Background: Down syndrome (DS) is frequently associated with Alzheimer’s disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients. Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases. Methods: We analyzed the distribution of neurodegenerative disease associated proteins in postmortem brain samples from 11 DS cases (6 females, median age 57, range 38–66 years). Sections were stained for phosphorylated tau, 3-repeat and 4-repeat tau, amyloid-β, alpha synuclein, phosphorylated TDP-43, and P62. A comprehensive anatomical mapping and staging were applied for all proteins. Results: Tau and amyloid-β pathology was prevalent in all cases and compatible with that typically seen in AD with some subtle deviations. Four of 11 cases presented with Lewy-related pathology (LRP). Two cases followed the Braak staging (stage 4 and 5) whereas 2 cases presented with an atypical distribution. Two cases showed limbic predominant age-related TDP-43 encephalopathy (LATE) (stage 1 and stage 2) neuropathologic change. Two cases exhibited aging-related tau astrogliopathy (ARTAG). Conclusion: In addition to subtle deviations from AD regarding the morphology of Aβ deposition and distribution of neuronal tau pathology, we find that the spectrum of mixed-pathologies in DS show distinctive features such as deviations from the Braak staging of LRP and that LATE neuropathologic change and ARTAG pathology can be seen in individuals younger than in sporadic AD cases. Our observations support the notion that DS has distinctive pathogenic pathways from sporadic AD.

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Background Neuropathological diagnosis of argyrophilic grain disease (AGD) is currently based primarily on the combination of argyrophilic grain (AG) visualized using Gallyas–Braak silver staining, phosphorylated tau-positive pretangles, coiled bodies, and ballooned neuron detection. Although AGD is common in patients with dementia and/or prominent psychiatric symptoms, whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear. Methods In 1449 serial forensic autopsy cases > 40 years old (823 males and 525 females, aged 40–101 years, mean age 70.0 ± 14.1 years), we examined the frequency and comorbid pathology of AGD cases and investigated the clinical appearance by comparing those with non-AGD cases using the propensity score. Results Of the 1449 cases, we detected 342 AGD cases (23.6%; mean age 79.7 years; 177 males and 165 females). The AGD frequency and stage increased with age (P < 0.001). Among AGD cases, 80 (23.4%) patients had dementia, and 51 (15.2%) had a history of psychiatric hospital visits. The frequency of suicide and history of psychiatric disorders were significantly higher in AGD cases than in AGD-negative cases, matched for age, sex, and comorbidity pathology, with a relative risk of suicide of 1.72 (1.30–2.26). The frequency of suicide was significantly higher in AGD cases than in non-AGD cases in female but not male cases. The relative risk of suicide increased to 2.27 (1.20–4.30) and 6.50 (1.58–26.76) in AGD patients with Lewy and progressive supranuclear palsy pathology, respectively, and decreased to 0.88 (0.38–2.10) in those with advanced AD pathology. In AGD cases, 23.4% had dementia; however, the difference was not significant after controlling for age, sex, and comorbid pathology. Conclusion Our study demonstrated that AGD is a significant and isolated risk factor for psychiatric hospital visits and suicide completion. In older adults, AGs may contribute to the progression of functional impairment of the limbic system, which leads to psychiatric disorders and suicide attempts.