From the Journals

Alzheimer’s disease subtypes follow neuropathologic patterns seen in the nucleus basalis of Meynert



Cholinergic neurons in the nucleus basalis of Meynert appear more susceptible to neurofibrillary tangles and neuronal destruction in women, patients carrying the apolipoprotein E–epsilon 4 (APOE4) allele, and people with hippocampal-sparing Alzheimer’s disease, a subtype characterized by early onset and rapid cognitive decline.

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Those findings and others from a postmortem study published in JAMA Neurology also suggests that the nucleus basalis of Meynert (nbM) could be the first place that neuronal damage appears in Alzheimer’s disease (AD), according to first author Fadi S. Hanna Al-Shaikh and colleagues.

The study also confirmed the authors’ previous categorization of three AD subtypes: early-onset, rapidly declining hippocampal-sparing AD (HpSp), typical sporadic AD, and limbic predominant AD, a later-onset form with a slower rate of decline.

“We observed a wave of vulnerability in which the exacerbation of nbM neurofibrillary tangles [NFTs] in HpSp AD may leave the cortex more vulnerable to [tangle] accumulation, perhaps via a biologically accelerated process or through a mechanism of disinhibition,” wrote Mr. Al-Shaikh, of the Mayo Clinic, Jacksonville, Fla., and colleagues. “By contrast, the limbic predominant AD cases had an exacerbation of areas vulnerable early in the Braak-like pattern of NFT accumulation, perhaps via a biologically restrictive process that relatively confines pathology to limbic areas.”

The nbM is of interest to researchers because 90% of its neurons are cholinergic with cortical penetration. “Postmortem studies of AD and more recent neuroimaging studies provide evidence that involvement of the nucleus basalis of Meynert may be critical and early in the molecular cascade of events,” the authors said. “The accumulation of NFTs in the nbM may precede entorhinal cortex and locus coeruleus involvement, making the nbM potentially one of the earliest sites where NFT accumulation occurs.”

Previously, this team had identified three AD subtypes based on patterns of corticolimbic neurofibrillary tangling. In HpSp, the hippocampus is relatively spared, while the cortex has a greater number of tangles. In limbic predominant AD, the cortex is relatively spared, and the hippocampus is severely involved. Typical AD shows the expected patterns of hippocampal and cortical tangling.

Cases in this study came from the Florida Autopsied Multi-Ethnic (FLAME) cohort, comprising 1,361 brain tissue samples from confirmed AD cases and 103 nondemented controls. The investigators sought to understand the patterns of neuronal demise in the nbM, and any associations with clinical signs, demographics, and the recently described three subtypes.

In the cohort, AD subtypes included 175 with HpSp, 1,014 with typical AD, and 172 with limbic predominant AD. Patients with HpSp were the youngest, with a median disease onset age of 65 years, compared with 71 years in typical AD and 78 in limbic predominant. There were fewer women in the HpSp group (35%), compared with the typical AD group (54%) and the limbic group (70%). More patients with HpSp had atypical presentation (38%) in comparison with typical (11%) and limbic predominant AD (2%). But patients with HpSp were less likely to be APOE4 positive (46%), whereas those with limbic predominant AD were most likely to be APOE4 positive (72%).

Cognitively, HpSp patients declined more rapidly, losing a median of 4 points per year on the Mini Mental State Exam (MMSE), compared with 2 and 1 points in those with typical and limbic predominant AD. At death, the HpSp patients had a median MMSE score of 7, versus 13 in the typical AD group and 18 in the limbic group.

Patients with HpSp had the highest concentration of tangles and the lowest neuronal density in the nbM. Limbic predominant cases had the lowest tangle burden and the highest neuronal density. Typical AD cases lay between these extremes on both measures.

A multivariate regression analysis determined the overlap of neuronal findings and AD subtypes. A younger age at symptom onset was significantly associated with higher tangle counts in the nbM regions among patients with HpSp. In women with typical AD, there were 2.5 times more tangles than in men. APOE4 carriers had 1.3 times more tangles than did noncarriers.

There were also associations with cognition. “For every 10-point decrease in final MMSE of typical AD cases, the number of nbM NFTs was expected to increase by 1.8,” the authors wrote.

Although limbic predominant AD wasn’t associated with any clinical or demographic variables in this analysis, it was associated with neuronal changes in the nbM. “For every 10 years’ younger age at onset, the number of neurons was expected to be lower by 4.6 [per mm2]. … In addition, limbic predominant cases were observed to have 4.3 [per mm2] fewer neurons for every 10-point decrease in MMSE,” the authors said.

This study was supported by the National Institute on Aging, the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program, a Gerstner Family Career Development Award, and the Alzheimer’s Association. Two authors reported financial relationships with industry outside the submitted work.

SOURCE: Al Shaikh FSH et al. JAMA Neurol. 2019 Oct 28. doi: 10.1001/jamaneurol.2019.3606.

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