According to the Alzheimer’s Association, around 11% of Americans over age 65 are living with Alzheimer’s, a disease characterized by two brain pathologies, amyloid-beta plaques and tau neurofibrillary tangles. But autopsies show that up to another 30% of older people have this neuropathology while never having exhibited cognitive impairment; that is, resilience to amyloid and tau is, by a long way, the rule rather than the exception. Genetic understanding of this resilience is hampered by the limited availability of postmortem brain assessments paired with genetics and cognitive performance measures.
To increase statistical power for genetic analysis, Jared Phillips, PhD, Timothy Hohman, PhD, and colleagues used molecular and demographic data to derive a proxy of Alzheimer’s neuropathology, applicable to the brains of living, breathing members of eight study cohorts devoted to aging. Billed as the largest genetic study of Alzheimer’s resilience to date, the team’s data harmonization and genetic analysis included 3,272 deceased participants with neuropathology data and 17,241 living participants assessed for neuropathology based on the proxy. Their report was published in the journal Brain.
Having measured the research utility of their proxy (by way of comparison with the fuller model with autopsy data), the team proceeded to genetic analyses involving both longitudinal models, hinging on memory, executive function and language (average follow-up six to eight years). They found novel genetic correlations with resilience across various cardiovascular and neuropsychiatric traits, for example, positive correlation with resting heart rate and negative correlations with Tourette’s syndrome, schizophrenia and multiple sclerosis.
Pathway-level analysis revealed separate associations between resilience and genes working together in three pathways: metabolism of amino acids and derivatives; negative regulation of transforming growth factor beta production; and severe acute respiratory syndrome. In single-variant genetic analysis, while no alleles exhibited genome-wide significance, several came close and were found highly biologically suggestive by the authors.
Others on the study from Vanderbilt are Logan Dumitrescu, PhD, Derek Archer, PhD, Alexandra Regelson, MS, Emily Mahoney, Michelle Clifton, MS, Julia Libby, Skylar Walters, MS, Katherine Gifford, PsyD, and Angela Jefferson, PhD. The study was supported by the National Institutes of Health, award numbers F31AG085980, U24AG074855, R01AG059716, R01AG073439.
