Alzheimer’s disease (AD) disproportionately affects females. We determined whether physiological biomarkers (neuroplasticity, immune, stress, epigenetic) explain why females are more susceptible to AD than males using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.
Methods Using the complete ADNI cohort, we analysed the effect of sex and APOE genotype (number of ε4 alleles) and sex and diagnosis (cognitively normal (CN), mild cognitive impairment (MCI), AD) on (1) AD related endpoints: memory scores, executive function scores, hippocampal volume, cerebrospinal fluid (CSF) amyloid beta, tau and p-tau; (2) markers of the immune system (interleukins, C-reactive protein, and immunoglobulins), neuroplasticity (intercellular adhesion molecule, ICAM1), and stress (cortisol); and (3) epigenetic age.
Results Females had higher levels of tau and p-tau compared to males and increasing alleles of APOEε4 disproportionately increased tau and p-tau compared to males. Females had larger hippocampal volume (corrected with intracranial volume) and better memory scores (that include verbal memory) than males, regardless of APOE genotype and diagnosis. There were also sex differences in biomarkers with females having higher levels of plasma C-reactive protein and lower levels of CSF IL-8, IL-16, immunoglobulin A, and ICAM1. We did not observe an association between sex, diagnosis, or APOE genotype and blood epigenetic age acceleration or intrinsic epigenetic age acceleration.
Conclusion In females tau pathology was increased but memory scores were higher and corrected hippocampal volume were larger compared to males suggesting females have a reserve against brain damage that delays either the onset of cognitive decline or diagnosis. In this ADNI cohort more males than females were diagnosed with MCI but with no significant difference in AD diagnosis, although more females presented with AD, suggesting the progression from CN, MCI to AD may be sex-specific. We found sex differences in immune biomarkers indicating that the underlying physiology may participate in differential aging with and without a diagnosis of AD or MCI between the sexes.
