Cognitive resilience to Alzheimer's disease characterized by cell-type abundance

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2024-09-11 DOI:10.1002/alz.14187

Nicholas O'Neill, Thor D. Stein, Oluwatosin A. Olayinka, Jenny A. Empawi, Junming Hu, Tong Tong, Xiaoling Zhang, Lindsay A. Farrer

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Abstract

INTRODUCTION

The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood.

METHODS

Abundance of 13 cell types and neuronal subtypes in brain bulk RNA-seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution.

RESULTS

PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (P_adj< 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (P_adj= 8.4 × 10⁻⁷) and PCC (P_adj= 0.0015). We identified genome-wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p = 6.08 × 10⁻¹²). rs13237518 was also associated with amyloid beta (p = 0.0085) and tangles (p = 0.0073).

DISCUSSION

High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology.

Highlights

Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience.
PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status.
A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology.

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以细胞类型丰富性为特征的阿尔茨海默病认知恢复能力

病理确诊的阿尔茨海默病（AD）病例认知恢复能力（CR）的分子基础尚不十分清楚。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.