Transcriptome Signatures for Cognitive Resilience Among Individuals with Pathologically Confirmed Alzheimer Disease

Limited success to date in development of drugs that target hallmark Alzheimer disease (AD) proteins as a means to slow AD-related cognitive decline has sparked interest in approaches focused on cognitive resilience. We sought to identify transcriptome signatures among brain donors with neuropathologically confirmed AD that distinguish those with cognitive impairment from those that were cognitively intact.

We compared gene expression patterns in brain tissue from donors in four cohorts who were cognitively and pathologically normal (controls), met clinical and pathological criteria for AD (SymAD), or were cognitively normal prior to death despite pathological evidence of AD (cognitively resilient or AsymAD). Differentially expressed genes (DEGs) at the transcriptome-wide significance (TWS) level (P<10 ^-6 ) in the total sample and nominally significant (P<0.05) in at least two datasets were further evaluated in analyses testing association of gene expression with co-calibrated and harmonized cognitive domain scores and AD-related neuropathological traits.

We identified 52 TWS DEGs, including 14 that surpassed a significance threshold of P<5×10 ^-8 . The three most significant DEGs, ADAMTS2 (Log2 fold change [Log2FC]=0.46, P=2.94×10 ^-14 ), S100A4 (Log2FC=0.61, P=3.98×10 ^-11 ) and NRIP2 (Log2FC=0.32, P=9.52×10 ^-11 ) were up-regulated in SymAD compared to AsymAD brains. ADAMTS2 and SLC6A9 were also significantly and nominally differentially expressed between AsymAD cases and controls (FDR P=0.45 and FDR P=0.57, respectively). Significant associations (P<0.0038) were identified for executive function with expression of ADAMTS2 (P=4.15×10 ^-8 ) and ARSG (P=1.09×10 ^-3 ), and for memory with PRELP (P=3.92×10 ^-5 ) and EMP3 (P=7.75×10 ^-4 ), and for language with SLC38A2 (P=6.76×10 ^-5 ) and SLC6A9 (P=2.13 ×10 ^-3 ). Expression of ARSG and FHIP1B were associated with measures of Tau pathology (AT8: P=1.5×10 ^-3 , and pTau181: P=3.64×10 ^-3 , respectively), and SLC6A9 expression was associated with multiple pTau isoforms including pTau181 (P=1.5×10 ^-3 ) and pTau396 (P=2.05×10 ^-3 ). PRELP expression was associated with synaptic density (PSD.95: P=6.18 ×10 ^-6 ). DEGs were significantly enriched in pathways involving E2F targets, cholesterol homeostasis, and oxidative phosphorylation.

We identified multiple DEGs that differentiate neuropathologically confirmed AD cases with and without cognitive impairment prior to death. Expression of several of these genes was also associated with measures of cognitive performance and AD-related neuropathological traits, thus providing important insights into cognitive resilience mechanisms and strategies for delaying clinical symptoms of AD.