Clinical heterogeneity in familial Alzheimer’s disease
Authors: Wiesje M Van der Flier
Journal: The Lancet Neurology (2016)

Two studies of non-amnestic manifestations of autosomal dominant familial Alzheimer’s disease (ADAD) are reported in The Lancet Neurology.1Tang M Ryman DC McDade E et al.for the Dominantly Inherited Alzheimer Network (DIAN)Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30229-0PubMed Google Scholar, 2Ryan NS Nicholas JM Weston PSJ et al.Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series.Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30193-4PubMed Google Scholar In the first study, Mengxuan Tang and colleagues1Tang M Ryman DC McDade E et al.for the Dominantly Inherited Alzheimer Network (DIAN)Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30229-0PubMed Google Scholar report, on behalf of the Dominantly Inherited Alzheimer Network (DIAN) consortium, a combined description of the DIAN observational study (DIAN-OBS) cohort and the scientific literature.1Tang M Ryman DC McDade E et al.for the Dominantly Inherited Alzheimer Network (DIAN)Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30229-0PubMed Google Scholar In the second study, Natalie Ryan and colleagues2Ryan NS Nicholas JM Weston PSJ et al.Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series.Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30193-4PubMed Google Scholar describe heterogeneous cognitive symptoms and neurological features in a large series of participants that were referred to the Dementia Research Centre in London, UK, over many years. Tang and colleagues1Tang M Ryman DC McDade E et al.for the Dominantly Inherited Alzheimer Network (DIAN)Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30229-0PubMed Google Scholar compare individual data from 1228 patients with ADAD (753 with detailed clinical data) with data from the DIAN-OBS cohort. They found that non-cognitive features, such as myoclonus and seizures, were commonly observed in patients reported on in the published work (each in approximately one of five patients). By contrast, motor features were far less common in the 107 symptomatic patients in the DIAN-OBS cohort (9% had myoclonus and 3% had seizures). Findings were inverted for non-amnestic cognitive symptoms: atypical presentations of aphasia, visual agnosia, and behavioural changes were quite common in the DIAN-OBS cohort (>50%) but were far more rare in the patients described in the published work (<30%). Ryan and colleagues2Ryan NS Nicholas JM Weston PSJ et al.Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series.Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30193-4PubMed Google Scholar describe a large case series of 213 patients with PSEN1 or APP mutations (detailed medical history was available for 121 only). Myoclonus and seizures were the most common non-cognitive neurological features, with myoclonus—observed in 33% of individuals with APP mutations and 47% of individuals with PSEN1 mutations—being a significant risk factor for seizures (occurring in about one in four patients). Individuals with APP mutations almost invariably had amnestic presentations (97%); by contrast, amnestic symptoms were significantly less common in patients with PSEN1 mutations (84%; p=0·037). Of note, even though Ryan and colleagues describe the non-amnestic presentations in patients with PSEN1 mutations as common, these non-amnestic presentations were far less common in their case series (16% in PSEN1, 3% in APP) than in DIAN-OBS (>50%). As such, Ryan and colleagues’ case series is similar to as described in the analysis of the literature by Tang and colleagues. It is not evident what explains these differences, but methodological aspects, particularly selection bias and measurement bias,3Moulder KL Snider BJ Mills SL et al.Dominantly Inherited Alzheimer Network: facilitating research and clinical trials.Alzheimers Res Ther. 2013; 5: 48Crossref PubMed Scopus (109) Google Scholar probably contribute to the difference in observed prevalence, as noted by both groups of authors. Both Articles share the important message that recognising clinical heterogeneity in Alzheimer’s disease is crucial. An accurate diagnosis is of great importance because this is the starting point for best patient management. Heterogeneity in Alzheimer’s disease needs to be recognised because diagnoses are too often missed in patients with atypical presentations, and understanding heterogeneity might provide keys to finding treatments. Also, a substantial proportion of patients with sporadic Alzheimer’s disease have non-amnestic presentations, such as visual agnosia, aphasia, or dysexecutive or behavioural phenotypes.4Crutch SJ Schott JM Rabinovici GD et al.Shining a light on posterior cortical atrophy.Alzheimers Dement. 2013; 9: 463-465Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 5Ossenkoppele R Pijnenburg YA Perry DC et al.The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features.Brain. 2015; 138: 2732-2749Crossref PubMed Scopus (294) Google Scholar, 6Gorno-Tempini ML Hillis AE Weintraub S et al.Classification of primary progressive aphasia and its variants.Neurology. 2011; 76: 1006-1014Crossref PubMed Scopus (3032) Google Scholar Clinicians should be aware that memory can be relatively spared in Alzheimer’s disease until advanced stages of the disease. Particularly in patients with an atypical presentation or an atypical age at onset, diagnosis is often missed because many professionals do not think of Alzheimer’s disease when they see a 50 year old complaining of losing track of deadlines at work or having difficulty mastering a novel software package. The likelihood of an atypical presentation gradually increases with a younger age at onset.7Barnes J Dickerson BC Frost C Jiskoot LC Wolk D van der Flier WM Alzheimer’s disease first symptoms are age dependent: Evidence from the NACC dataset.Alzheimers Dement. 2015; 11: 1349-1357Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Patients with an onset later than 80 years typically present with early and prominent amnestic problems, but in those with an onset before the age of 65 years, atypical presentations occur in roughly one of three patients.8Koedam EL Lauffer V van der Vlies AE van der Flier WM Scheltens P Pijnenburg YA Early-versus late-onset Alzheimer’s disease: more than age alone.J Alzheimers Dis. 2010; 19: 1401-1408Crossref PubMed Scopus (288) Google Scholar, 9van der Flier WM Pijnenburg YA Fox NC Scheltens P Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE varepsilon4 allele.Lancet Neurol. 2011; 10: 280-288Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar The latest diagnostic criteria reflect these findings; the National Institute on Aging—Alzheimer’s Association (NIA-AA) criteria and the International Working Group (IWG) criteria no longer require memory impairment for a clinical diagnosis of Alzheimer’s disease, as they recognise that Alzheimer’s disease might also start with deficits in other cognitive domains.10McKhann GM Knopman DS Chertkow H et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement. 2011; 7: 263-269Summary Full Text Full Text PDF PubMed Scopus (9202) Google Scholar, 11Dubois B Feldman HH Jacova C et al.Revising the definition of Alzheimer’s disease: a new lexicon.Lancet Neurol. 2010; 9: 1118-1127Summary Full Text Full Text PDF PubMed Scopus (1467) Google Scholar Additionally, the NIA-AA criteria list changes in personality, behaviour, or comportment as a fifth cognitive domain. These criteria fit the observations in the study by Tang and colleagues, who observed changes in personality and behaviour in 61% of the DIAN participants and 32% of the cases described in the published work. However, a drawback of listing these changes as a fifth cognitive domain is that it is quite difficult to establish norms or cut offs. When is behaviour so abnormal that it should count as an impaired domain on which to establish a diagnosis of dementia? In the course of dementia, almost every patient encounters behavioural problems to some extent, which might be intrinsically caused by the disease process or be a reaction their experience of ongoing decline. By contrast to changes in cognition, behavioural impairment does not show a monotonic decline with the disease process, but rather has a sinoid-like course. For example, a patient might experience depression early on, but, as the disease progresses, their mood may actually lift. Additionally, behavioural symptoms come and go over the course of disease, and symptoms such as delusions or aberrant motor activity might develop at any time. Neither the NIA-AA or IWG criteria mentions non-cognitive neurological features in the diagnosis of Alzheimer’s disease, other than in the context of mixed dementia due to stroke or Lewy body pathology. These neurological features seem to only present in a later stage of the disease and hence are of less relevance for diagnosis. Heterogeneity in manifestation might reflect variation in underlying molecular pathways, and disentangling the various routes to dementia due to Alzheimer’s disease could ultimately lead to different therapeutic strategies tailored to specific patient groups. As a first possibility, the heterogeneity in clinical presentation might be due to mixed pathology. For example, in late-onset Alzheimer’s disease mixed disease is the norm rather than the exception, and co-occurring Lewy body pathology or vascular pathology might contribute to clinical heterogeneity. If patients present with mixed disease, it would seem logical to target treatment for each of the contributing pathologies, rather than base treatment strategies on the prevailing clinical diagnosis alone.12Scheltens P Blennow K Breteler MM et al.Alzheimer’s disease.Lancet. 2016; 388: 505-517Summary Full Text Full Text PDF PubMed Scopus (1887) Google Scholar However, mixed disease cannot be the only explanation for clinical heterogeneity. This is illustrated by the fact that clinical heterogeneity is even more common in patients with an early age of onset, and within the spectrum of Alzheimer’s disease, vulnerability of brain regions to disease seems to vary among patients. For example, although most patients with Alzheimer’s disease have a predominantly temporal distribution of pathology, pathology is more posterior in others. These studies1Tang M Ryman DC McDade E et al.for the Dominantly Inherited Alzheimer Network (DIAN)Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30229-0PubMed Google Scholar, 2Ryan NS Nicholas JM Weston PSJ et al.Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series.Lancet Neurol. 2016; (published online Oct 21.)http://dx.doi.org/10.1016/S1474-4422(16)30193-4PubMed Google Scholar support this idea that even monogenetic forms of the disease do not present with one uniform manifestation. Although Tang and colleagues report that mutation type was related in some extent to variation in age at onset and Ryan and colleagues report an association with likelihood of atypical cognitive symptoms, this did not explain a large proportion of the observed heterogeneity. Instead, the origin of the observed variability in pathology could lie in other factors (eg, environmental, metabolic, or epigenetic). A second possibility is that the heterogeneity observed in these two studies does have a genetic origin, with genes other than the major causative ones contributing to variations in vulnerability of specific brain regions. As an example, former studies have suggested that APOE ε4-negative patients are more likely to present with atypical cognitive symptoms.7Barnes J Dickerson BC Frost C Jiskoot LC Wolk D van der Flier WM Alzheimer’s disease first symptoms are age dependent: Evidence from the NACC dataset.Alzheimers Dement. 2015; 11: 1349-1357Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Developmental factors might also contribute to regional vulnerability. For example, individuals that had language learning disability as a child might be more prone to have a logopenic progressive aphasia related to Alzheimer’s disease at a later age.13Miller ZA Mandelli ML Rankin KP et al.Handedness and language learning disability differentially distribute in progressive aphasia variants.Brain. 2013; 136: 3461-3473Crossref PubMed Scopus (88) Google Scholar This notion would fit with the general idea that the strength of specific neural networks not only lie at the heart of variability in regional vulnerability,14Mandelli ML Vilaplana E Brown JA et al.Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia.Brain. 2016; 139: 2778-2791Crossref PubMed Scopus (78) Google Scholar, 15Mesulam MM A plasticity-based theory of the pathogenesis of Alzheimer’s disease.Ann N Y Acad Sci. 2000; 924: 42-52Crossref PubMed Scopus (108) Google Scholar, 16Mattsson N Schott JM Hardy J Turner MR Zetterberg H Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer’s disease.J Neurol Neurosurg Psychiatry. 2016; 87: 1000-1004Crossref PubMed Scopus (48) Google Scholar but also that strengthening specific neural networks might be at the core of resilience to pathology, and, as such, provide a target for treatment. The notion that we will find one treatment that cures all patients with Alzheimer’s disease is quickly losing ground. Far more likely is the idea that in the future, specific subtypes of Alzheimer’s disease could benefit from specific medications. To attain that goal, recognition and deep understanding of heterogeneity in clinical manifestation of Alzheimer’s disease is a necessary step. I declare no competing interests. Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)The non-cognitive clinical manifestations of Alzheimer’s disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer’s disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. Full-Text PDF Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case seriesADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Full-Text PDF Open Access