Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease

Abstract

Despite recent advances in the understanding of clinical aspects of sex differences in Alzheimer's disease (AD), the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. The purpose of this study is to elucidate sex disparities in brain aging profiles focusing on 2 major areas—energy and amyloid metabolism—that are most significantly affected in preclinical development of AD. Total RNA isolated from hippocampal tissues of both female and male 129/C57BL/6 mice at ages of 6, 9, 12, or 15 months were comparatively analyzed by custom-designed Taqman low-density arrays for quantitative real-time polymerase chain reaction detection of a total of 182 genes involved in a broad spectrum of biological processes modulating energy production and amyloid homeostasis. Gene expression profiles revealed substantial differences in the trajectory of aging changes between female and male brains. In female brains, 44.2% of genes were significantly changed from 6 months to 9 months and two-thirds showed downregulation. In contrast, in male brains, only 5.4% of genes were significantly altered at this age transition. Subsequent changes in female brains were at a much smaller magnitude, including 10.9% from 9 months to 12 months and 6.1% from 12 months to 15 months. In male brains, most changes occurred from 12 months to 15 months and the majority were upregulated. Furthermore, gene network analysis revealed that clusterin appeared to serve as a link between the overall decreased bioenergetic metabolism and increased amyloid dyshomeostasis associated with the earliest transition in female brains. Together, results from this study indicate that: (1) female and male brains follow profoundly dissimilar trajectories as they age; (2) female brains undergo age-related changes much earlier than male brains; (3) early changes in female brains signal the onset of a hypometabolic phenotype at risk for AD. These findings provide a mechanistic rationale for female susceptibility to AD and suggest a potential window of opportunity for AD prevention and risk reduction in women.

Introduction

As the leading cause of dementia and rated as the most feared human disease by the American public, Alzheimer's disease (AD) currently affects approximately 35 million people worldwide, including 5.1 million Americans (Thies and Bleiler, 2013). These numbers are predicted to triple by 2050, with one new case of AD expected to develop every 33 seconds, or nearly a million new cases per year (Thies and Bleiler, 2013). There is no cure currently available, and no success has been found from more than 100 human trials conducted over the last decade in an attempt to find an effective treatment for mid- to late-stage AD (McBride, 2012, Schnabel, 2013). These unprecedented challenges underscore the significance and priority for increased research efforts aimed at defining the risk factors and the underlying mechanisms that would allow institution of AD prevention and early intervention, when a treatment continues to be sought (Mullard, 2012, Rice, 2014).

AD affects women and men differently on many levels (Carter et al., 2012, Regitz-Zagrosek and Seeland, 2012). Of the current AD cases, nearly two-thirds are women (Brookmeyer et al., 2011). After the age of 65, the lifetime risk of AD is 1 in 6 for women (16.7%), whereas it is 1 in 11 for men (9.1%) (Thies and Bleiler, 2013). In addition, sex has been demonstrated to play a major role in the pathogenesis, progression, and clinical manifestation of AD. For instance, depression is associated with a 2-fold increased risk for AD in women but not in men; in contrast, stroke is associated with a 3-fold increased risk for AD in men but not in women (Artero et al., 2008). Women with AD tend to exhibit a broader spectrum of dementia-related behavioral symptoms and experience greater cognitive deterioration than men in the progression of the disease (Barnes et al., 2005, Chapman et al., 2011, Hall et al., 2012, Irvine et al., 2012, Schmidt et al., 2008). Moreover, several studies presented at the recent Alzheimer's Association International Conference provide new evidence supporting the long-held belief that women's brains are more vulnerable than men's brains to AD (Alzheimer's Society, 2015a, Hamilton, 2015).

Increasing evidence indicates that sex also modulates the impact of genetic factors in the etiology of AD. Cognitively normal individuals with a maternal family history of AD were found to express greater phenotypic changes in AD-vulnerable brain regions suggesting a higher risk for developing AD as compared with those with a paternal history or no family history (Berti et al., 2011, Honea et al., 2011, Mosconi et al., 2010). Furthermore, some genetic variants appear to interact with sex to modify the risk for AD. As an example, the ε4 allele of the apolipoprotein E gene (APOE4), the strongest genetic risk factor for late-onset AD, has been associated with a far more pronounced risk for AD in women than in men (Altmann et al., 2014, Bretsky et al., 1999, Farrer et al., 1997, Mortensen and Hogh, 2001, Payami et al., 1996, Ungar et al., 2014). In contrast, the ε2 allele of the APOE gene (APOE2), which is considered as a neuroprotective variant, has been shown to confer a greater protection against AD in men than in women (Altmann et al., 2014, Johnson et al., 1998, Ungar et al., 2014).

Despite recent advances in the understanding of clinical aspects of sex differences in AD, the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. In this study, using custom-designed Taqman low-density arrays (TLDAs) and Ingenuity pathway analysis (IPA) computing tools, we sought to determine sex disparities in brain aging profiles focusing on 2 major areas—energy and amyloid metabolism—that are most significantly affected in preclinical development of AD. The data revealed substantial differences in the overall trajectory of aging changes between female and male brains. Early changes indicative of the onset of a hypometabolic phenotype in female brains could serve as an important mechanistic rationale for female susceptibility to AD; and timely intervention at this transition could potentially halt the progression of metabolic deficits and ultimately reduce the risk of developing AD in women.