Alzheimer Disease: Scientific Breakthroughs and Translational Challenges

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.

Figure 1

Photomicrographs of frequent diffuse and neuritic plaques (Campbell-Switzer silver stain, middle frontal gyrus, 100x), and neurofibrillary tangles (Gallyas silver stain, cerebral cortex, 100x) in a patient with Alzheimer’s disease.

Figure 2

Metabolic pathways of amyloid precursor protein illustrating the nonamyloidogenic cleavage by alpha secretase and the amyloidogenic cleavage by beta secretase (BACE1) that results in the insoluble Aβ fragment. CTF=carboxyl terminal fragment; sAPP=soluble amyloid precursor protein.

Figure 3

Porcupine plots of longitudinal memory performance on the Auditory Verbal Memory Test (AVLT) Long Term Memory Score in apolipoprotein E (APOE) ε4 homozygotes (blue), heterozygotes (red), and noncarriers (black) demonstrating ε4 gene dose-related preclinical decline in memory performance in 34 carriers.

Figure 4

A 58 year old woman with a 3 year history of symptoms of visual dysfunction diagnosed as the visual variant of Alzheimer’s disease (posterior cortical atrophy). A. Pittsburgh Imaging Compound B (PIB) amyloid positron emission tomography (PET) scan showing diffuse increased tracer retention throughout cortex. B. AV1451 Tau PET scan showing marked tracer retention in the posterior cortical regions. C. Statistical Surface Reconstruction of fluorodeoxyglucose (FDG) PET showing asymmetric posterior parietal hypometabolism.