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Background: Older adults with heart failure are at elevated risk of Alzheimer's disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms. [ABSTRACT FROM AUTHOR]

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2. [ABSTRACT FROM AUTHOR]

Autosomal dominant familial Alzheimer's disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson's disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD-related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation. [ABSTRACT FROM AUTHOR]