Neurology. 2025 Nov 25;105(10):e214310. doi: 10.1212/WNL.0000000000214310. Epub 2025 Oct 29.
ABSTRACT
BACKGROUND AND OBJECTIVES: Prospective cohort studies have demonstrated elevated risks of incident dementia in patients with essential tremor (ET). The explanation for this enhanced risk of dementia in ET is unknown. We aimed to elucidate the underlying neuropathologic features of ET-dementia.
METHODS: In a 10-year, prospective cohort study of cognition in ET, we followed participants with detailed neuropsychological testing (assessing 5 primary domains) and assigned cognitive diagnoses (normal cognition, mild cognitive impairment [MCI], or dementia) by expert consensus; brains were collected at death. Participants resided in 43 US states. The detailed neuropathologic assessment included a Braak neurofibrillary tangle stage, Braak Lewy pathology stage, Thal β-amyloid score, and neuritic plaque score. The overall level of Alzheimer disease neuropathologic changes (ADNCs) was reported using the “ABC” scale. Other tauopathies and comorbid cerebrovascular pathologies were diagnosed. During statistical comparisons, we stratified each of the above neuropathologic features into 2 categories: high vs low. We examined how neuropathologic findings mapped onto cognitive diagnoses.
RESULTS: The 381 participants yielded 86 brains (mean age at death 90.1 years, 55.8% female). Participants with ET-dementia (n = 40) had higher odds of having severe AD-type pathologies than ET-NC (n = 30): advanced Braak AD stage odds ratio (OR) = 22.8, Thal score OR = 8.0, Consortium to Establish a Registry for Alzheimer Disease score OR = 5.7, and ADNC score OR = 21.1; cerebral amyloid angiopathy scores were also higher (OR = 4.3) (all p ≤ 0.01). Participants with ET-MCI (n = 16) demonstrated intermediate neuropathology, with greater odds of higher Braak AD stages than those with ET-NC (OR = 8.0, p = 0.009). Other neuropathologies were similar across cognitive groups.
DISCUSSION: Our neuropathologic description of ET-dementia shows that, in this sample of 40 participants with ET-dementia, Alzheimer pathology is the prime driver of marked cognitive impairment in ET. Further studies are needed to refine our understanding of the nature of tau aggregation in ET and the extent to which this is similar to or diverges from that seen in AD. One implication of the current finding, which is a more direct link between ET and AD, is that this opens the door to blood-based biomarker testing in individuals with ET who are experiencing cognitive difficulties.
PMID:41160795 | DOI:10.1212/WNL.0000000000214310
