. Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer's disease. medRχiv September 20, 2019


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  1. Rik Ossenkoppele and co-authors have extended their previous study (Ossenkoppele et al., 2015) using functional metabolic measures. Whereas structural MRI does not significantly distinguish between bvAD and typical AD, metabolic PET and connectivity have shown decreased activity of frontoinsular and anterior default mode network in bvAD, similar to bvFTD.

    The clinical differential diagnosis between bvAD and typical AD is quite simple when the behavioral symptoms are clear and evident at the onset of the disease. However, the diagnosis between bvAD and bvFTD is clinically very difficult without imaging.

    It might be interesting to apply the functional measures used in this study in patients presenting with apathy and dysexecutive syndrome in comparison with patients presenting with disinhibition and abnormal behavior. This evaluation could provide further hints for research on discriminating between AD and FTD.  


    . The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain. 2015 Sep;138(Pt 9):2732-49. Epub 2015 Jul 2 PubMed.

    View all comments by Massimo Tabaton
  2. Singleton et al. show that Alzheimer’s disease, which typically leads to an amnestic dementia, can also have behavioral variants and that the determinant of the phenotype is the anatomy of the neurodegeneration. Similar patterns of heterogeneity were previously reported in primary progressive aphasia (PPA). PPA can be caused by frontotemporal lobar degenerations (FTLD) or AD. When PPA is caused by AD, the atrophy and neurofibrillary tangles can be more prominent within the language network than in medial temporal cortex (Gefen et al., 2012). Perturbations of functional connectivity by AD are more pronounced within the language network in the PPA phenotype and within the hippocampal network in the typical amnestic phenotype (Martersteck et al., in press). 

    The Singleton et al. paper shows that similar principles of heterogeneity are also identifiable in the behavioral dementias. It will be interesting to see if the reported findings on the behavioral variant of AD can be extended to the level of functional connectivity and neuropathology, as has been done in PPA. From a practical point of view, these developments further show that the relationship of phenotype to underlying disease is probabilistic rather than deterministic and that the judicious use of biomarkers is essential for the differential diagnosis of dementias.


    . Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain. 2012 May;135(Pt 5):1554-65. PubMed.

    . Differential neurocognitive network perturbation in amnestic and aphasic Alzheimer disease. Neurology. 2020 Feb 18;94(7):e699-e704. Epub 2020 Jan 22 PubMed.

    View all comments by Marsel Mesulam
  3. This large study has better clarified both that there is indeed a behavioral variant of Alzheimer’s disease and that more anterior pathology underpins this variant. There are at least four variants of AD—the more typical amnestic variant, logopenic aphasia, and posterior cortical atrophy are the other three, but there may be more. This should be expected—no disease has an identical phenotype in all those affected. With AD, however, it is important to recognize this frontal variant, because many would otherwise be assumed to have behavioral-variant frontotemporal dementia.

    We know that amyloid sends tau from the medial temporal lobe into other cortical brain regions—this amyloid “trigger” sends off the tau “bullet.” Usually the pathology travels through the default mode network, affecting predominantly the posterior cingulate and the precunei, and usually only later does the pathology spread to other networks, but in some people these other networks are involved earlier, and thus the different initial phenotypes. Why this happens is unclear—as in many other diseases (why are cataracts usually more advanced in one eye, why is psoriasis worse in a region on one side than on the other side?). What is clear is that the presence of behavioral/frontal features in a person with an amnestic disorder, and with neuroimaging and other features otherwise suggestive of AD, should not lead to the diagnosis of AD being discarded.

    In the future this will impact on matching disease-modifying treatments to the patient, and even now may impact on recruitment into trials. We need the right diagnosis and the right treatment—and it is a little more complex than was previously thought.    

    View all comments by Michael Woodward

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This paper appears in the following:


  1. Frontal Metabolic Patterns Mark Behavioral Subtype of AD