In patients with Alzheimer disease (AD) there is an association between the severity of neurofibrillary tangles (NFT) pathology in the nucleus basalis of Meynert (nbM) and neuropathologic subtypes of AD, which may contribute to the differential benefit of acetyl-cholinesterase inhibitor treatment, according to study results published in JAMA Neurology.
Studies have suggested that the nbM may be among the earliest sites of NFT accumulation. Previously, researchers demonstrated 3 distinct regional patterns of corticolimbic NFT accumulation in subtypes of AD, including hippocampal sparing AD, limbic predominant AD, and typical AD. These subtypes have striking differences in demographic and clinical progression.
As the nbM is a significant target for cholinergic treatment, the goal of the current study was to assess the selective vulnerability of the cholinergic system in AD by exploring the severity of accumulation and neuronal loss in the nbM among AD subtypes.
The cross-sectional study included 1361 AD cases and 103 control individuals without dementia from the Florida Autopsied Multi-Ethnic (FLAME) cohort. Quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic.
The accumulation of NFT (count per 0.125mm2) in the anterior level of the nbM was highest in 163 hippocampal sparing AD cases (median, 14; interquartile range [IQR], 9-20), lower in 937 typical AD cases (median, 10; IQR, 5-16), and lowest in 163 limbic predominant AD (median 8; IQR, 5-11) (P <.001).
Neuronal density (per millimeter squared) in the nbM was lowest in 148 hippocampal sparing AD cases (median, 22; IQR, 17-28), compared to 727 typical AD (median, 25; IQR, 19-30) and 127 limbic predominant AD (median, 26; IQR, 19-32) (P =.002).
Multivariable regression analysis revealed a significant association between higher NFT accumulation in the nbM and a younger age of AD onset. For every 10 years younger age at onset, the number of NFTs was expected to be higher by 1.5 (95% CI, −2.9 to −0.15; P =.03) in hippocampal sparing AD cases and by 3.2 (95%CI, −3.9 to−2.4; P <.001) in typical AD cases. In addition, amongst typical AD cases, females were expected to have 2.5 (95% CI, 1.4- 3.5) more NFTs than males (P <.001).
Further, the increased NFT accumulation in the nbM of typical AD cases was associated with apolipoprotein ε4 allele, as APOEε4 carriers were expected to have 1.3 (95%CI, 0.15-2.5) more NFTs than APOEε4 non-carriers (P =.03). For every 10-point decrease
in final Mini-Mental State Examination of typical AD cases, the number of nbM NFTs was expected to increase by 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.
The researchers acknowledged several study limitations, including various biases associated with consenting to autopsy, such as self-selection, higher educational level, marital status, and race/ethnicity.
“The findings reported in the present study, as well as those reported by others, underscore the importance of considering age at onset, sex, and APOE genotype when interpreting outcomes in AD,” concluded the researchers.
Hanna Al-Shaikh FS, Duara R, Crook JE, et al. Selective vulnerability of the nucleus basalis of Meynert among neuropathologic subtypes of Alzheimer disease. [published online October 28, 2019]. JAMA Neurol. doi: 10.1001/jamaneurol.2019.3606