ReviewSex differences in cognitive impairment and Alzheimer’s disease
Introduction
The popular quote, “Men are from Mars and women are from Venus”, has been commonly applied to many different situations including physiology, sociology and pathology; the gender differences in cognitive functioning are no exception. The differences of learning and memory between male and female brains are confirmed by both human and animal studies from early development stages throughout their life spans. In addition, many neurological diseases exhibit gender biases, such that one sex has a greater prevalence or severity of the disease than the other. Neurological diseases in the young and the elderly also demonstrate gender-specific responses to therapies. However, the question is how much, rather than whether or not, the biology of sex contributes to normal cognitive function. Accordingly, such understanding may provide better insight into the factors that contribute to the risk of cognitive impairment. Here, we will be focusing on sex hormones – especially the role of estrogens, progesterone and testosterone – on mechanisms that relate to neuronal function and associated cognitive ability in the adult and aged individual.
Section snippets
Sex differences in cognition
Gender differences in cognitive function in adulthood and ageing have been well demonstrated. For example, men perform better on spatial memory while women excel at verbal and object location (Table 1). The sex differences in cognitive function and brain structures in later life have been demonstrated by magnetic resonance imaging (MRI) in human studies. For instance, studies found that men demonstrated larger amygdala and thalamus volumes compared to women (Neufang et al., 2009, Bramen et al.,
Sex differences in prevalence of Alzheimer’s disease
AD is the most common cause of dementia in the elderly and is characterized by two major pathological lesions: intracellular inclusions of tau protein in the form of neurofibrillary tangles, and extracellular plaque formation by accumulations of amyloid beta peptide (Aβ) derived from the β-amyloid precursor protein (APP). Accumulating Aβ, a proteolytic byproduct of amyloid precursor protein (APP) metabolism, is an important aspect of AD pathology. APP is processed by two competing pathways, the
The potential protective role of estrogens, progestins and androgens in AD – evidence from pre-clinical and clinical studies
While studies that reported impairments (or increased vulnerability) of brain function resulting from surgical removal of the ovaries supported the potential benefit of estrogens in maintaining a healthy brain, it is important to recognize that ovariectomy (like the menopause) leads to a significant reduction in not only circulating estradiol, but also in circulating progesterone. As such, the structural and functional impairments that are reported to occur following ovariectomy may result from
Summary
The differences in learning and memory between male and female brains are confirmed by both human and animal studies from early development stage throughout their life spans. In addition, many neurological diseases exhibit sex differences, exemplified by one sex having a greater prevalence or severity of the disease than the other sex. Women not only have a higher prevalence of AD than age-matched men, but also showed significantly age-related faster decline and greater deterioration of
Acknowledgments
This work was supported by the American Health Assistance Foundation (G2006-118), and the National Institutes of Health (R01AG032441-01, AG022550, AG027956). We also thank Juliet Shen for editing and proofreading.
References (348)
- et al.
Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism
Brain Res.
(2001) - et al.
Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer’s disease
Neuroscience
(2010) - et al.
A characterization of performance by men and women in a virtual Morris water task: a large and reliable sex difference
Behav. Brain Res.
(1998) - et al.
Hormonal state affects recovery from frontal cortex lesions in adult female rats
Behav. Neural Biol.
(1987) - et al.
Role for estradiol in female-typical brain and behavioral sexual differentiation
Front. Neuroendocrinol.
(2008) - et al.
Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders
Front. Neuroendocrinol.
(2011) - et al.
Motherhood alters the cellular response to estrogens in the hippocampus later in life
Neurobiol. Aging
(2011) - et al.
Cognitive effects of variations in pubertal timing: is puberty a period of brain organization for human sex-typed cognition?
Horm. Behav.
(2013) - et al.
Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro
Mol. Cell. Neurosci.
(1994) - et al.
Cerebral hemodynamic lateralization during memory tasks as assessed by functional transcranial Doppler (fTCD) sonography: effects of gender and healthy aging
Cortex
(2011)
Evidence for the influence of testosterone in the performance of spatial navigation in a virtual water maze in women but not in men
Horm. Behav.
Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice
Am. J. Pathol.
Neuroprotective effects of progesterone on damage elicited by acute global cerebral ischemia in neurons of the caudate nucleus
Arch. Med. Res.
Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat
J. Neurol. Sci.
Sex differences in neurogenesis and activation of new neurons in response to spatial learning and memory
Psychoneuroendocrinology
Evolving knowledge of sex differences in brain structure, function, and chemistry
Biol. Psychiatry
Sex hormones and mental rotation: an intensive longitudinal investigation
Horm. Behav.
Estrogen synthesis and signaling pathways during aging: from periphery to brain
Trends Mol. Med.
Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion
Horm. Behav.
Prevalence and incidence of dementia among 75–80-year-old community-dwelling elderly in different districts of Antwerp, Belgium: the Antwerp Cognition (ANCOG) Study
Clin. Neurol. Neurosurg.
The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents
Neurosci. Biobehav. Rev.
Virtual navigation in humans: the impact of age, sex, and hormones on place learning
Horm. Behav.
Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway
J. Biol. Chem.
Hippocampus-dependent strategy choice predicts low levels of cell proliferation in the dentate gyrus
Neurobiol. Learn. Mem.
Estrogen-regulated synaptogenesis in the hippocampus: sexual dimorphism in vivo but not in vitro
J. Steroid Biochem. Mol. Biol.
Effects of progesterone administration and APPswe+PSEN1Deltae9 mutation for cognitive performance of mid-aged mice
Neurobiol. Learn. Mem.
Neuroprotection by estradiol
Prog. Neurobiol.
Effects of long-term hormone replacement and of tibolone on choline acetyltransferase and acetylcholinesterase activities in the brains of ovariectomized, cynomologus monkeys
Neuroscience
Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer’s disease in a study of diagnostic concordance
Neuropsychologia
Basis of progesterone protection in spinal cord neurodegeneration
J. Steroid Biochem. Mol. Biol.
Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis
Arterioscler. Thromb. Vasc. Biol.
Androgen treatment of neonatal rats decreases susceptibility of cerebellar granule neurons to oxidative stress in vitro
Eur. J. Neurosci.
Gender-linked brain injury in experimental stroke
Stroke
Exploring the contribution of estrogen to amyloid-Beta regulation: a novel multifactorial computational modeling approach
Front. Pharmacol.
Sex differences in the associations between lipid levels and incident dementia
J. Alzheimers Dis.
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial
JAMA
Sex influences on the neurobiology of learning and memory
Learn. Mem.
Gender differences in cognitive development
Dev. Psychol.
Women, myocardial infarction, and dementia in the very old
Neurology
Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study
Neurology
Hormonal regulation of adult partner preference behavior in neonatally ATD-treated male rats
Behav. Neurosci.
Endogenous reproductive hormones and nocturnal rhythms in partner preference and sexual behavior of ATD-treated male rats
Neuroendocrinology
Altered spatial learning and delay discounting in a rat model of human third trimester binge ethanol exposure
Behav. Pharmacol.
Functional specialization in the human medial temporal lobe
J. Neurosci.
Sex hormones, aging, and Alzheimer’s disease
Front. Biosci. (Elite Ed.)
Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients
J. Neurotrauma
Sex difference in geographical knowledge: driving experience is not essential
J. Int. Neuropsychol. Soc.
Neuroprotection against oxidative stress by estrogens: structure–activity relationship
Mol. Pharmacol.
Role of the hippocampus in sex differences in verbal memory: memory outcome following left anterior temporal lobectomy
Neuropsychology
Early androgen effects on spatial and mechanical abilities: evidence from congenital adrenal hyperplasia
Behav. Neurosci.
Cited by (350)
Smaller grey matter volume in the central olfactory system in mild cognitive impairment
2023, Experimental GerontologyNumber of children and cognitive function among Chinese menopausal women: The mediating role of depressive symptoms and social participation
2023, Journal of Affective DisordersHarmonisation of later-life cognitive function across national contexts: results from the Harmonized Cognitive Assessment Protocols
2023, The Lancet Healthy LongevityReal-world prediction of preclinical Alzheimer's disease with a deep generative model
2023, Artificial Intelligence in Medicine