Alzheimer Disease: Scientific Breakthroughs and Translational Challenges

Research output: Contribution to journalReview article

21 Citations (Scopus)

Abstract

Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E ε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it.

Original languageEnglish (US)
Pages (from-to)978-994
Number of pages17
JournalMayo Clinic Proceedings
Volume92
Issue number6
DOIs
StatePublished - Jun 1 2017

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Alzheimer Disease
Dementia
Amyloid
Hope
Apolipoprotein E4
Molecular Imaging
Genome-Wide Association Study
Memory Disorders
Rare Diseases
Immunotherapy
Cerebrospinal Fluid
Therapeutics
Biomarkers
Alleles
Pathology
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Alzheimer Disease : Scientific Breakthroughs and Translational Challenges. / Caselli, Richard John; Beach, Thomas G.; Knopman, David S; Graff Radford, Neill R.

In: Mayo Clinic Proceedings, Vol. 92, No. 6, 01.06.2017, p. 978-994.

Research output: Contribution to journalReview article

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