• Alzheimer’s Disease
• Cognitive impairment
• Diet
• Nutraceuticals
• Vitamins

• Humans
• Alzheimer Disease/metabolism
• Neurodegenerative Diseases
• Micronutrients/therapeutic use
• Amyloid beta-Peptides/metabolism
• Dietary Supplements
• Cognition
• Antioxidants/therapeutic use

• APOE
• Alzheimer’s disease
• MRI
• mild cognitive impairment
• quantitative susceptibility mapping

• amyloid
• neurodegeneration
• radiation therapy

Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders that have been studied for more than 100 years. Although an increased level of amyloid precursor protein is considered a key contributor to the development of AD, the exact pathogenic mechanism remains known. Multiple factors are related to AD, such as genetic factors, aging, lifestyle, and nutrients. Both epidemiological and clinical evidence has shown that the levels of micronutrients, such as copper, zinc, and iron, are closely related to the development of AD. In this review, we summarize the roles of eight micronutrients, including copper, zinc, iron, selenium, silicon, manganese, arsenic, and vitamin D in AD based on recently published studies.

• Alzheimer’s disease
• Iron
• Micronutrient
• Zinc

• Alzheimer’s disease
• iron MRI
• iron X-ray methods
• iron imaging
• iron imaging methods
• iron mechanism
• iron microscopy methods
• iron pathology

• R01 AG061120 NIA NIH HHS
• R21 AG072675 NIA NIH HHS
• National Institutes of Health

• amyloid β
• cerebral amyloid angiopathy
• immunotherapy
• siderosis

• Alzheimer's disease
• Ex vivo MRI
• Hippocampal layers
• Histology
• Susceptibility

To employ an off‐resonance saturation method to measure the mineral‐iron pool in the postmortem brain, which is an endogenous contrast agent that can give information on cellular iron status.

An off‐resonance saturation acquisition protocol was implemented on a 7 Tesla preclinical scanner, and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland‐Altman analysis on a ferritin‐containing phantom. Mineral‐iron maps were obtained from postmortem tissue of patients with neurological diseases characterized by brain iron accumulation, that is, Alzheimer disease, Huntington disease, and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were used for comparison.

In postmortem tissue, the mineral‐iron contrast colocalizes with histological iron staining in all the cases. Iron concentrations obtained via the off‐resonance saturation method are in agreement with literature.

Off‐resonance saturation is an effective way to detect iron in gray matter structures and partially mitigate for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of diseases characterized by brain iron accumulation and can complement existing iron‐sensitive parametric methods.

• ferritin
• iron
• neurodegenerative diseases
• postmortem MRI

•

Ferrihydrite-iron is the most abundant iron form in the aceruloplasminemia brain.

Aceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron deposits, of which the molecular composition is unknown. We aimed to quantitatively determine the molecular iron forms in the aceruloplasminemia brain, and to illustrate their influence on iron-sensitive MRI metrics.

The inhomogeneous transverse relaxation rate (R₂*) and magnetic susceptibility obtained from 7 T MRI were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry. The basal ganglia, thalamus, red nucleus, dentate nucleus, superior- and middle temporal gyrus and white matter of a post-mortem aceruloplasminemia brain were studied. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison.

The brain iron pool in aceruloplasminemia detected in this study consisted of EPR-detectable Fe³⁺ ions, magnetic Fe³⁺ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe³⁺ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Ferrihydrite-iron represented above 90% of all iron and was the main driver of iron-sensitive MRI contrast. Although deep gray matter structures were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron was already six times more abundant in the temporal cortex of the patient with aceruloplasminemia compared to the healthy situation (162 µg/g vs. 27 µg/g), on average. The concentrations of Fe³⁺ ions and maghemite-iron in the temporal cortex in aceruloplasminemia were within the range of those in the control subjects.

Iron-related neurodegeneration in aceruloplasminemia is primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.

• Aceruloplasminemia
• Ferritin
• Iron
• Magnetometry
• Post-mortem MRI

Treatments for Alzheimer’s disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer’s pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.

• Alzheimer’s disease
• PBT2
• clioquinol
• copper
• ferroptosis
• iron
• selenium
• zinc