The Genetics of Very Early Onset Alzheimer Disease

Filley, Christopher M.; Rollins, Yvonne D.; Anderson, Craig; Arciniegas, David B.; Howard, Kathleen P.; Murrell, Jill R.; Boyer, Philip J.; Kleinschmidt-DeMasters, Belte K.; Ghetti, Bernardino

doi:10.1097/wnn.0b013e318145a8c8

Cited by 47 publications

(36 citation statements)

References 73 publications

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“…Only 3 individuals were diagnosed as having AD, and one of these presented with posterior cortical atrophy. Although the rarity of AD in this YOD cohort may account for the lack of early memory disturbance in the neurodegenerative etiological category in comparison to others, the pattern of cognitive decline in earlyonset AD has been reported to differ substantially from that of late-onset AD [2,16] .…”

Section: Neurodegenerative Etiologiescontrasting

confidence: 57%

“…This observation is also supported by several epidemiological studies of EOD cohorts [7,8,[10][11][12][13][14][15] . Although the relative infrequency of AD within these YOD and EOD populations may account for some of the observed increased frequency of early psychiatric and behavioral features, increased rates of neuropsychiatric features have been noted in early-onset AD populations as well [2,16] . Further, the similar findings in young-onset CJD and in our YOD cohort suggest that other age-specific factors play an important role.…”

Section: Cognitive Domainsmentioning

confidence: 94%

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Cognitive and Noncognitive Neurological Features of Young-Onset Dementia

Kelley

Boeve

Josephs

2009

Dement Geriatr Cogn Disord

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Background: The rarity of young-onset dementia (YOD), the broad differential diagnosis and unusual clinical presentations present unique challenges to correctly recognize the condition and establish an accurate diagnosis. Limited data exist regarding clinical features associated with dementia prior to the age of 45. Methods: We retrospectively assessed cognitive and noncognitive neurological characteristics of 235 patients who presented for evaluation of YOD to investigate the clinical characteristics of YOD compared to later-onset dementias and to identify clinical features associated with specific etiologies that may aid in the evaluation of YOD. Results: Multiple cognitive domains were affected in most patients, and no significant differences in affected domains existed between groups. Early psychiatric and behavioral features occurred at very high frequencies. Nearly 80% of this YOD cohort had additional noncognitive symptoms or signs as a feature of their disease. Chorea was strongly associated with Huntington disease. Parkinsonism was not seen in patients having an autoimmune/inflammatory etiology. Conclusions: The rarity of YOD and the high frequency of early psychiatric features led to frequent misdiagnosis early in the clinical course. The high frequency of noncognitive symptoms and signs may aid clinicians in distinguishing patients requiring a more extensive evaluation for YOD.

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Section: Neurodegenerative Etiologiescontrasting

confidence: 57%

Section: Cognitive Domainsmentioning

confidence: 94%

Cognitive and Noncognitive Neurological Features of Young-Onset Dementia

Kelley

Boeve

Josephs

2009

Dement Geriatr Cogn Disord

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“…Age is one of the most common risk factors (47) and mitochondrial dysfunction plays a central role. The mode of action of current medications in, for example, the treatment of Alzheimer's disease, like acetylcholine esterase inhibition or NMDA receptor channel blockade only remotely (if at all) correspond to firmly established genetic risk factors such as amyloid precursor protein, presenilins, neuregulin-1 or ApoE4 (48)(49)(50)(51)(52).…”

Section: Multi-target Drugsmentioning

confidence: 99%

Systems Biology Approaches and Tools for Analysis of Interactomes and Multi-target Drugs

Schrattenholz

Groebe²,

Šoškić³

2010

Methods in Molecular Biology

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Systems biology is essentially a proteomic and epigenetic exercise because the relatively condensed information of genomes unfolds on the level of proteins. The flexibility of cellular architectures is not only mediated by a dazzling number of proteinaceous species but moreover by the kinetics of their molecular changes: The time scales of posttranslational modifications range from milliseconds to years. The genetic framework of an organism only provides the blue print of protein embodiments which are constantly shaped by external input. Indeed, posttranslational modifications of proteins represent the scope and velocity of these inputs and fulfil the requirements of integration of external spatiotemporal signal transduction inside an organism. The optimization of biochemical networks for this type of information processing and storage results in chemically extremely fine tuned molecular entities. The huge dynamic range of concentrations, the chemical diversity and the necessity of synchronisation of complex protein expression patterns pose the major challenge of systemic analysis of biological models. One further message is that many of the key reactions in living systems are essentially based on interactions of moderate affinities and moderate selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. In complex disorders such as cancer or neurodegenerative diseases, which initially appear to be rooted in relatively subtle dysfunctions of multimodal physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which has been dominating the pharmaceutical industry for a long time, increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade, and the treatment of "complex diseases" remains a most pressing medical need. Currently, a change of paradigm can be observed with regard to a new interest in agents that modulate multiple targets simultaneously, essentially "dirty drugs." Targeting cellular function as a system rather than on the level of the single target, significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data. But the key is the extraction of relevant molecular information from biological systems by implementing rigid statistical procedures to differential proteomic analytics.

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“…Additional genetic and environmental factors appear to be responsible for variations in penetrance because PS2 mutations tend to have variations in age of onset and symptom severity, even within the same pedigree [93]. These variations were not accounted for by apolipoprotein E (ApoE) polymorphisms [93,94], of which APOE ε4 is associated with increased risk for AD [95].…”

Section: S383mentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.

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The Genetics of Very Early Onset Alzheimer Disease

Cited by 47 publications

References 73 publications

Cognitive and Noncognitive Neurological Features of Young-Onset Dementia

Cognitive and Noncognitive Neurological Features of Young-Onset Dementia

Systems Biology Approaches and Tools for Analysis of Interactomes and Multi-target Drugs

The Mitochondrial Secret(ase) of Alzheimer's Disease

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