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Resilience to Autosomal-Dominant Alzheimer's Disease Pathology May Be Greater in Women Than Men

Key findings

  • The PSEN1 E280A mutation kindred in Colombia is well suited to studying sex differences in Alzheimer's disease (AD) because mild cognitive impairment and dementia generally occur before age-related comorbidities become a confounding factor
  • Members of the kindred are participating in a trial of crenezumab for AD prevention, and this analysis compared baseline data on 167 PSEN1 mutation carriers and 75 age-matched non-carriers; all subjects were cognitively normal
  • Among both mutation carriers and non-carriers, women and men were similar in Aß burden and two markers of neurodegeneration: hippocampal volume and glucose metabolism in the precuneus, a brain region involved in recollection and memory
  • Yet women demonstrated better delayed memory recall than men after adjustment for age, PSEN1 status, Aß burden and precuneus glucose metabolism
  • Research in an independent cohort is planned to evaluate the generalizability of these findings

Increasing evidence suggests the risk of Alzheimer's disease is greater in women than men. Findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD-pathology and neurodegeneration than males.

Massachusetts General Hospital researchers have been investigating this issue in a large Colombian kindred that has the E280A mutation in Presenilin-1 (PSEN1). In the Journal of Alzheimer's Disease they previously showed cognitively unimpaired female carriers of the mutation had better global cognition than male carriers despite having similar hippocampal volume.

Clara Vila-Castelar, PhD, a clinical neuropsychologist at the Multicultural Alzheimer's Prevention Program, Yakeel T. Quiroz, PhD, director of the Familial Dementia Neuroimaging Lab and the Multicultural Assessment and Research Center in the Department of Psychiatry and the Department of Neurology, and colleagues recently corroborated and expanded on those findings in a more detailed study of a larger sample that only included unimpaired individuals. Their report appears in Alzheimer's & Dementia.


Members of the Colombian kindred, the world's largest with autosomal-dominant AD due to a single mutation, are participating in a trial of crenezumab for AD prevention. In this kindred PSEN1 mutation carriers are destined to develop early-onset AD, with symptoms of mild cognitive impairment emerging at a median age of 44 and dementia at age 49.

Therefore, they have few age-related comorbidities, including those that are known to vary by sex, such as cardiovascular disease, or survival bias that can confound studies of AD risk.

For this analysis, the researchers compared baseline trial data on 167 PSEN1 mutation carriers and 75 age-matched non-carriers. All subjects were cognitively healthy at that point, and there was no difference between the two groups in sex ratio (60% of carriers and 67% of non-carriers were female; P=0.36).

The participants completed a battery of clinical and cognitive questionnaires. They also underwent imaging measurement of β-amyloid (Aβ) and two markers of neurodegeneration: hippocampal volume and glucose metabolism in the precuneus, a brain region involved in recollection and memory, among other complex functions.

Cognition, Pathology and Neurodegeneration

  • Female carriers were younger than male carriers, but Aβ levels and markers of neurodegeneration did not differ between female and male carriers, when controlling for age
  • Non-carrier females and males did not differ in Aβ burden, levels of neurodegeneration or cognitive performance

Relationship Between Pathology and Neurodegeneration

  • As expected, a greater Aβ burden predicted lower glucose metabolism in the precuneus but not hippocampal volume
  • The effect of Aβ burden on markers of neurodegeneration did not vary by sex

Relationship Between Neurodegeneration and Memory Recall

  • Women (carriers and non-carriers considered together) showed a better delayed recall than men after adjustment for age, PSEN1 status, Aβ burden and precuneus glucose metabolism, although the effect dissipated when controlling for hippocampal volume
  • The interaction effects between sex and markers of neurodegeneration were not significant in predicting verbal memory

Next Steps

In this cohort of cognitively unimpaired individuals at genetic risk of autosomal-dominant AD, memory performance was better preserved in women even though their levels of pathology and neurodegeneration were similar to men's. Comparable results have been reported from studies of sporadic AD.

Replication of the results in independent cohorts will be needed to determine generalizability to other groups at risk of familial and sporadic AD. Once this clinical trial is completed, the research team plans to examine sex differences in longitudinal neuroimaging and cognitive markers and as part of the ongoing MGH Colombia–Boston (COLBOS) Biomarker study of autosomal-dominant AD.

Learn more about the Multicultural Alzheimer's Prevention Program

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Researchers at Massachusetts General Hospital have identified some of the earliest brain changes associated with the risk to develop Alzheimer's disease by studying a kindred with the PSEN1 E280A gene mutation.


Mass General researchers were part of the first study to demonstrate the ability of optical coherence tomography to detect retinal biomarkers in carriers of the most common gene causing familial Alzheimer's disease.