Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes
Baayla D.C. Boon, Sydney A. Labuzan, Zhongwei Peng, Billie J. Matchett, Naomi Kouri, Kelly M. Hinkle, Christian Lachner, Owen A. Ross, Nilüfer Ertekin‐Taner, Rickey E. Carter, Tanis J. Ferman, Ranjan Duara, Dennis W. Dickson, Neill R. Graff‐Radford, Melissa E. Murray
Abstract
<h3>Background:</h3> Alzheimer’s disease (AD) is neuropathologically classified into three corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed “minimal atrophy”, was identified using structural MRI. <h3>Objective:</h3> The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype. <h3>Methods:</h3> We applied two strategies in the FLorida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak IV tangle stage because of the relative paucity of neocortical tangle involvement compared to Braak>IV. Braak IV cases were compared to the three AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75<sup>th</sup> percentile) were defined as minimal atrophy. <h3>Results:</h3> Braak IV cases (n=37) differed from AD subtypes (limbic predominant [n=174], typical [n=986], and hippocampal sparing [n=187] AD) in terms of having the least years of education (median 12 years, group-wise p<0.001) and the highest brain weight (median 1140 grams, p=0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of <i>APOE ε4</i> carriers (75%, p<0.001), an amnestic syndrome (100%, p<0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p<0.001). Only 5% of Braak IV had amygdala predominant Lewy bodies (the lowest frequency observed, p=0.017), whereas 32% had coexisting pathology of Lewy body disease which was greater than the other subtypes (p=0.005). Nearly half (47%) of the Braak IV sample had coexisting limbic-predominant age-related TDP-43 encephalopathy neuropathologic change. Cases with a high brain weight (n=201) were less likely to have amygdala predominant Lewy bodies (14%, p=0.006) and most likely to have Lewy body disease (31%, p=0.042) compared to those with middle (n=455) and low brain weight (n=203). <h3>Discussion:</h3> The frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.