Sex and APOE4 Affect Cognitive Decline

Posted September 14, 2023

In 2004, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was founded to develop tools to aid in the early detection and tracking of Alzheimer’s disease (AD). The ADNI gathers and analyzes brain scans, genetic profiles, and blood and cerebrospinal fluid biomarkers from its participants.

Over ten years, researchers tracked how sex and APOE4 status impacted cognitive decline in participants with mild cognitive impairment. They found the following:

  • Cognition declined more in females than males.
  • Inheriting the APOE4 gene sped up the decline in both sexes.
  • Female APOE4 carriers declined faster than male carriers.

These data show that a person’s sex and APOE4 status influence the pace and severity of cognitive decline.

Longitudinal studies track patients over an extended period, allowing researchers to identify trends that occur over time. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been collecting data on mild cognitive impairment and AD in patients since 2004. Researchers used this longitudinal study to investigate the role of sex on cognitive decline over a ten-year period.

Researchers focused on participants with mild cognitive impairment (MCI). This is an intermediate stage between normal cognition and dementia. While people with MCI have memory and cognition problems, they can still care for themselves and carry out everyday activities.

Within this group, females showed greater cognitive decline over the ten years than males. Regardless of sex, even a single copy of APOE4, the strongest genetic risk factor for AD, accelerated the rate of cognitive decline. Among APOE4 carriers with MCI, females experienced the fastest decline.

MCI usually progresses into dementia or AD. AD pathology is characterized by the accumulation of amyloid beta and tau tangles. Researchers looked for evidence of these markers in the cerebrospinal fluid of MCI patients. They found that those with the highest levels of amyloid beta and tau had much greater cognitive decline than those with lower levels. When males and females with high levels of AD biomarkers were compared, women again displayed greater cognitive decline.

Identifying that women have worse cognitive outcomes underscores the importance of sex-specific timelines for dementia and AD progression.

Published in Scientific Reports.

Sex Differences in Cognitive Decline in Subjects with High Likelihood of Mild Cognitive Impairment due to Alzheimer’s disease

Murali Doraiswamy, M.B.B.S., Duke University School of Medicine

Rudy Tanzi, Ph.D., Massachusetts General Hospital/Harvard Medical School