Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities

Jeffrey L. Cummings, Harry V. Vinters, Gregory M. Cole, Zaven S. Khachaturian

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of β-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a β-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to- cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., τ), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.

Original languageEnglish (US)
JournalNeurology
Volume51
Issue number1 SUPPL.
StatePublished - 1998
Externally publishedYes

Fingerprint

Cognitive Reserve
Alzheimer Disease
Amyloid
Chromosomes, Human, Pair 19
Amyloid Plaques
Brain
Intelligence
Therapeutics
Dementia
Autopsy
Apolipoprotein E2
Genes
Neurons
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 21
Neurobehavioral Manifestations
Mutation
Chromosomes, Human, Pair 6
Neurofibrillary Tangles

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cummings, J. L., Vinters, H. V., Cole, G. M., & Khachaturian, Z. S. (1998). Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology, 51(1 SUPPL.).

Alzheimer's disease : Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. / Cummings, Jeffrey L.; Vinters, Harry V.; Cole, Gregory M.; Khachaturian, Zaven S.

In: Neurology, Vol. 51, No. 1 SUPPL., 1998.

Research output: Contribution to journalArticle

Cummings, JL, Vinters, HV, Cole, GM & Khachaturian, ZS 1998, 'Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities', Neurology, vol. 51, no. 1 SUPPL..
Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998;51(1 SUPPL.).
Cummings, Jeffrey L. ; Vinters, Harry V. ; Cole, Gregory M. ; Khachaturian, Zaven S. / Alzheimer's disease : Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. In: Neurology. 1998 ; Vol. 51, No. 1 SUPPL.
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