Metabolites produced by an altered gut microbiota might mediate the effects in the brain. Among metabolites, the fecal volatile organic compounds (VOCs) are considered to be potential biomarkers. In this study, we examined both the VOCs and bacterial taxa in the feces from healthy subjects and Alzheimer’s disease (AD) patients at early and middle stages. Remarkably, 29 fecal VOCs and 13 bacterial genera were differentiated from the healthy subjects and the AD patients. In general, higher amounts of acids and esters were found in in the feces of the AD patients and terpenes, sulfur compounds and aldehydes in the healthy subjects. At the early stage of AD, the most relevant VOCs with a higher abundance were short-chain fatty acids and their producing bacteria, Faecalibacterium and Lachnoclostridium. Coinciding with the development of dementia in the AD patients, parallel rises of heptanoic acid and Peptococcus were observed. At a more advanced stage of AD, the microbiota and volatiles shifted towards a profile in the feces with increases in hexanoic acid, Ruminococcus and Blautia. The most remarkable VOCs that were associated with the healthy subjects were 4-ethyl-phenol and dodecanol, together with their possible producers Clostridium and Coprococcus. Our results revealed a VOCs and microbiota crosstalk in AD development and their profiles in the feces were specific depending on the stage of AD. Additionally, some of the most significant fecal VOCs identified in our study could be used as potential biomarkers for the initiation and progression of AD.

Background: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by early progressive visual dysfunction in the context of relative preservation of memory and a pattern of atrophy mainly involving the posterior cortex. The aim of the present study is to characterize the neuropsychiatric profile of PCA. Methods: The Neuropsychiatric Inventory was used to assess 12 neuropsychiatric symptoms (NPS) in 28 patients with PCA and 34 patients with typical Alzheimer disease (AD) matched by age, disease duration, and illness severity. Results: The most commonly reported NPS in both groups were depression, anxiety, apathy, and irritability. However, aside from a trend toward lower rates of apathy in patients with PCA, there were no differences in the percentage of NPS presented in each group. All those patients presenting visual hallucinations in the PCA group also met diagnostic criteria for dementia with Lewy bodies (DLB). Auditory hallucinations were only present in patients meeting diagnosis criteria for DLB. Conclusion: Prevalence of the 12 NPS examined was similar between patients with PCA and AD. Hallucinations in PCA may be helpful in the differential diagnosis between PCA-AD and PCA-DLB.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10⁻²⁰) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Background: Discerning dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) is one of the most common and challenging differential diagnoses at the memory clinic. Although the neuropsychiatric manifestations have been widely reported as one of the main key points in the differential diagnosis between these two diseases, to date no neuropsychiatric questionnaire has been specifically devised for this purpose. Methods: We administered the Neuropsychiatric Inventory (NPI) and the Columbia University Scale for Psychopathology in Alzheimer's Disease (CUSPAD) to a memory clinic sample of 80 patients with probable DLB and 85 age- and severity-matched patients with probable AD. Diagnosis of probable DLB was supported with a positive dopamine transporter SPECT scan. We examined the usefulness of these two neuropsychiatric tools designed for AD in the differential diagnosis between DLB and AD. We also investigated the correlations between psychotic symptoms and measures of cognitive and functional decline. Results: Auditory hallucinations were very specific of DLB and were usually preceded by visual hallucinations. Misinterpretation of real visual stimuli (illusions) was more frequent in DLB. Delusions were both quantitatively and qualitatively different between DLB and AD: delusional misidentifications were significantly more characteristic of DLB, while paranoid delusions did not show specificity for DLB. Conclusions: Neuropsychiatric tools are useful to discriminate DLB from AD. Hallucinations and delusions are not only more frequent in DLB than in AD but also have distinct qualitative characteristics and patterns of progression that can help clinicians to make a more accurate differential diagnosis.

Patients with semantic dementia (SD) may undergo successful relearning of object names, but these gains are usually restricted to the trained exemplars, demonstrating poor generalization. We hypothesized that generalization could be improved by restoring an item's semantic network through specific strategies that recruit the remaining personal semantic memories (conceptual enrichment therapies). We describe the case of a patient with SD who showed greater generalization of learning following a conceptual enrichment therapy than when learning items in a word-retrieval therapy. Our results suggest that enhancing an item's semantic network connections may result in improved generalization of learning in SD. A learning mechanism in the presence of compromised hippocampi is also discussed.

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.