Early-onset Alzheimer Disease and Its Variants

Abstract

Purpose of review: Early-onset Alzheimer disease (AD) is defined as having an age of onset younger than 65 years. While early-onset AD is often overshadowed by the more common late-onset AD, recognition of the differences between early- and late-onset AD is important for clinicians.

Recent findings: Early-onset AD comprises about 5% to 6% of cases of AD and includes a substantial percentage of phenotypic variants that differ from the usual amnestic presentation of typical AD. Characteristics of early-onset AD in comparison to late-onset AD include a larger genetic predisposition (familial mutations and summed polygenic risk), more aggressive course, more frequent delay in diagnosis, higher prevalence of traumatic brain injury, less memory impairment and greater involvement of other cognitive domains on presentation, and greater psychosocial difficulties. Neuroimaging features of early-onset AD in comparison to late-onset AD include greater frequency of hippocampal sparing and posterior neocortical atrophy, increased tau burden, and greater connectomic changes affecting frontoparietal networks rather than the default mode network.

Summary: Early-onset AD differs substantially from late-onset AD, with different phenotypic presentations, greater genetic predisposition, and differences in neuropathologic burden and topography. Early-onset AD more often presents with nonamnestic phenotypic variants that spare the hippocampi and with greater tau burden in posterior neocortices. The early-onset AD phenotypic variants involve different neural networks than typical AD. The management of early-onset AD is similar to that of late-onset AD but with special emphasis on targeting specific cognitive areas and more age-appropriate psychosocial support and education.

FIGURE 2-1

Tensor-based morphometry studies of MRI (A) and fludeoxyglucose positron emission tomography (FDG-PET) overlaid on normalized T1-weighted MRI (B) showing subtraction of late-onset Alzheimer disease (AD) changes from those for early-onset AD. Both neuroimaging techniques reveal greater involvement of parietal regions in early-onset AD (brown on MRI, blue on FDG-PET). Greater precuneus/parietal atrophy (A) and hypometabolism (B) are seen in early-onset AD compared to with late-onset AD, indicating differences in the distribution of neuropathology.

FIGURE 2-2

Phenotypic variants of early-onset Alzheimer disease compared to typical amnestic Alzheimer disease across the age spectrum. The different colored lines in the graph are meant to represent the probable distributions of different phenotypic variants of early-onset Alzheimer disease, such as posterior cortical atrophy, logopenic variant primary progressive aphasia, the behavioral/dysexecutive variant, and the acalculic variant. Modified with permission from van der Flier WM, et al, Lancet Neurol. © 2010 Elsevier Ltd.

FIGURE 2-3

Voxel-based morphometry of parietal overlap of early-onset Alzheimer disease phenotypes, showing cortical atrophy in 10 patients with logopenic variant primary progressive aphasia compared to 64 normal controls. These two composite images show the pattern of atrophy in this aphasic variant of Alzheimer disease when subtracted from the healthy controls. The dark regions show the foci of greater atrophy in logopenic variant primary progressive aphasia asymmetrically affecting the left parietal and posterior temporal region in the left hemisphere with much less involvement of the right hemisphere. The composite images particularly illustrate how this variant of Alzheimer disease results from asymmetric involvement of the left hemisphere. Courtesy of Maria Luisa Gorno-Tempini, MD, PhD, University of California, San Francisco.