Atypical clinical variants of Alzheimer's disease: are they really atypical?

Abstract

Alzheimer's disease (AD) is a neuropathological disorder defined by the deposition of the proteins, tau and β-amyloid. Alzheimer's disease is commonly thought of as a disease of the elderly that is associated with episodic memory loss. However, the very first patient described with AD was in her 50's with impairments in multiple cognitive domains. It is now clear that AD can present with multiple different non-amnestic clinical variants which have been labeled as atypical variants of AD. Instead of these variants of AD being considered "atypical," I propose that they provide an excellent disease model of AD and reflect the true clinical heterogeneity of AD. The atypical variants of AD usually have a relatively young age at onset, and they show striking cortical tau deposition on molecular PET imaging which relates strongly with patterns of neurodegeneration and clinical outcomes. In contrast, elderly patients with AD show less tau deposition on PET, and neuroimaging and clinical outcomes are confounded by other age-related pathologies, including TDP-43 and vascular pathology. There is also considerable clinical and anatomical heterogeneity across atypical and young-onset amnestic variants of AD which reflects the fact that AD is a disease that causes impairments in multiple cognitive domains. Future studies should focus on careful characterization of cognitive impairment in AD and consider the full clinical spectrum of AD, including atypical AD, in the design of research studies investigating disease mechanisms in AD and clinical treatment trials, particularly with therapeutics targeting tau.

Keywords: Alzheimer’s disease; TDP-43; biomarkers; corticobasal; logopenic aphasia; neuroimaging; posterior cortical atrophy; tau PET.

Figure 1

Patterns of FDG-PET hypometabolism and flortaucipir PET uptake in individual patients with different variants of atypical AD. The FDG-PET images are shown as CortexID Z score images of hypometabolism compared to age-matched controls. The flortaucipir PET images are shown as standardized uptake value ratio (SUVR) images referenced to the cerebellar crus grey matter. The language variant of AD shows left temporoparietal hypometabolism and flortaucipir uptake; the visual variant shows abnormalities predominantly in the occipital lobe; the motor variant shows abnormalities in the posterior temporal, parietal and frontal lobes, predominantly on the right; the dysexecutive variant shows left-sided abnormalities predominantly in the superior parietal and frontal lobes; the behavioral variant showed abnormalities in the temporal lobes, with milder changes in the parietal and frontal lobe.

Figure 2

Flortaucipir PET uptake and white matter hyperintensities on FLAIR in young-onset and late-onset amnestic AD patients. The flortaucipir PET images are shown as standardized uptake value ratio (SUVR) images referenced to the cerebellar crus grey matter. The young-onset patient shows widespread flortaucipir uptake with no WMHs, while the late-onset patient shows milder flortaucipir uptake and moderate WMHs.