Objective This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large‐scale emerging evidence. Background Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. New/updated hypothesis We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. Major challenges for the hypothesis While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti‐ferroptotic/iron compound in AD patients. Linkage to other major theories Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well‐established consequence of aging and inflammation, which are major theories of disease pathogenesis.

The purpose of the study was to investigate the relationship between Demirjian's method and the improved cervical vertebrae maturation (CVM) method. The material consisted of the clinical files and panoramic and lateral cephalometric radiographs of 718 children (431 girls and 287 boys) aged from 6 to 17 years, inhabitants of the Mazovia region (Central Poland). Dental age according to Demirjian was estimated using panoramic radiographs and the cervical stages (CS) of the CVM were evaluated on cephalometric radiographs. Descriptive statistics of the chronological and dental ages of the patients for a particular CS of skeletal maturity was calculated for girls and boys separately. Linear regression analysis and correlation (Pearson's r coefficient), as well as the Spearman rank correlation coefficient (R) were applied to measure the association between CS and dental calcification stages of all analysed teeth. A consistently earlier occurrence (by about 6 months) for each CS was observed in females. A moderate, but statistically significant, correlation between Demirjian's dental developmental stages and CS was determined. The level of the correlation was different for individual teeth: the teeth showing the highest relationship with CVM were the second premolars and canines (in female and male subjects, respectively). The central incisor demonstrated the poorest correlation in both genders. The findings confirmed that both dental and skeletal maturity should be assessed if the maturity stage of a growing child is to be relevant to clinical practice. The results indicate the usefulness of dental calcification stages as a simple first-level diagnostic test to determine the skeletal maturity status of a subject.

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IMPORTANCEOlder age, high levels of β-amyloid (Aβ), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aβ, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aβ-positive ε4 carriers and noncarriers has not been determined.OBJECTIVE To determine the association of age, Aβ level, and APOE ε4 with memory decline in a large group of cognitively healthy older adults. DESIGN, SETTING, AND PARTICIPANTS This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent Aβ imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable. EXPOSURES β-Amyloid imaging using positron emission tomography, genotyping for APOE ε4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up. MAIN OUTCOMES AND MEASURES Episodic memory composite score. RESULTS Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each Aβ-ε4 group (24 of 51 Aβ-positive ε4 noncarriers [47.1%] ; 35 of 64 Aβ-negative ε4 carriers [54.7%]; 40 of 72 Aβ-positive ε4 carriers [55.6%]; and 145 of 260 Aβ-negative ε4 noncarriers [55.8%]). Adults with Aβ findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for Aβ (mean [SD] age, 69.8 [6.1] years).Memory decline diverged significantly from Aβ-negative ε4 noncarriers at an earlier age in Aβ-positive ε4 carriers (64.5 years) than in Aβ-positive ε4 noncarriers (76.5 years), such that by 85 years of age, Aβ-positive ε4 carriers performed approximately 1.5 SD units worse on the episodic memory composite than Aβ-negative ε4 noncarriers and approximately 0.8 SD units worse than Aβ-positive ε4 noncarriers. Memory performance of Aβ-negative ε4 carriers did not differ from that of the Aβ-negative ε4 noncarriers (estimate [SE], 0.001 [0.001]; t = 0.526; P = .77). CONCLUSIONS AND RELEVANCEPrior work has shown that Aβ and ε4 combine to influence memory decline in nondemented older adults. Results of this study indicate that increasing age may further exacerbate these effects. The estimates provided may be used to determine the risk of memory decline associated with Aβ and ε4 at each age.