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Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) is a heterogeneous disorder. OBJECTIVE:To investigate whether cognitive AD subtypes are associated with different rates of disease progression. METHODS:We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n?=?290), Alzheimer's Disease Neuroimaging Initiative (n?=?268), Dementia Competence Network (n?=?226), and University of California, San Francisco (n?=?282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n?=?663) and one with most prominent non-memory impairment (n?=?403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. RESULTS:Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p?

SUBMITTER: Scheltens NME

PROVIDER: S-EPMC6588161 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.

Scheltens Nienke M E NME Tijms Betty M BM Heymans Martijn W MW Rabinovici Gil D GD Cohn-Sheehy Brendan I BI Miller Bruce L BL Kramer Joel H JH Wolfsgruber Steffen S Wagner Michael M Kornhuber Johannes J Peters Oliver O Scheltens Philip P van der Flier Wiesje M WM

Journal of Alzheimer's disease : JAD 20180101 3

<h4>Background</h4>Alzheimer's disease (AD) is a heterogeneous disorder.<h4>Objective</h4>To investigate whether cognitive AD subtypes are associated with different rates of disease progression.<h4>Methods</h4>We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously c ...[more]

PMID: 30103316

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Project description:BackgroundRecently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer's disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD.MethodsWe used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo-/-) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses.ResultsOur in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo-/- mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo-/- mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism.ConclusionOur findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.

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Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.

Publications

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.

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