Neuropathologic Assessment of Dementia Markers in Identical and Fraternal Twins

Iacono, Diego; Volkman, Inga; Nennesmo, Inger; Pedersen, Nancy L.; Fratiglioni, Laura; Johansson, Boo; Karlsson, David; Winblad, Bengt; Gatz, Margaret

doi:10.1111/bpa.12127

Cited by 14 publications

(8 citation statements)

References 72 publications

(121 reference statements)

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“…The moderate concordance of AD among twins (Iacono et al, 2014) suggests other factors, potentially epigenetic and environmental, are related to AD pathogenesis. Epigenetics relate to stable and heritable patterns of gene expression and genomic functions that do not involve changes in DNA sequence, but act at the interface of genetic and environmental factors.…”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

233

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

233

142

View full text Add to dashboard Cite

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“…Complex gene-environment interactions, in fact, seem to determine an increased or decreased risk of dementia later in life. Recent studies on twins describe, for example, that even identical twins can differ in their onset of dementia and have different amounts of AD pathology at autopsy [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study

et al. 2015

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Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.

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“…A detailed description of the methods, criteria, and antibodies used to assess these twin brains have been previously described. 14 The following brain regions were selected for semi-quantitative assessments of each brain: middle frontal gyrus (MFG), medial temporal gyrus (MTG), anterior cingulate gyrus (ACG), posterior hippocampus (PH; at the level of the corpus geniculate lateral), amygdala (AMY), mesencephalon (MES; including the substantia nigra, SN), and pons (PONS; including the locus coeruleus, LC).…”

Section: Methodsmentioning

confidence: 99%