Transcriptome signatures associated with cognitively unimpaired individuals with pathologically confirmed Alzheimer disease

There is growing interest in cognitive resilience to Alzheimer’s disease (AD), given limited success of therapies targeting hallmark proteins. Gene expression in the prefrontal cortex region obtained from brain donors in three cohorts was compared among pathological controls and pathological confirmed AD cases who met clinical criteria for AD (SymAD) or were cognitively normal (AsymAD) prior to death. Expression of genes that were differentially expressed at a transcriptome-wide significance level (TWS, P < 3.06 × 10⁻⁶) were tested for association with measures of performance in three cognitive domains and AD-related neuropathological traits. We also conducted gene network analyses seeded with nominally significant differentially expressed genes (DEGs, P < 0.05) to identify AD-related pathways. We identified 39 TWS DEGs distinguishing SymAD from AsymAD cases. Increased expression of two of the top-ranked DEGs, ADAMTS2 and PAFAH1B3 , was associated with poorer memory, language and executive function performance and lower tau protein level and synaptic density. Increased expression of HMGN2 was associated with better memory performance. Pathway analyses showed that significant DEGs are involved in neuron projection, BDNF signaling and ciliopathy pathways. This study identified DEGs for cognitive resilience, revealing potential targets for delaying AD symptoms.