Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: A retrospective study

By M. Murray, N. Graff-Radford, O. Ross, Ronald C. Petersen, R. Duara, Dennis W. Dickson. Lancet Neurology, 2011

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Objective Neurofibrillary pathology has a stereotypic progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme. Some AD cases do not fit the Braak staging scheme and are considered atypical. The purpose of this study was to compare clinical and pathological features of typical AD with atypical AD that had either hippocampal sparing (HpSp) and limbic-predominant (LP) neurofibrillary pathology. Methods A mathematical algorithm was devised to classify AD cases into typical, HpSp and LP according to the density and distribution of neurofibrillary tangle (NFT) counts from thioflavin S fluorescent microscopy in three cortical regions and two Hp sectors. The algorithm was applied to NFT counts of 889 cases of AD (409 men and 480 women; age at death: 37-103 years). Cases so classified were compared on clinical, demographic, pathological and genetic grounds. An independent series of 113 cases of AD were similarly evaluated to validate findings from the initial cohort. Findings In comparison to typical AD, HpSp (n=97) had higher NFT densities in cortical areas and lower NFT densities in hippocampus, while LP (n=127) had lower NFT densities in cortical areas and higher NFT densities in the Hp. HpSp had less Hp atrophy than typical AD (11%) and LP (14%). HpSp were younger, with a higher proportion of men, whereas LP was older, with a higher proportion of women. MAPT H1H1 genotype was more frequent in LP compared with HpSp, but not between LP and typical AD. APOE ε4 allele status differed among AD subtypes only when age of onset was considered. Clinical presentation, age of onset, disease duration, and rate of decline differed among the AD subtypes. The findings were confirmed in a replication cohort. Interpretation Our data supports the hypothesis of distinct clinicopathologic subtypes of AD. HpSp and LP AD account for about 25% of AD and are important to consider in clinical, genetic, biomarker and treatment studies.

Subfields: Neurology, Physiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/44037b2927daae519e52244a6b3e4d9bbcf2bd8c

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Citations in the corpus

Primary age-related tauopathy (PART): a common pathology associated with human aging (2014, background): “along a common continuum with PART [76, 79, 105].”
PET Imaging of Tau Deposition in the Aging Human Brain (2016, neutral): “…many patients with early age of onset (mean age at PET 65) and nonamnestic clinical presentations, both of which are associated with neocortical-predominant neurodegeneration and relative sparing of MTL in terms of both atrophy and tau burden (Murray et al., 2011; Ossenkoppele et al., 2015a).”
Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease (2017, background): “Finally, both post-mortem (Hof et al., 1989; Murray et al., 2011; Gefen et al., 2012) and in vivo (Dronse et al.”
Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer's Disease Centers, 2005–2010 (2012, background): “This is a useful addition, although other clinically and neuropathologically defined AD subtypes have not been addressed (51).”
Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. (2016, background): “…of ‘hippocampal-sparing’ Alzheimer’s disease, where greater tangle burden in cortical versus medial temporal regions is observed in a subset of patients, and is correlated with early age-of-onset, non-amnestic clinical presentations, and lower prevalence of the APOE e4 allele (Murray et al., 2011).”
Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. (2018, background): “Atypical pathological forms of AD, such as posterior cortical atrophy and frontal variants, tend to not conform to Braak’s staging and may spare the hippocampus (Murray et al. 2011).”
The neuropathological diagnosis of Alzheimer’s disease (2019, background): “Genetic analyses of APOE suggest APOE4 is more closely linked to typical or limbic predominant than hippocampal sparing AD [3].”
Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012, background): “It remains to be determined whether these individuals died early in the course of an idiosyncratic subtype of AD (12) or instead reﬂect a completely different pathogenesis.”
Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models (2014, background): “Not all AD cases fall within the standard NFT distribution described by the Braak staging (Hof et al., 1997; Abner et al., 2011; Murray et al., 2011).”