Neuropathological heterogeneity in Alzheimer’s disease: A study of 80 cases using principal components analysis

Abstract

Three hypotheses have been proposed to explain neuropathological heterogeneity in Alzheimer's disease (AD): the presence of distinct subtypes ('subtype hypothesis'), variation in the stage of the disease ('phase hypothesis') and variation in the origin and progression of the disease ('compensation hypothesis'). To test these hypotheses, variation in the distribution and severity of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in 80 cases of AD using principal components analysis (PCA). Principal components analysis using the cases as variables (Q-type analysis) suggested that individual differences between patients were continuously distributed rather than the cases being clustered into distinct subtypes. In addition, PCA using the abundances of SP and NFT as variables (R-type analysis) suggested that variations in the presence and abundance of lesions in the frontal and occipital lobes, the cingulate gyrus and the posterior parahippocampal gyrus were the most important sources of heterogeneity consistent with the presence of different stages of the disease. In addition, in a subgroup of patients, individual differences were related to apolipoprotein E (ApoE) genotype, the presence and severity of SP in the frontal and occipital cortex being significantly increased in patients expressing apolipoprotein (Apo)E allele epsilon4. It was concluded that some of the neuropathological heterogeneity in our AD cases may be consistent with the 'phase hypothesis'. A major factor determining this variation in late-onset cases was ApoE genotype with accelerated rates of spread of the pathology in patients expressing allele epsilon4.

A critical analysis of the ‘amyloid cascade hypothesis’

“…These observations suggest that in early-onset FAD, Aβ within SP is the residue of the effects of a pathogenic gene mutation which, via the accumulation of toxic and insoluble Aβ oligomers, leads to the formation of NFT, cell death, and dementia. Since the pathological phenotype of FAD is similar, apart from age of onset, to that of the more common SAD [13,59,97], similar mechanisms, via additional genetic risk factors and/or environmental factors, are assumed to be involved in the pathogenesis of all types of AD [128]. A more fully developed version of the ACH incorporating these various features is shown in Figure 2.…”

Characterization of brain anatomical patterns by comparing region intensity distributions: Applications to the description of Alzheimer's disease

“…Although the disease progression has been traditionally assessed under the Braak and Braak staging scheme (Braak & Braak, 1991), several reports (Akatsu et al., 2002; Armstrong, Nochlin, & Bird, 2000; Janocko et al., 2012; Murray et al., 2014) have demonstrated a very variable AD clinical picture: Neither the progression patterns nor the same anatomical areas are involved or follow a reproducible anatomic sequence, even in series of patients belonging to comparable social and cultural environments. Approximately 25% of AD brains show atypical patterns of structural damage, usually classified as hippocampal sparing and limbic predominant AD (Murray et al., 2011).…”

On the ‘classification’ of neurodegenerative disorders: discrete entities, overlap or continuum?

“…One possible method is to use a non-hierarchical system based on 'ordination', i.e., by arranging cases of disease with reference to a coordinate frame so that the interrelationships between cases are spatially represented [117]. Such methods have been used to examine the degree of neuropathological heterogeneity in cases of AD [13] and FTLD-TDP [20] and often reveal a continuum but have not to date been used to provide a conceptual framework for the 'classification' of neurodegenerative disease.…”