Human cognitive functions change with age, both normally and pathologically. Some cognitive abilities, such as vocabulary, are resilient to brain aging, while other abilities such as conceptual reasoning, memory, and processing speed, decline with age (Harada et al., 2013). Age-related cognitive impairment is an increasing problem for society. As the global population aged over 65 years continue to increase, and the number of older persons is projected to double to 1.5 billion in 2050 (United Nation, 2019), it is expected that the clinical and economic burden of cognitive impairment on society will increase. Understanding cognitive aging and its possible therapeutic targets should thus be an important research focus to help delay or prevent age-related cognitive impairment.

Cognitive functions are usually assessed by administering a battery of neuropsychological tests. For example, verbal episodic memory can be assessed by logical memory tests for immediate and delayed recall. Working memory can be assessed by administering the digit span forward and backward tests, and processing speed and executive control can be assessed by administering the Digit Symbol Substitution Test (DSST). Several of these tests are under strong genetic control with heritability ranging from 16% to 68% (Cirulli et al., 2010), and over the past years several genome-wide association studies (GWAS) have identified common genetic variants associated with cognitive functions (Davies et al., 2015; Trampush et al., 2017). A recent GWAS of 300,486 individuals identified 148 independent genetic loci that associate with general cognitive function defined as the first principal component of multiple cognitive test scores (Davies et al., 2018).

The heritability of the DSST score is strong, ranging from 0.36-0.68 (Cirulli et al., 2010) but, despite such a high heritability, previous genome-wide association studies only identified one common genetic variant, rs17518584 in the gene encoding cell adhesion molecule 2 (CADM2) on chromosome 3, associated with DSST score (Ibrahim-Verbaas et al., 2016; Luciano et al., 2011). Previous studies focused attention on the association between common genetic variants and DSST scores in the general population. Here, we leverage the unique family-based design and the enrichment for healthy agers of the Long Life Family Study (LLFS) to identify rare variants potentially associated with preservation of DSST scores with aging. The LLFS includes very old subjects (90+ years old) who maintained good DSST scores compared to individuals without familial longevity. The study administered the DSST at enrollment and approximately 8 years after and, by studying the longitudinal changes of DSST, we showed that there are individuals whose DSST scores decline slower compared to others (Sebastiani et al., 2020). In addition, we showed that the heritability of DSST at baseline and its change over time was over 40% (Wojczynski & Province, 2019). These results suggest that those extremely long lived individuals with normal cognitive function may carry protective genetic variants that make them resilient to cognitive decline as they age. We therefore conducted a genome-wide association study of DSST scores measured in subjects enrolled in the LLFS. The genetic findings were further replicated in middle-aged and elderly twins from the Danish Twin Registry.