Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate‐length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate‐length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho‐alpha‐synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate‐length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate‐length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate‐length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182–187

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Conventional x-ray diffraction topography is currently used to map defects in the bulk of protein crystals, but the lack of sufficient contrast is frequently a limiting factor. We experimentally demonstrate that this barrier can be circumvented using a method that combines phase sensitive and diffraction imaging principles. Details of defects revealed in tetragonal lysozyme and cubic ferritin crystals are presented and discussed. The approach enabling the detection of the phase changes of diffracted x rays should prove to be useful in the study of defect structures in a broad range of biological macromolecular crystals.