Tau aggregation plays a critical role in the development and progression of Alzheimer's disease (AD). Tau aggregates of different sizes and shapes are formed, which ultimately lead to the deposition of fibrillar tangles. We used single‐molecule techniques to characterize tau aggregates in the middle temporal gyrus and somatosensory cortex in post‐mortem brain homogenates at different Braak stages from patients with AD. Total and phosphorylated tau aggregates increased dramatically in late Braak stages. The aggregates showed greater multi‐site phosphorylation with increased Braak stage, but there was only a moderate change in the aggregate size distribution. Paired single nuclei transcriptomic analyses provided evidence for greater pro‐inflammatory microglial and complement pathway activation with increasing phosphorylated tau aggregate concentration and length. Based on this correlation, we hypothesize a cascade of disease progression in which microglial inflammation induces tau aggregation in neighboring neurons that, in turn, further enhances inflammation and the spread of tau pathology to increase the concentration of small tau aggregates.

Monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab have been developed for treatment of Alzheimer’s disease. Here, we have used single-molecule detection techniques and super-resolution imaging to characterise the binding of these antibodies to beta-amyloid aggregates including human post-mortem brain samples. Lecanemab is the best antibody in terms of binding to the small-soluble beta-amyloid aggregates, affinity, aggregate coating, and the ability to bind to post-translationally modified species, explaining its therapeutic success.

Background: As a leading cause of death worldwide, research into dementia‐related diseases is crucial. Women represent two‐thirds of people with dementia, yet women are underrepresented in dementia research leadership. To explore this, our gender‐stratified study of dementia researchers investigated their motivations, role satisfaction, and perceived barriers to career progression and retention. Method: Our global survey targeted early career dementia researchers (ECDRs) through social media and email lists. Multi‐choice questions were used, often with an ‘Other’ write‐in option. Descriptive statistics were compared using chi‐square or Fisher's exact tests as appropriate. For gender comparisons, women and men were included, given the low sample size of other genders. Result: Three‐hundred‐and‐nine respondents included undergraduates to full professors: 68% women, 30% men, and 1% genderqueer, non‐binary, or self‐described. Half of respondents were considering leaving dementia research, particularly women (57% vs. 46% of men, p = 0.07) and ECDRs (40% of undergraduates, 61% postgraduates, 63% postdocs, 30% assistant professors, 21% full professors, p = 0.009). One in five women, but no men, reported their gender as one of the most significant barriers to their career progression. Job availability/security and work‐life balance were also considered career barriers by more women than men (70% vs. 47%, p <0.001; 62% vs. 49%, p = 0.034). Similarly, more women than men selected job security as one of the biggest challenges for ECDRs to stay in dementia research (90% vs. 79%, p = 0.04), whilst men more frequently cited the need for international experience (47% vs. 30%, p = 0.02). Eight female respondents had left academic dementia research, commonly because they could not find a job or funding. To return, they stated they would need longer contracts, funding opportunities and higher salaries. Conclusion: The high proportion of ECDRs considering leaving threatens dementia research progress. Women are more likely than men to consider leaving; with more female than male dementia researchers claiming their career progress and retention is disadvantaged by insufficient job availability, security, funding and work‐life balance. Targeted efforts to lessen these barriers will be essential for equitable representation and enhanced dementia research outcomes.

There is growing interest in understanding the connection between concussions on physical and mental health acutely and, in retirement, on neurodegenerative diseases. In this study, we utilised a “high-impact trauma” (HIT) device to investigate the effects of multiple concussions on the motor activity, and lifespan of the adult female Drosophila melanogaster as well as reactive oxygen and nitrogen species (RONS) levels in the fly brain and body. We found that repetitive hits, while not having acute physical effects, significantly increased long-term mobility deficits, and shortened lifespan, and exacerbated oxidative stress in both the brain and body. Notably, the novel CONKA product (Withania somnifera, Curcuma longa, Melissa officinalis, Rhodiola rosea, Vaccinium myrtillus) demonstrated promising protective effects, including mitigation of motor deficits, extension of lifespan, and reduction of oxidative stress in both the brain and body of the flies. When evaluating the contributions of individual components within the CONKA formulation, Curcuma longa, despite extending lifespan, did not contribute to mobility improvement or oxidative stress amelioration. This suggests that the benefits of CONKA are largely driven by its other four components, which displayed all the positive effects evaluated. The exclusion of Curcuma longa may streamline the formulation without diminishing its brain and body effects following a history of repetitive concussions, although this would require further study to confirm. Oral bioavailability may be an issue with Curcuma longa. Taken together, the findings validate that Drosophila melanogaster is a suitable system to mimic and investigate the effects of repetitive concussions on bodies and brains and assess the effects of health products and drug therapies.