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

Abstract

The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood. 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. PVALB+ 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 (p=6.08×10-12). rs13237518 was also associated with amyloid beta (p=0.0085) and tangles (p=0.0073). High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology. 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.