1. Widespread cholinergic deficits found in early-onset Alzheimer’s disease (AD) may be a result of neurofibrillary tangle accumulation in the nucleus basalis of Meynert, specifically in those with hippocampal sparing AD.
Evidence Rating Level: 1 (Excellent)
The nucleus basalis of Meynert (nbM) is a well-known target for cholinergic therapy, suggesting that Alzheimer’s disease (AD) subtype heterogeneity may illuminate differences in neuronal loss and neurofibrillary tangle (NFT) accumulation in the nbM. Three distinct patterns of corticolimbic neurofibrillary tangle (NFT) accumulation have been discovered in the following subtypes of AD, from least to most hippocampal involvement: 1) hippocampal sparing (HpSp) AD; 2) typical AD; and, 3) limbic predominant AD. This study was a cross-sectional, retrospective abstraction of clinical records and quantitative assessments of NFTs and neuron counts in the anterior nbM through the Florida Autopsied Multi-Ethnic (FLAME) cohort. Data was collected from 1991 to 2015, including 1,361 AD subtypes and 103 non-dementia controls. Median age at death was 72 (95% CI 66 to 80) years for HpSp AD, 81 (95% CI 76-86) years for typical AD, and 86 (95% CI 82-90) years for limbic predominant AD. It was found that the nbM of HpSP AD had the highest median count per 0.125mm2 of thioflavin S-positive NFTs (14 [9-20]), which was lower in typical AD (10 [5-16]) and lowest in limbic predominant AD (8 [5-11]), which were clinically significant differences (p<0.001). Median neuronal density per mm2 was lowest in HpSp AD (22 [17-28]), higher in typical AD (25 [19-30]), and highest in limbic predominant AD (26 [19-32]). Overlap of neuronal density and NFT accumulation were further assessed with multi-variable regression modeling, finding that NFT accumulation was inversely related with age of onset in HpSp AD (B -1.5, 95% CI -2.9 to -0.15, p=0.03) and typical AD (B -3.2, 95% CI -3.9 to -2.4, p<0.001). In HpSp AD, the number of NFTs was expected to be higher by 1.5 for every 10 years earlier the onset (95% CI -2.9 to -0.15, p=0.03). Higher NFT accumulation in nbM of typical AD was also associated with apolipoprotein E (APOE) ε4 allele (B 1.3; 95% CI 0.15 to 2.5, p=0.03), female sex (B 2.5, 95% CI 1.4 to 3.5, p<0.001), and lower Mini-Mental Status Examination scores (B -1.8, 95% CI -3.2 to -0.31, p=0.02). These variables were not associated with nbM-specific NFT accumulation in limbic predominant AD, though the neuron count in this group was expected to be lower by 4.6 for every 10 years earlier the onset (95% CI 2.3 to 7.0, p<0.001). This study suggests that NFT accumulation in the nbM may be an important factor in the cholinergic deficits found in early-onset AD, specifically those with HpSp AD. These findings highlight a noteworthy basis for considering specific variables during assessment of AD outcomes, such as age of onset, APOE genotype, and sex.
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