Exploring Alzheimer's Disease Subtypes at the Prodromal Stage

Magdalena A. Kolanko; Paresh A. Malhotra


Brain. 2018;141(12):3285-3287. 

'Alzheimer's disease is a disease of the medial temporal lobe'. These are words that one of us remembers vividly from a particularly interesting undergraduate lecture nearly 25 years ago, and similar statements have been heard many times in many lecture theatres since. Countless studies have indeed shown that medial temporal lobe atrophy is predictive of the development of Alzheimer's dementia, and that this relates to changes in episodic memory. However, the medial temporal lobe is not always the first brain region to diminish in volume in Alzheimer's disease, and cognitive impairment does not always begin with episodic memory dysfunction. Alzheimer's disease has a range of presentations, each with well described behavioural characteristics and an associated pattern of atrophy that can be visualized with MRI. As well as the typical episodic memory-medial temporal lobe profile, individuals may present with predominant visuospatial impairment (posterior cortical atrophy), with profound language deficits (logopenic aphasia) or with frontal signs (Benson et al., 1988; Gorno-Tempini et al., 2011; Ossenkoppele et al., 2015). The increasing use of biomarkers such as CSF analysis and amyloid PET (Figure 1) is enabling clinicians to better identify patients with variants of Alzheimer's disease in memory clinics (Carswell et al., 2018), and allowing greater understanding of how these syndromes relate to each other. Furthermore, the use of such biomarkers, in combination with comprehensive behavioural testing and longitudinal scanning, in large research cohorts has enabled researchers to explore atrophy patterns and cognitive profiles in mild cognitive impairment in addition to Alzheimer's dementia (Zhang et al., 2016). In this issue of Brain, ten Kate and co-workers have taken this approach further by using a data-driven cluster analysis to identify subtypes in multiple Alzheimer's disease dementia cohorts, and then attempting to group biomarker-positive individuals with prodromal Alzheimer's disease into these subtypes (ten Kate et al., 2018).

Figure 1.

Amyloid PET scan in Alzheimer's disease. Colour image of an amyloid PET scan from a patient with increasing episodic memory impairment. There is loss of grey/white matter differentiation in multiple regions strongly suggestive of widespread amyloid deposition. Courtesy of Dr Zarni Win.

The authors identified four atrophy subtypes in a dataset of patients with dementia imaged with a single scanner in Amsterdam, before validating these subtypes in a separate cohort of patients from Amsterdam as well as individuals with dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. In addition to the 'classical' medial-temporal-predominant atrophy group with memory and language dysfunction, they found three other clusters: a posterior atrophy group with poor executive function/attention and poor visuospatial function, a group with mild atrophy with relatively better cognition, and a subtype with diffuse cortical atrophy and intermediate cognitive features (Table 1). Critically, age, biomarker profile and other features formed part of the defining characteristics. For example, the mild atrophy group was relatively young with the highest CSF tau levels, whereas patients in the medial-temporal atrophy group were older, and had the greatest burden of vascular lesions and the lowest CSF tau levels. The authors applied their classification to over 600 individuals with prodromal Alzheimer's disease (from the Amsterdam Dementia Cohort and from the ADNI) and found that the four subgroups manifested subtle differences in their rate and profile of cognitive decline.

This important study by ten Kate et al. builds on previous work and provides further evidence for an intermediate subtype of Alzheimer's dementia that does not strongly conform to a specific set of cognitive features. Furthermore, the data suggest that the mapping between CSF biomarkers and cognitive profile is not straightforward, and that particular molecular biomarker characteristics may relate to specific cognitive features rather than there being a one-to-many mapping (Husain, 2017). The study also adds to recent work by Dong and co-workers (2017), suggesting that subtypes exist at the prodromal stage. However, it should be noted that around 21% of prodromal subjects in the current study showed a match to more than one subtype, and that the proportion of subjects in each group was different for the prodromal dataset versus the Alzheimer's disease dementia subsets. In particular, a larger proportion (55%) of the prodromal patients belonged to the milder atrophy group. Thus, one issue that deserves further evaluation is whether the different subtypes observed in the prodromal Alzheimer's disease population may represent points on the same trajectory, rather than distinct patient groups. ten Kate et al. suggest that the biomarker profiles from their study indicate that this is not the case, and their account would be in keeping with longitudinal data previously published by Zhang and colleagues (2016). However, it is still possible that a significant proportion of individuals with Alzheimer's disease show longitudinal crossover between subtypes (i.e. mild to diffuse or mild to medial-temporal), whereas other individuals (e.g. parieto-occipital) remain 'true-to-subtype' for a much longer period.

Another aspect of the study that must be considered is that, although the cluster analysis employed by the authors is data-driven and unbiased, it can only work with the cohort data that are available; hence the conflation of attention and executive function into a single neuropsychological domain in this study. It is possible that datasets with more detailed cognitive measures might allow better definition of existing subtypes and the identification of more disease clusters. An additional area that is likely to be of particular interest is the neuropsychiatric symptom profile in prodromal Alzheimer's disease. Recent research suggests that symptoms such as agitation, anxiety, appetite changes and depression can occur at the earliest pathological stages of the disease (Ehrenberg et al., 2018). Exactly how these psychiatric symptoms map onto each of the four subtypes described by ten Kate and colleagues is of great interest. Moreover, although the classification in the current study included the presence of white matter hyperintensities on MRI, the datasets do not include systematic information regarding comorbidities. Particularly in older individuals, further knowledge concerning co-existing conditions such as diabetes and hypertension is likely to throw light on the pathogenesis and development of Alzheimer's disease. Specifically, knowing whether certain subtypes are more likely to suffer from one or more of these conditions may further inform our understanding of the variable rate of progression across subtypes (Li et al., 2011). The lectures will keep becoming more complicated, and even more interesting.