Recognizing Atypical Presentations of Alzheimer's Disease: The Importance of CSF Biomarkers in Clinical Practice

Abstract

Besides the typical amnestic presentation, neuropathological studies indicate that Alzheimer's disease (AD) may present with atypical clinical pictures. The relative frequencies of typical and atypical or mixed presentations within the entire spectrum of AD remain unclear, while some mixed or atypical presentations may have not received adequate attention for them to be included in diagnostic criteria. We investigated the spectrum of clinical presentations in patients with the AD CSF biomarker profile (high tau and phospho-tau, low Aβ42 levels), hospitalized in a tertiary academic center. Among 98 patients with the CSF AD profile, 46% of patients had the typical presentation of "hippocampal" amnestic dementia. Additionally, 23.5% and 15.3% fulfilled the criteria of mixed or atypical presentations, respectively, as described in the IWG-2 criteria. The remaining 15.3% had unusual presentations, including non-logopenic (semantic and non-fluent agrammatic) primary progressive aphasia, corticobasal syndrome, and Richardson syndrome, or could be diagnosed with normal pressure hydrocephalus. Despite selection bias (academic center), atypical clinical presentations of AD may be more common than previously thought. CSF biomarkers seem to be a useful tool for antemortem identification of such patients, which is likely to affect therapeutic decisions. Some of the unusual presentations described above should be incorporated in diagnostic criteria.

Keywords: Alzheimer’s disease; amyloid-beta; atypical presentations; cerebrospinal fluid biomarkers; phospho-tau; tau.

Figure 1

Pie chart of the clinical phenotypes of patients with an AD biochemical profile.

Figure 2

Scatterplot of CSF concentrations of Aβ₄₂ (a), τ_T (b), and τ_P-181 (c) in AD subgroups. Horizontal broken lines indicate the cut-off values of our laboratory. Horizontal bars indicate median values. For typical presentations, white circles indicate dementia stage and half-filled circles indicate MCI stage. For mixed presentations, black circles indicate mixed with VD and white circles indicate mixed with Lewy bodies. For atypical presentations, upward white triangles indicate frontal, downward white triangles indicate posterior, and white circles indicate logopenic presentations. For other unusual presentations, black triangles indicate PSP-like, white circles indicate non-logopenic PPA, dotted white circles indicate NPH, and white squares indicate CBS presentations.