Abstract
Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.
Highlights
The median count per 0.125 mm[2] of thioflavin S–positive neurofibrillary tangle (NFT) was highest in the nucleus basalis of Meynert (nbM) of hippocampal sparing (HpSp) Alzheimer disease (AD) (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001)
Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, −1.5; 95% CI, −2.9 to −0.15; P = .03) and typical AD (β, −3.2; 95% CI, −3.9 to −2.4; P < .001)
Higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, −1.8; 95% CI, −3.2 to −0.31; P = .02)
Summary
Study Samples The Florida Autopsied Multi-Ethnic (FLAME) cohort, 14,15 which had been accessioned from 1991 to 2015, is derived from a consecutive series of patients who elected to participate in a deeded autopsy program via memory disorder clinic referral services. These services included community-based educational seminars for caregivers of patients with dementia and Alzheimer Association educational support groups. The FLAME cohort, which comprised 2809 individuals (1436 [51%] males and 1373 [49%] females), with an age at death ranging between 36 and 104 years, was queried for neuropathologically diagnosed AD cases and normal controls who were nondemented. Of the remaining 121 controls who were nondemented (Braak tangle stage
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