Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiol Aging

Department of Neurology, University of Virginia Health System, McKim Hall, 1 Hospital Drive, P.O. Box 800394, Charlottesville, VA 22908, United States.
Neurobiology of aging (Impact Factor: 4.85). 11/2007; 28(10):1465-80. DOI: 10.1016/j.neurobiolaging.2006.06.021
Source: PubMed

ABSTRACT For 70 years after Alois Alzheimer described a disorder of tangle-and-plaque dementia, Alzheimer's disease was a condition of the relatively young. Definitions of Alzheimer's disease (AD) have, however, changed over the past 30 years and under the revised view AD has truly become an age-related disease. Most now diagnosed with AD are elderly and would not have been diagnosed with AD as originally conceived. Accordingly, younger patients that qualify for a diagnosis of AD under both original and current Alzheimer's disease constructs now represent an exceptionally small percentage of the diagnosed population. The question of whether pathogenesis of the "early" and "late" onset cases is similar enough to qualify as a single disease was previously raised although not conclusively settled. Interestingly, debate on this issue has not kept pace with advancing knowledge about the molecular, biochemical and clinical underpinnings of tangle-and-plaque dementias. Since the question of whether both forms of AD share a common pathogenesis could profoundly impact diagnostic and treatment development efforts, it seems worthwhile to revisit this debate.

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    • "Alzheimer'sdisease(AD)isthemostcommoncauseof dementiaoccurringinmiddleandlatelife.Populationbased surveysestimatethatADaffects7–10%ofindividuals>65yearsof ageandpossibly50–60%ofpeopleover85yearsofage.ADnow affectsabout2%ofthepopulation,orabout4millionpeopleinthe USAandmorethan35millionpeopleworldwide[75].The prevalenceofADisincreasingproportionallytoincreasedlife expectancyandestimatespredictthattheprevalencewillreach approximatelyover100millionworld-widebymiddleofthis century[75]. Ithasbeenreportedthatmitochondrialabnormalitiescorrelate withdystrophicneurites,thelossofdendriticbranchesandthe pathologicalalterationofthedendriticspinespresentinthebrains ofAlzheimer'sdisease(AD)cases[76].SwerdlowandKhan[77] [78] proposedthemitochondrialcascadehypothesistoexplainlateonset ,sporadicAD,statingthatAbdepositionasplaques, neurofibrillarytangleformationandneurodegenerationare consequenteventsofmitochondrialmalfunction.Thishypothesis emphasizesageingasthemainriskfactorforthedevelopmentof thesporadicformofAD.Inparticularitpostulatesthatthe accumulationofAb42,thetoxicformofAbduetoinappropriate processingofamyloidprecursorproteins,isaconsequenceof ageing[79]ratherthanthecauseoftheevolutionofthe neuropathologyasiswidelyreportedinthecaseoffamilialAD. Ab42canbetransportedtomitochondriawhereitmayadversely interactwithmitochondrialelectrontransportchainproteins, causeanincreaseinROSproduction,promoteexcessaccumulation ofmitochondrialcalciumions,decreasethenumberoffunctionally activemitochondriaand,ultimately,neurondamage[80] [81] [82] [83] [84].In turn,productionofreactiveoxygenspecies(ROS),ATPproduction failure,andpotentialdisruptionofmitochondrialmembranecould causeopeningofmitochondrialpermeabilitytransitionpores, releaseofcytochromec,andinductionofapoptosis[85]. "
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    ABSTRACT: Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/2013; 759C(1). DOI:10.1016/j.mrrev.2013.09.001 · 4.44 Impact Factor
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    • "Strikingly, the analysis revealed significant (Bonferroni corrected P = 0.0016) enrichment for genes (CDH13, GDF10, NTRK3, PENK, RBP1, RBP4, UCHL1, WIF1) whose expression values are known to be downregulated in early Alzheimer's disease [28]. Age is one of the biggest risk factors for developing Alzheimer's disease [29]. While DNA methylation is known to play a role in age-related neurodegenerative diseases such as Alzheimer's disease [30,31], our results indicate that a methylation footprint may also be found in blood tissue. "
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    ABSTRACT: Background Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. Results We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. Conclusions Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles.
    Genome biology 10/2012; 13(10):R97. DOI:10.1186/gb-2012-13-10-r97 · 10.47 Impact Factor
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    • "Similar results were obtained with APP + -ob ⁄ ob type 2 diabetic (T2D) mice, which showed enhanced, AD-like cognitive dysfunction together with cerebrovascular inflammation and amyloid angiopathy (Takeda et al., 2010). The vast majority of the mouse models used to study the diabetes ⁄ AD interaction rely on genetic manipulation to generate models of familial AD, which account for less than 5% of all AD cases (Swerdlow, 2007). However, these models do not reflect the natural onset and progression of the disease that occurs for the most patients. "
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    ABSTRACT: Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Aβ and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated Aβ within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals.
    Aging cell 09/2012; 11(6). DOI:10.1111/acel.12002 · 5.94 Impact Factor
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