Sex-related differences in genetically determined Alzheimer's disease

Abstract

We reviewed the literature on sex differences in genetically determined Alzheimer's disease (AD), focusing on autosomal dominant AD (ADAD), Down syndrome-associated AD (DSAD), and APOE4 homozygosity, particularly regarding disease penetrance, symptom onset and clinical progression, and trajectories for markers of amyloidosis (A), tau pathology (T) and neurodegeneration (N). Data suggests that sex differences in disease penetrance, symptom onset, and AT(N) biomarker trajectories are typically subtle for genetically determined AD populations. Noteworthy exceptions, such as increased neurodegeneration in later stages of the disease in females while similar cognitive outcomes, suggest a potential differential cognitive reserve that warrants further investigation. Additionally, the interaction between APOE genotype and sex reveals complex and multifaceted effects in DSAD, with potential implications for ADAD that remain underexplored. The smaller sex differences observed compared to sporadic AD offer insights into the different underlying disease mechanisms in genetically determined AD populations. Future research should prioritize sex-specific investigations in genetically determined AD, focusing on refining methodologies. This includes prioritizing longitudinal designs, adjustment for key confounders, and adherence to sex-specific guidelines.

Keywords: AT(N) biomarker trajectories in Alzheimer’s disease (amyloid, tau and neurodegeneration biomarkers); apolipoprotein E epsilon 4 (APOE4) homozygosity; autosomal dominant Alzheimer’s disease (ADAD); disease penetrance in Alzheimer’s disease; down syndrome-associated Alzheimer’s disease (DS-AD); genetically determined Alzheimer’s disease; sex differences in Alzheimer’s disease; symptom onset in Alzheimer’s disease.

Figure 1

Illustration of sexual dimorphism in cognitive performance and brain structures across asymptomatic genetically determined Alzheimer’s disease (AD) populations (including Down syndrome [DS], autosomal dominant AD [ADAD], and APOE44 carriers) compared to the general population. The figure highlights differences in total brain volume, cortical thickness, and hippocampal volume (normalized by total intracranial volume), with females generally exhibiting smaller brain structures compared to males. However, after adjustment for intracranial volume, sex differences in hippocampal volume largely disappear (except for APOE44 and the general population). Cognitive differences between sexes are mild, with females showing an advantage in episodic memory across population. Notably, research gaps persist in understanding sex differences in some cognitive areas and brain structures.

Figure 2

Sex differences in penetrance, symptom onset, and biomarker progression in Alzheimer’s disease (AD) across genetically determined AD populations. This figure illustrates the near-full penetrance of AD in autosomal dominant Alzheimer’s disease (ADAD), Down syndrome-associated AD (DSAD), and APOE44 carriers, alongside the predictable sequence of AD biomarker changes (amyloid deposition, tau accumulation, and neurodegeneration). No significant sex differences were observed in most aspects of penetrance, symptom onset, or biomarker progression. However, notable exceptions include increased cortical thinning and reduced hippocampal and amygdala volumes in female ADAD carriers compared to males. Additionally, earlier decreases in Aβ42 levels were reported in APOE44 males, while greater cortical thickness was observed in APOE44 females. Conflicting findings were noted in DSAD for penetrance and symptom onset, with larger recent studies reporting no significant sex differences.

Figure 3

Overview of the main effects of APOE4 and its interaction with sex in Alzheimer’s disease (AD) penetrance, symptom onset and biomarker changes in autosomal dominant AD (ADAD) and Down syndrome-associated AD (DSAD). In ADAD, there are conflicting findings regarding the role of APOE4 in penetrance and symptom onset, with notable research gaps in amyloid and tau changes. However elevated neurofilament light chain (NfL) concentrations have been observed in PSEN1 and APOE4 carriers. The figure also highlights limited evidence for sex-APOE interactions in symptom onset and amyloid changes in ADAD, with many research gaps (RG). In DSAD, APOE4 shows an effect on penetrance, symptom onset, and biomarker changes. Regarding sex, APOE4 appears to influence symptom onset more in females than males, with a stronger impact on amyloid and neurodegeneration, though there are RG in tau biomarker changes.