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

Author:

O'Neill Nicholas12,Stein Thor D.345,Olayinka Oluwatosin A.12,Empawi Jenny A.2,Hu Junming12,Tong Tong12,Zhang Xiaoling126,Farrer Lindsay A.12678

Affiliation:

1. Bioinformatics Program Boston University Boston Massachusetts USA

2. Department of Medicine (Section of Biomedical Genetics) Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA

3. Department of Pathology and Laboratory Medicine Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA

4. VA Bedford Healthcare System Bedford Massachusetts USA

5. VA Boston Healthcare Center Boston Massachusetts USA

6. Department of Biostatistics Boston University School of Public Health Boston Massachusetts USA

7. Department of Neurology Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA

8. Department of Ophthalmology Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA

Abstract

AbstractINTRODUCTIONThe molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood.METHODSAbundance 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.RESULTSPVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (Padj < 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (Padj = 8.4 × 10−7) and PCC (Padj = 0.0015). We identified genome‐wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (= 6.08 × 10−12). rs13237518 was also associated with amyloid beta (= 0.0085) and tangles (= 0.0073).DISCUSSIONHigh 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.

Funder

National Institute on Aging

Illinois Department of Public Health

Translational Genomics Research Institute

Publisher

Wiley

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