Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?

doi:10.1016/j.neurobiolaging.2006.06.021

Neurobiology of Aging

Volume 28, Issue 10, October 2007, Pages 1465-1480

https://doi.org/10.1016/j.neurobiolaging.2006.06.021 Get rights and content

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.

Section snippets

Beta amyloid and the “Amyloidization” of Alzheimer's disease

If the field of dementia research has indeed experienced “Alzheimerization” in recent decades, then AD research can be further said to have undergone “amyloidization”. Many investigators feel the key to understanding AD lies in deciphering the nature of the extracellular plaques seen in those with the disease. These plaques consist largely of an amyloid protein derivative called beta amyloid.

Amyloid proteins are beta-sheet proteins that can aggregate. When viewed by polarized light microscopy,

Tau and tangle pathology in the most common “Tauopathy”

Intracellular neurofibrillary tangles consist of tau protein. Tau normally exists in phosphorylated and unphosphorylated states [73], [124]. The phosphorylated state is characteristically seen in undifferentiated dividing cells, and is called fetal tau. Differentiated cells contain unphosphorylated tau. In differentiated cells, tau associates with the microtubule cytoskeleton. Phosphorylated tau appears not to associate with cytoskeletal microtubules. Tau phosphorylation status is regulated by

Epidemiology and genetics of early and late onset AD

Epidemiologic data identify two distinct AD populations, those with clearly recognizable autosomal dominant inheritance and those without. Patients with autosomal dominant AD typically present at far younger ages than those without obvious autosomal dominant inheritance. The late onset group tends to manifest either sporadic or pseudosporadic epidemiology. In this regard, the term pseudosporadic is technically more accurate, because it acknowledges that while classic Mendelian inheritance is

Clinical knowledge advances: Alzheimer's, mild cognitive impairment, and beyond

Establishing AD as a common condition justified creation of centralized AD research centers [98]. Over the past two decades, these centers have to a large degree defined current AD clinical perspectives. Most of the subjects studied at these centers are elderly, and therefore this approach has mostly advanced our knowledge of the late onset form of the disease. Thanks largely to these centers, we now have both cognitive exam and clinical history-based diagnostic approaches that are fairly

Implications for diagnostics development

AD is still primarily a clinical diagnosis [135]. For the clinician, convincing oneself a patient truly has AD can consume considerable time. It is often necessary to obtain the history from, in addition to the patient, one or more informants and informants may not present consistent stories. In addition to general medical and neurologic examinations, a cognitive examination is indicated. Further complicating matters is the fact that for the elderly, the main challenge of the physician is not

Implications for treatment development

AD treatment preclinical development relies heavily on the use of AD transgenic mice. These mice are engineered to express mutated human APP genes, mutated human presenilin 1 genes or combinations of both. Mice utilized by different investigators also vary in the type of promoter used to express the transgene, the nature of the transgene mutation, and for mutant APP mice the isoform (length) of the APP protein product [17], [64], [89]. Mice that express a mutated human tau transgene in addition

Conclusions

Whether or not late-life dementia represents a disease state or is part of aging, it is imperative to recognize it destroys lives. Efforts to intervene medically are justified at both humanistic and economic levels. Katzman's 1976 editorial pointed out it was irrational to assume those dementing before the age of 65 had a medical problem, while those dementing after 65 did not. The case was persuasively made based on data available at the time. As Katzman wrote, when considering persons with

Acknowledgement

Funded by NIH AG022407.

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ReviewIs aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?

Abstract

Section snippets

Beta amyloid and the “Amyloidization” of Alzheimer's disease

Tau and tangle pathology in the most common “Tauopathy”

Epidemiology and genetics of early and late onset AD

Clinical knowledge advances: Alzheimer's, mild cognitive impairment, and beyond

Implications for diagnostics development

Implications for treatment development

Conclusions

Acknowledgement

Mechanisms of Ageing and Development

J Neurol Sci

Neurobiol Aging

Neurobiol Aging

Am J Hum Genet

J Biol Chem

Neurobiol Aging

Lancet Neurol

Neurodegeneration

J Biol Chem

Prog Brain Res

J Biol Chem

Lancet Neurol

Trends Pharmacol Sci

J Biol Chem

Am J Geriatr Psychiatry

Neuropharmacology

Neurobiol Aging

Exp Neurol

Biochim Biophys Acta

J Biol Chem

Atherosclerosis

Neurobiol Aging

J Biol Chem

The Alzheimerization of aging

Gerontologist

Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial

JAMA

Uber eine eigenartige Erkrankung der Hirnrinde

Allg Z Psychiat Psych-Gerichtl Med

Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology

Neurology

Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition

Neuroreport

Learning and memory in transgenic mice modeling Alzheimer's disease

Learn Mem

Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis

Neuropsychology

Gene knockout of amyloid precursor protein and amyloid precursor-like protein-2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts

J Neurochem

Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older

Arch Neurol

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype

Arch Neurol

Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease

J Neurosci

Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration

Biochem J

A placebo controlled, double-blind trial of the selective Aβ-lowering agent Flurizan in patients with mild to moderate Alzheimer's disease: efficacy, safety, and follow-on study results

The genetics of Alzheimer disease: current status and future prospects

Arch Neurol

The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects

Br J Psychiatry

Mouse models of human neurodegenerative disorders: requirements for medication development

Arch Neurol

Neuropathological staging of Alzheimer-related changes

Acta Neuropathol

Do nonsteroidal anti-inflammatory drugs reduce the risk of Alzheimer's disease?

N Engl J Med

Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis

Am J Ment Retard

Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles

J Neuropathol Exp Neurol

Progressive reduction of synaptophysin message in single neurons in Alzheimer's disease

J Neuropathol Exp Neurol

A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60

Science

Six month recovery from mild to moderate traumatic brain injury: the role of APOE-epsilon 4 allele

Brain

Review
Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?