's Disease (SAD). We a propose a model that will use 7PA2 cells which is a CHO modified to express the V717F mutation for APP (Indiana mutation). The 7PA2 cells will then be placed inside alginate microbeads to produce a factory that constantly produces amyloid species.

Basic Science and Pathogenesis.

Background: As neurodegenerative diseases advance, postmitotic neurons are affected by disturbed proteostasis and the accumulation of misfolded proteins. This renders neurons sensitive to cell death, ultimately leading to progressive neuron loss. Multiple studies show the involvement of distinct pathways of regulated cell death (RCD) in neurodegenerative diseases, such as necroptosis.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the primary cause of dementia, characterized by early amyloid beta accumulation, subsequent tau pathology, and eventually synaptic and neuronal loss. Sleep disturbances, a clinical phenotype in AD, are linked to amyloid beta and impaired protein clearance. However, the influence of tau pathology on sleep is less explored.

Basic Science and Pathogenesis.

Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset.

Basic Science and Pathogenesis.

Background: Maintaining synaptic health is essential for normal neurological function, yet neurodegenerative diseases like Alzheimer's disease and Progressive Supranuclear Palsy (PSP) exhibit synaptic loss. In these conditions, synaptic loss precedes neuronal degeneration, and the degree of synaptic loss correlates closely with the severity of clinical symptoms. Both Aβ, which accumulates in amyloid plaques in AD, and tau protein which accumulates intracellularly in tauopathies, including AD and PSP, accumulate within synaptic terminals.

Basic Science and Pathogenesis.

Background: Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) have distinct molecular pathologies, with Tau and TDP43 aggregation, and distinct patterns of regional brain atrophy. However, they share the synaptotoxicity of protein aggregation, and neurotransmitter loss (including GABA), which contribute to clinical and neurophysiological similarities. Defining the relationships between synaptic loss, network physiology and cognition builds bridges between preclinical and clinical studies, and facilitates early phase trials.

Basic Science and Pathogenesis.

Background: Alzheimer's (AD) and Parkinson's disease (PD) feature progressive neurodegeneration in a remarkably regionally selective manner. Post mortem studies have posited a role for cell autonomous mechanisms driving this, so we aimed to examine a live human induced pluripotent stem cell (iPSC) model to see whether it can replicate the phenomenon of selective neuronal vulnerability, so to better determine disease mechanisms and therapeutic targets.

Method: iPSC-derived neurons offer a rare opportunity to examine cell autonomous vulnerability in live human cells.

Basic Science and Pathogenesis.

Background: Neuroinflammation is a key component of Alzheimer's Disease (AD) pathology. Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial to microglial involvement in AD, mediating trem2-dependent activation and Disease-Associated Microglia (DAM) polarization. However, GWAS revealed that loss-of-function mutations of its encoding gene are an important risk factor for AD.

Basic Science and Pathogenesis.

Background: Various explanations have been proposed for how hearing impairment might be associated with increased risk of dementia. Several theories have proposed direct links with Alzheimer's disease (AD) neuropathology, either due to shared aetiology (i.e.

Basic Science and Pathogenesis.

Background: Microglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer's Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic response with both beneficial and deleterious effects at distinct stages of AD.

Basic Science and Pathogenesis.

Background: TDP-43 is a multifunctional heterogeneous nuclear ribonucleoprotein and is the major pathological protein in motor neuron disease. Previously, TDP-43 pathology has been described in up to 50% of those with Alzheimer's disease. Recent evaluation of this cohort revealed a distinct pathological staging of TDP-43 proteinopathy in an aged population, called Limbic predominant age-related TDP-43 encephalopathy (LATE).