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Abstract

Alzheimer's disease (AD) is not an inevitable consequence of aging and may be modified by both adverse and protective factors. The pathological changes of AD commence in midlife and AD has a long preclinical phase that may be diagnosed by biomarkers in the cerebrospinal fluid and by brain MRI. New clinical criteria for the diagnosis of AD dementia and AD mild cognitive impairment (MCI) have been proposed. MCI and dementia are frequently the result of AD and cerebrovascular disease combined. Over the age of 85 years, MCI and dementia are more common in women than in men. Women with a surgical premature menopause have an increased risk of MCI and AD. Menopausal hormone therapy from the menopause to the age of 60 years, when any risks of menopausal hormone therapy are extremely small, may provide a ‘window of opportunity’ to reduce the risk of MCI and AD in later life. Many measures may help to prevent, delay or minimize AD in both women and men and should be actively encouraged.

Keywords

Alzheimer's disease dementia menopause menopause hormonal therapy MHT mild cognitive impairment

“Do not go gentle into that good night, Old age should burn and rave at close of day; Rage, rage against the dying of the light.”

– Dylan Thomas

Alzheimer's disease (AD) is one of the most common and most feared consequences of advancing age, with impairment of cognitive abilities, progressive decline in occupational and social functioning, and deterioration in personality. The disease may progress to complete loss of memory, inability to function mentally, physically and socially, and loss of any awareness and involvement in the surroundings. In the last 20 years, great progress has been made in the understanding of AD and its milder form ‘mild cognitive impairment’ (MCI). Progress has also been made in the understanding of vascular dementia (VaD) and its milder form ‘vascular cognitive impairment’ (VaCI). AD, VaD, MCI and VaCI are no longer regarded as inevitable with advancing age and the risks may be modified by both adverse and protective factors; the protective factors in women may include menopausal hormone therapy (MHT) [1].

Some degree of cognitive decline is generally accepted as a normal part of aging, starting sometime around the age of 65 years. A 10-year study of 5198 men and 2192 women from the Civil Service in London (UK) found that cognition declined in all areas except vocabulary, starting at the age of 45 years with a faster decline in people over the age of 65 years [2]. Everyone who eventually develops AD or VaD goes through a transitional period of mild, but detectable, cognitive impairment, but not everyone who is diagnosed with MCI or VaCI goes on to develop AD or VaD. Considerable research has been focused on verbal and episodic memory as a measure of cognition and as a valid predictor of the risk of clinical AD dementia [3 –5].

Difficulty has arisen with the nomenclature of AD, VaD, MCI, VaCI and dementia. The term ‘Alzheimer's disease’ is frequently used to cover all forms of cognitive impairment of a lesser or greater degree and the term ‘dementia’, which is associated with being demented, is often avoided particularly in nonmedical circles. Attempts have been made to limit the use of the term ‘Alzheimer's disease’ to the age-related neurodegenerative process distinguished by the presence of β-amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in the brain [6]. The attempts to limit the term ‘Alzheimer's disease’ to this specific pathology have only been partly successful and AD is frequently used loosely to cover all forms of age-related cognitive impairment and dementia.

Epidemiology

The incidence of AD increases with age. In the USA, 90% of cases occur in individuals older than 60 years. It was estimated that in 2011, AD dementia affected 5.4 million individuals in the USA and that a much larger number had MCI. By 2015 it is predicted that, with an increasingly aging population, AD alone will affect 11–16 million individuals [7]. A WHO integrative review of 47 surveys across 17 countries estimated that the rate of dementia from any cause was 1% in individuals aged 60–69 years and 39% in those aged 90–95 years; the rate doubling every 5 years of age [101]. In a detailed study of 1299 ‘oldest old’ women 85 years and older with an average age of 88.2 years, 17.8% were diagnosed as having dementia and 23.3% as having MCI; 59% were cognitively normal. AD and mixed dementia were the most common types of dementia, each accounting for 40% of cases. Cognitive impairment was significantly more common in women with less education, depression or those who had a stroke [8]. AD is a leading cause of death and the total number of deaths from AD in the USA has been increasing while deaths from other causes have been falling [7]. A number of risk factors that may predispose to AD and dementia and some factors that may be protective against AD and dementia have been identified (Box 1). MHT in perimenopausal women and other protective measures in both women and men, if implemented sufficiently widely, may help to reduce the incidence and prevent the predicted increase of AD.

Pathology of AD & dementia

The pathophysiological process in AD is characterized by the accumulation of Aβ in the brain, resulting in Aβ plaques, and by the aggregation of tau protein and the formation of NFTs. In AD, plaques of Aβ develop in the hippocampus, the area of the brain that encodes memory, and in the cerebral cortex, the area used for thinking and decision-making. NFTs are most densely distributed in the hippocampus, entorhinal cortex and temporal lobe. Aβ plaques and NFTs may begin to develop as early as the fifth decade of life [9]. The changes of AD take place over many years and decades before the onset of MCI and AD, and constitute a preclinical phase of the disease [10]. The diagnosis of the preclinical phase of MCI and AD has been made possible by the discovery of biomarkers of Aβ deposition and of neuronal degeneration and by new brain imaging techniques [11]. Markers of Aβ include Aβ in the cerebrospinal fluid (CSF) and the presence of Aβ on PET. Markers of neuronal degeneration include: elevated tau in the CSF; decreased metabolism in the temporal and parietal cortices on flurodeoxy-glucose PET; and atrophy of the temporal and parietal cortices on MRI [12]. The standard biomarkers for AD are Aβ, total tau and hyperphosphorylated tau and α-synuclein in the CSF. In young adults at genetic risk for autosomal dominant AD, biomarkers in the CSF indicative of overproduction of Aβ have been found up to 28 years before the predicted mean age of the development of AD dementia [13,14]. Biomarkers, PET and MRI have been used to predict cognitive decline from MCI to AD and to differentiate between AD and parkinsonian disorders [15,16]. Biomarkers and MRI have proved invaluable in research and have contributed enormously to understanding, but are not currently recommended for use in clinical practice.

Box 1.

Adverse and protective factors for Alzheimer's disease and dementia.

Risk factors for Alzheimer's disease & dementia

Advancing age

Family history of Alzheimer's disease or dementia

Depression

Sleep deprivation

Low vitamin D

Obesity

Insulin resistance

Dyslipidemia

Hypertension

Vascular disease

Traumatic brain injury

Down's syndrome

ApoE E4 genotype

Factors that may be protective against Alzheimer's disease

Cognitive training

Mediterranean diet

Mental, physical and social activity

Use of angiotensin II receptor blockers

Use of β-blockers

Use of aspirin in women at high risk of cardiovascular disease

Use of NSAIDs

Etiology of AD

It is believed that converging genetic and environmental factors trigger a pathophysiological cascade that over decades leads to AD, MCI and dementia. There is a continuum in the pathophysiology of normal aging and AD and at autopsy up to 75% of cognitively normal elderly patients have changes similar to those found in the brain of individuals with AD dementia [17,18]. Not all cognitively normal individuals with biomarkers of AD necessarily progress to MCI or AD and some individuals may have efficient compensatory mechanisms. These individuals have been designated as ‘stable asymptomatic cerebral amyloidosis’ [6]. Aβ does have a number of potential beneficial activities, including activation of kinase enzymes [19,20], protection against oxidative stress [21,22], regulation of cholesterol transport [23,24] and antimicrobial activity [25]. It is suggested that soluble oligomeric forms of Aβ, in particular Aβ^*56 and Aβ trimmers, may be the causative agents of AD [26 –28]. A number of genetic, cell biology, biochemical and animal studies support the concept that Aβ plays a central role in the development of AD pathology [29,30]. Most cases of AD are sporadic and are not related to a specific genotype, although familial clustering does occur. Autosomal dominant AD accounts for less than 5% of cases and occurs almost exclusively in early-onset AD. No polymorphisms have been found consistently in late-onset AD except for the ApoE 4 genotype. The presence of an ApoE E4 allele is a risk factor for the development of AD before the age of 70 years. Many ApoE E4 carriers, however, do not develop clinical AD and most subjects with AD do not have the ApoE 4 allele [31]. Cognitive impairment and dementia are often the result of a combination of AD and VaD and are frequently associated with other medical comorbidities. Cognitive impairment and dementia may also result from a number of rare disorders (Box 2).

Diagnosis

The diagnosis of AD and MCI is a clinical one and the National Institute on Aging and the Alzheimer's Association of the USA published new criteria and guidelines for diagnosis in 2011 [32 –34]. The new diagnostic categories are MCI, MCI due to AD, AD dementia and nonspecified ‘all-cause dementia’, which includes AD. Three stages of AD are recognized: preclinical AD requiring changes in biomarkers and/or poor performance on challenging cognitive tests; MCI due to AD with mild changes in memory and other cognitive abilities that do not interfere with day-to-day activities; and AD with changes in two or more aspects of cognition and behavior interfering with day-to-day function.

The diagnosis of AD and MCI is based on clinical criteria and the degree of certainty of the diagnosis of AD dementia and MCI. The authors of the guidelines stress that the fundamental difference between MCI and dementia is whether there is a significant change in the ability to function at work or in daily activities [35]. Many men and women in midlife complain of becoming forgetful or having difficulty in remembering the names of people, places or objects, and this may present a problem to the clinician, particularly when the complaints are self-reported. The symptoms may be transient, drug-induced or a consequence of depression or other psychological disorders, rather than to any organic brain changes presaging the development of AD or dementia. The diagnosis of MCI and AD requires clinical judgment and may require specialist evaluation.

Box 2.

Conditions resulting in cognitive impairment and dementia.

Alzheimer's disease

Vascular dementia

Fronto-temporal dementia (e.g., Pick's disease)

HIV immunodeficiency disease

Lewy body disease

Parkinson's disease

Prion disease (e.g., Creutzfeldt–Jakob disease)

Tauopathies

Effect of age on cognition

It may be difficult to differentiate between the ‘normal decline’ in cognitive ability with age and a decline that is more than expected for age and meriting a diagnosis of MCI, VaCI, AD or VaD. Different aspects of cognition decline at different rates and some functions may remain relatively stable while others may decline faster, which may make evaluation difficult (Box 3). To demonstrate that a patients' cognitive function is worse than expected for his/her age may require neuropsychological testing so that the patient's performance may be compared with an age-matched standard. Different tests measure different aspects of cognition and batteries of tests have been used in many investigations. One of the most commonly used tests is the shortened Mini-Mental State Examination (MMSE), but it is under copyright and its use requires the payment of a fee [36]. The Alzheimer's Association of the USA have reviewed the tests for the detection of cognitive impairment in the primary care setting [37]. Three brief tests (each takes 5–10 min) were approved for patient assessment: the General Practitioner Assessment of Cognition (GPCOG), the Memory Impairment Screen (MIS) and the Mini-Cog™ test. Three tests were approved for the informant assessment: the GPCOG, AD8 (Dementia Screening Interview) and Informant Questionnaire on Cognitive in the Elderly (IQCOD). The GPCOG has both patient and informant assessment components. The Alzheimer's Association advised that one test for patient assessment and one test for informant assessment should be used to decide on possible referral for full dementia evaluation. The GPCOG, Mini-Cog and MIS tests are under copyright, but the owners allow free use by clinicians as clinical tools. The aim of the tests is to reduce the number of missed or delayed diagnoses of MCI or dementia. In the future, early diagnosis and early treatment will undoubtedly play a major part in the care of patients with suspected MCI or dementia.

Box 3.

Effect of age on memory.

Memory functions that tend to remain relatively stable with age

Semantic memory: facts and general knowledge about the world

Procedural memory: acquisition/performance of cognitive and motor skills

Memory functions that tend to decrease with age

Working memory: holding and manipulating information

Episodic memory: personal events and experience

Processing speed

Prospective memory: ability to remember to perform future action

Ability to remember new information and to access prior knowledge

Recollection: particularly specific information: names of people, places and objects

Gender & AD

In the Aging, Demographics and Memory Study in the USA there were no differences in the risk of AD and all-cause dementia between men and women aged 71 years and older [38]. By contrast, in a pooled analysis of four population-based prospective cohort studies in the EURODERM study there was a significant gender difference in the incidence of AD after the age of 85 years [39]. At the age of 90 years the rate for AD per 1000 person-years was 81.7 (95% CI: 63.8–104.7) in women and 24.0 (95% CI: 10.3–55.6) in men. The cumulative risk of developing AD for 65-year-old women and men by the age of 95 years was 0.22 and 0.09, respectively. Smoking (more strongly in men) and low levels of education (more strongly in women) significantly increased the risk of AD. There were no gender differences in the rates of development of VaD. At the Radiological Society of North America 98th Scientific Assembly in 2013, Spaminto reported significant gender differences in the loss of gray matter in AD on MRI [40]. The men and women studied were very similar clinically and at the same stage of the disease. On MRI, brain atrophy began sooner in women than in men, but their cognitive decline was less rapid. Brain atrophy started later in men, but men had a greater loss of brain volume during the progression from MCI to AD. The differences between women and men eventually disappeared because although the atrophic changes developed at an earlier stage in women, men had greater brain loss later at the time of cognitive decline. This study suggests that early intervention by preventive measures before pathological changes occur, such as MHT in perimenopausal women, is required to prevent brain atrophy and cognitive decline.

Menopause & cognition

The increased prevalence of AD in women compared with men of the same age suggests that gender difference and the menopause may play a part in the pathogenesis of AD and MCI. The menopause is associated with marked decrease in concentrations of circulating estradiol and this change has the potential to affect the CNS [41]. Estrogens have several possible neuroprotective effects on the aging brain, including inhibition of Aβ formation, stimulation of cholinergic activity and reduction of oxidative cell damage [42]. Estrogens also increase cerebral blood flow and MHT significantly affected blood flow in different areas of the brain during the performance of memory tasks in postmenopausal women [43,44]. The natural menopause has been reported not to be associated with any proven objective changes in cognition [45]. No consistent associations have been found between endogenous serum estrogen concentrations and episodic memory or executive functions in midlife and older women with a natural menopause [46].

The SWAN study found that cognitive performance was transiently reduced during the perimenopause and that during this time learning and verbal memory did not improve with repeated testing [47]. High levels of depression and anxiety were directly related to poor cognitive performance, but in multivariate analysis, depression and anxiety did not influence the negative effect of the perimenopause on learning and memory.

In a recent cross-sectional study of cognition in the different stages of the perimenopause, 117 middle-aged women were divided into four separate categories: late reproductive with change in menstrual flow or cycle; early menopause transition with persistent menstrual irregularity; late menopause transition with amenorrhea of 60 days or more; and early menopause in the first 12 months after the final menstrual period [48]. The women were investigated with a battery of neuropsychological tests covering six cognitive domains. The women in the first year postmenopause performed significantly worse on measures of verbal learning, verbal memory and fine motor function than women in the late reproductive and late menopausal transition phases. Women in the first year postmenopause also performed significantly worse in attention and working memory tests than women in the late transition phase. The differences were not related to menopausal symptoms, depression or anxiety, or to serum estradiol or follicle stimulating hormone levels at the time of testing. The effect of the menopause on cognition at the time of the menopause and the possible relationship of the menopause to the later development of MCI and AD requires further investigation.

Effect of MHT on cognition

In the WHIMS study of women aged 65 years and older, conjugated equine estrogens (CEE) plus medroxy-progesterone acetate (MPA) and CEE alone increased the risk of probable dementia, but did not have a significant effect on MCI [49,50]. In the WHIMSCA trial of women aged 65–79 years, CEE plus MPA had a negative effect on verbal memory, but a trend toward positive effect on figural memory. CEE alone in the WHIMSCA trial did not improve cognition, but was associated with lower spatial rotational performance [51,52]. A Cochrane review of 24 trials in 2008 concluded that MHT did not prevent cognitive decline in older postmenopausal women either in the short or longer term (up to 5 years) [53]. A meta-analysis of 36 randomized trials concluded that overall MHT did not impact on cognitive function, but that cognition was negatively affected by combined estrogen and progestin therapy [54]. There was a trend (p = 0.07) for verbal memory to be improved with MHT in younger postmenopausal women (under the age of 62 years), but most trials of MHT with positive outcomes were of 12 weeks or less and negative outcomes of MHT were more common in trials of more than 12 weeks. In a review of 29 studies of MHT in the prevention of cognitive decline and dementia in healthy postmenopausal women, it was concluded that MHT does not convey any benefits in asymptomatic women during the menopausal transition [55]. In women with vasomotor symptoms, however, there were improvements with MHT in verbal memory, vigilance, reasoning and motor speed, but not in other cognitive functions. In a meta-analysis of twelve observational studies that was part of the same review, MHT was found to be associated with a reduced risk of dementia in later life (odds ratio: 0.66; 95% CI: 0.53–0.82), but the authors cautioned that possible biases and potential confounders limit the interpretation of the analysis. The effect of MHT given from the time of the menopause to the age of 60 years – the ‘window of opportunity’ – on cognition at the menopause and the later development of AD requires further elucidation.

Effect of bilateral oophorectomy & MHT

In women who undergo bilateral oophorectomy before the menopause there is an immediate sharp drop in estrogen levels. There is also a fall in the levels of testosterone and androgens that are precursors of estrogens and the main source of estrogens in postmenopausal women. There is evidence that androgens as well as estrogens may have an effect on cognition and the development of dementia [42]. In the Mayo Clinic Cohort Study of Oophorectomy and Aging, 676 women who had bilateral oophorectomy and 813 women who had unilateral oophorectomy before the onset of the menopause were matched with 1472 women from the same population who had not undergone oophorectomy [56]. The women who had undergone oophorectomy had a significant increased risk of cognitive impairment or dementia (hazard ratio [HR]: 1.46; 95% CI: 1.13–1.90). The risk increased with younger age at oophorectomy (p = 0.0001 for trend), but women treated with estrogen from the time of oophorectomy until the age of 50 years did not have any increased risk of dementia. At the 65th Annual Meeting of the Academy of Neurology in March 2013, Bove reported on the results of two longitudinal studies of 1837 women, 33% having had a surgical menopause [57]. In the group of women with a surgical menopause, earlier age was associated with a faster decline in semantic memory (p = 0.002), episodic memory and global cognition (p < 0.001). There was also a significant association between earlier age at surgical menopause and the neuropathological changes (p = 0.01) and the global pathology score (p = 0.04). In women who had a natural menopause, no significant associations were found between earlier age and cognitive decline. Bilateral oophorectomy before the menopause, except for compelling reasons such as ovarian carcinoma, should not be performed.

Effect of different estrogen/progestin combinations & of different routes of administration

In randomized controlled trials of MHT in postmenopausal women, oral CEE plus MPA was associated with an increased risk of dementia and a negative effect on verbal memory [49,51]. By contrast, in a similar group of hysterectomized women, oral CEE alone had an essentially neutral effect, suggesting that MPA may have a deleterious effect in MHT formulations [50,52]. A study of 24 naturally menopausal women treated with CEE plus placebo, CEE plus MPA or CEE plus micronized progesterone found that CEE plus MPA decreased verbal memory, but increased working memory compared with the other two groups [58]. These findings are consistent with the negative effects of MPA in antagonizing estrogen upregulation in brain mitochondria; blocking estrogen-induced rises in intracellular calcium and inhibition of neural progenitor cell proliferation [5]. In mice, MPA has significant deleterious effects on brain function, whereas 19 nor-progesterone (P4) is neuroprotective [59]. It has, in fact, been suggested that the loss of progesterone during the postmenopause may be a contributing factor in the development of AD [60]. In a study, 68 healthy postmenopausal women at increased risk of AD were treated with either CEE or 17β estradiol for 1 year. The women allocated to 17β estradiol showed significantly better verbal performance than those treated with CEE [61]. The authors suggested that the particular type of estrogen may influence selective memory domains and may help to explain some of the controversy with regard to the role of MHT in the protection against neurodegeneration. Investigations of the effect of transdermal estrogens on cognition have been limited to relatively short periods of administration (not more than 3 years) on verbal memory. Most have shown neutral effects [62 –64]. In the one double-blind controlled study of transdermal estradiol patches that showed a significant improvement of executive functioning, the majority of the women had hot flushes or sleep impairment [65]. Transdermal administration of estrogens in postmenopausal women may be associated with a lower risk of venous thromboembolic disease and stroke compared with oral administration, and inferentially may be associated with a decreased risk of VaD [66,67]. In a review of randomized clinical trials of MHT including possible differential effects of different progestins, different estrogens and different routes of administration, it was concluded that the type of progestin is a more important determinant of the effects of MHT on memory than the type of estrogen [68]. Transdermal estradiol, in women with an intact uterus of micronized progesterone or a progestin other than MPA, may be the preferred treatment in the prevention of AD.

Timing & duration of MHT: a ‘window of opportunity’?

Initiation of MHT in older postmenopausal women does not improve cognition, but this does not exclude a possible benefit of MHT given to younger peri- and post-menopausal women during the ‘window of opportunity’ to prevent or reduce the severity of AD in later life. In the Cache County prospective study of incident dementia, 1357 men (average age: 73.2 years) and 1889 women (average age: 74.5 years) were followed-up for 3 years and 35 men (2.6%) and 88 women (4.7%) developed AD [69]. The incidence of AD in women increased over the age of 80 years and exceeded the risk in men (HR: 2.11; 95% CI: 1.22–3.86). Women who had used MHT had a reduced risk of AD (HR: 0.59; 95% CI: 0.36–0.96) compared with nonusers and the risk of AD decreased with increasing duration of HRT. After 10 or more years use of HRT, the relative increase in the risk of AD in women compared with men disappeared completely. In a further analysis of the Cache County Study, women who had used any type of MHT within 5 years of the menopause had a 30% lower risk of AD (HR: 0.66; 95% CI: 0.49–0.99) and the risk was reduced further in those who had used MHT for 10 years or more [70]. In women who had started MHT more than 5 years after the menopause, the risk of AD was not decreased. MHT with estrogen plus progestin initiated very much later, within 3 years of the start of the Cache County Study, increased the risk of AD (HR: 1.93; 95% CI: 0.94–3.96).

In the MIRAGE case–control study, the relationship between MHT and AD risk was investigated in 971 postmenopausal women, including 426 patients with AD and 545 relatives without dementia who had all used estrogen-containing MHT for more that 6 months [71]. There was a significant interaction between age and AD risk, and a significant protective effect of MHT in the youngest group of women aged 50–63 years (odds ratio: 0.35; 95% CI: 0.19–0.66). On multivariate analysis, the increasing risk with increasing age was not influenced by alcohol use, cigarette smoking, the use of NSAIDs or by prior hysterectomy or oophorectomy.

In the Northern Californian Kaiser Permanente managed healthcare consortium, the self-reported use of MHT in 5504 postmenopausal women was analyzed. Compared with women who had never used MHT, 26% of the women who had taken MHT in midlife had a reduced risk of dementia, whereas 48% of women who had taken MHT in late life had an increased risk of dementia [72].

A study of the neurobiological mechanisms that underlie the effect of estrogens on the brain using in vivo techniques suggests that the positive effects of estrogen may be limited to young postmenopausal women, particularly those under the age of 49 years, and to older women who initiated MHT around the time of the menopause [73]. These studies provide substantial evidence of the benefit of MHT given during a ‘window of opportunity’ in the prevention of AD in women.

A ‘window of opportunity’ to prevent AD & VaD?

The development of atherosclerosis and pathological changes in the cardiovascular system, including cerebrovascular disease, follow a similar time course to the development of the pathological changes of AD in the brain. Both conditions commence in midlife, are initially asymptomatic and progress over several decades, resulting in the clinical conditions of AD and cardiovascular disease (CVD), including cerebrovascular disease. There is increasing evidence that MHT commenced at the time of the menopause and continued until the age of 60 years significantly reduces the incidence of CVD [74]. Dementia is often the result of the combined effects of AD and VaD, and MHT could well have a beneficial effect in preventing or minimizing both conditions. There have been no long-term randomized controlled trials of the effect of MHT given during the ‘window of opportunity’ on the incidence of MCI and AD and it is unlikely that there will be in the future [75]. Two randomized, short-term (3-year) trials of MHT in postmenopausal women in the USA are underway; the ELITE trial [102] and the KEEPS trial [76,103]. In the ELITE trial, the effects of early and late estradiol on coronary artery calcium and neurocognitive function in postmenopausal women are being investigated. In the KEEPS trial of postmenopausal women between the ages of 42 and 58 years, the effects of oral CEE and transdermal estradiol on coronary arterial calcification, carotid intima–media thickness and on cognitive and affective scores on standard psychometric tests are being investigated. These trials should provide valuable information on the effect of MHT on cognition and on the factors that may influence the development of MCI and AD in women. At the present time, there is sufficient evidence to justify the use of MHT in healthy menopausal women during the ‘window of opportunity’, not only to relieve menopausal symptoms, but to prevent AD, as well as CVD and osteoporosis.

Measures that may prevent or reduce the incidence of AD, VaD & dementia in both women & men

A large number of measures, in addition to MHT in perimenopausal women, such as higher physical fitness in midlife, have been claimed to influence the development of MCI and AD dementia [77,78].

Diet

Elderly people on a Mediterranean diet are reported to be less likely to develop MCI or progress from MCI to dementia [79]. In the Mayo Clinic study on aging, overeating (2100–6000 calories day) doubled the risk for MCI; there was a dose–response pattern between calorie intake and the incidence of MCI [80]. In the Nurses Health Study, increased consumption of blueberries and strawberries significantly slowed memory decline from 1.5 to 2.5 years [81].

Vitamin D

Men and women with AD have lower plasma levels of vitamin D. Whether this is because older people tend to have poorer nutrition and less exposure to sunlight or whether, as some believe, vitamin D has a direct effect on ‘brain health’ remains to be established [82,83]. The possible prevention or amelioration of AD dementia and MCI is nevertheless a good reason for recommending supplementation of vitamin D in the elderly.

Sleep deprivation

Sleep, or lack of it, has a major effect on cognition [84]. In the Nurses Health Study, women who regularly slept 5 h or less a night, or 9 h or more a night, had an increased risk of cognitive decline compared with women who regularly slept for an average of 7 h per night [85]. Poor sleep quality (frequent napping 3 or more days per week), but not sleep quantity, is associated with increased Aβ deposition in the preclinical stage of AD [86].

Depression

Men and women with AD or MCI are often depressed. It is not clear, however, whether depression is a consequence of, or a risk factor for, the development of MCI and AD dementia. In a study of 13,535 long-term Kaiser Permanete members in California (USA) with a mean age of 81.1 years, depressive symptoms were present in 14.1% of subjects in midlife, 9.2% in late life and 4.2% in both mid- and late life. During 6 years of follow-up, dementia was diagnosed in 22.5% of the women. Compared with the women without depressive symptoms, the adjusted HRs for the development of dementia were for midlife symptoms HR: 1.19 (95% CI: 1.07–1.32), for late-life symptoms HR: 1.72 (95% CI: 1.54–1.92) and for both HR: 1.77 (95% CI: 1.52–2.06) [87]. In a study of302 women aged 85 years or more, depressive symptoms were measured using a 15-item Geriatric Depression Scale and the women were followed-up for 5 years [88]. After adjustment for age, education, alcohol and benzodiazepine use, women with an elevated score of 6 or more were 3.71 (95% CI: 1.30–10.59)-times more likely to develop MCI than those with lower scores at the start of the study. Similarly, women with an elevated score were 3.15 (95% CI: 1.03–9.65)-times more likely to develop dementia. After 5 years, the percentage of women with normal cognitive status was only 19% in the women with an elevated score at the start of the trial compared with 46% in the women who had normal scores at the start (relative risk: 0.28; 95% CI: 0.11–0.73). It was suggested that depression is a ‘prodrome’ or part of the preclinical phase of AD.

Cognitive interventions

A systematic review of 35 studies concluded that both in healthy older adults and in people with MCI, cognitive training can improve cognitive functioning, including memory performance, executive functioning, processing speed, attention, fluid intelligence and subjective cognitive performance [89]. Everyday tasks that draw on cognitive skills, such as driving a car, when based on established expertise and supported by routine and familiarity may be preserved with increasing age [90]. New skills such as mastering information technology may also be learnt, albeit more slowly than in younger adults [91]. It remains to be established whether cognitive interventions can prevent or reduce the pathological changes of AD. A study of Aβ deposition in the brain measured by PET in 65 healthy older adults and ten patients with AD found that individuals with greater early and midlife cognitive activity had less Aβ deposition. The amount of Aβ deposition in those in the highest tertile of cognitive ability was comparable to young controls, whereas the amount of Aβ deposition in those in the lowest tertile was comparable to patients with AD [92].

Treatment of hypertension & hypercholesterolemia to prevent CVD

Active treatment of hypertension and hypercholesterolemia to restore normal levels of blood pressure and cholesterol should help to prevent VaD and VaCI. The use of angiotensin receptor blockers and of β-blockers has been claimed to be associated with less AD-related pathology at autopsy [93,94]. The use of low dose aspirin in elderly women at high vascular risk has been reported to be associated with significantly less decline in cognition over a period of 5 years compared with a similar group of women not taking aspirin [95]. Aspirin and anti-platelet therapy have an important place in the prevention of stroke, which is a major cause of MCI and AD [96]. NSAIDs have been claimed to influence the development of AD [97].

It is strongly advocated that the above measures to prevent AD should be widely implemented in the same way that preventive measures are currently advocated in order to prevent ischemic CVD and diabetes.

Conclusion & future perspective

Until recent times, AD was regarded as an inexorable disease increasing in incidence with advancing age and progressing over a variable period of time to dementia. The recognition of the long preclinical phase of the disease and better understanding of the underlying pathophysiological processes have led to a complete change in perspective. Much current research is focused on the processes that result in Aβ deposition in neurons and the formation of tau protein and NFTs. BACE precipitates the formation of Aβ in neurons and an inhibitor of BACE has been found to reduce CSF Aβ by up to 94%. Clinical trials of a new Aβ inhibitor agent (MK8931, Merck) are currently in progress in patients with AD and healthy volunteers [98]. An agent that inhibits Hsp70, a ‘chaperone protein’ supervising the activity of tau inside nerve cells, has been shown to rapidly reduce the levels of tau in the brain. Current Hsp70 inhibitors are not very potent, require high doses and have inherent problems [99]. The day may not be too far distant, however, when effective and safe substances are discovered that reduce the accumulation of Aβ and of tau proteins in the brain and retard or prevent the development of AD. The discovery of safe and effective treatments for AD may initiate a new era similar to the discovery of statins (inhibitors of the enzyme HMD CoA reductase) that reduce plasma cholesterol and prevent atherosclerosis and its consequences. The inhibitors of Aβ and tau protein synthesis, and other agents including monoclonal antibodies that are under trial, provide hope for the future. In the meantime, the concept of AD as a disease that is immutable should be challenged, and measures that prevent or retard AD, VaD and dementia and are currently available, including diet, lifestyle changes, stimulating activities and active treatment of CVD, should be strongly encouraged. MHT in women from the time of the menopause (particularly in those with a premature menopause) to the age of 60 years during the ‘window of opportunity’ may not only alleviate the symptoms of the menopause, but may prove to play an important part in the prevention of AD and dementia in later life.

Executive summary

Alzheimer's disease (AD), mild cognitive impairment (MCI), vascular dementia (VaD) and vascular cognitive impairment are not inevitable consequences of aging and may be modified by adverse and protective factors; the protective factors in women may include menopausal hormone therapy (MHT).

AD strictly applies to the neurodegenerative process characterized by neurofibrillary tangles in the brain. The term ‘Alzheimer's disease’, however, is often used, particularly in nonmedical circles, to cover all forms of cognitive impairment of a lesser or greater degree, including dementia.

β-amyloid plaques and neurofibrillary tangles may begin to develop from midlife onwards and the changes of AD take place over many years and decades before the onset of MCI and AD and constitute a preclinical phase of the disease.

The preclinical phase of AD can be diagnosed by biomarkers in the cerebrospinal fluid of β-amyloid production and of neurodegenerative proteins and by MRI and PET brain imaging.

The etiology of AD is unknown, but β-amyloid is believed to play an important role. The only genetic abnormality commonly found in AD is the ApoE E4 allele, which is present in approximately 5% of cases.

Cognitive impairment and dementia are often the result of a combination of AD and VaD and are more rarely the result of other neurodegenerative diseases.

The diagnosis of AD and MCI is a clinical one and the National Institute of Aging and Alzheimer's Association in the USA have published new criteria and guidelines for diagnosis.

The prevalence of MCI, AD, vascular cognitive impairment and VaD increases with age, MCI and AD accounting for approximately two-thirds of cases. In a group of women 85 years and older, MCI was diagnosed in 23.3% and AD in 17.8%; 59.9% were cognitively normal.

Cognition, particularly memory and recall, decline with increasing age from midlife onwards. Neuropsychological testing may be required to differentiate between ‘normal decline’ with aging and a decline meriting a diagnosis of MCI or dementia.

Over the age of 85 years, MCI and AD are more common in women than men. The incidence of AD dementia in the population-based EURODERM study was 81.7 in women and 24.0 in men per 1000 person-years.

Gender difference and the menopause may play a part in the pathogenesis of AD and VaD. The natural menopause, however, is not associated with marked changes in cognition, except in women with vasomotor symptoms.

MHT with combined conjugated equine estrogens and medroxy-progesterone acetate in women over the age of 65 years is associated with an increased risk of dementia. However, MHT from the menopause to the age of 60 years when the risks are extremely small – the ‘window of opportunity’ – may prevent, delay the onset or reduce the severity of AD.

Transdermal estradiol and, in women with an intact uterus, the addition of micronized progesterone or a progestin other than medroxy-progesterone acetate (medroxy-progesterone acetate is probably deleterious), may be the preferred treatment.

In a Mayo Clinic study, women who had a bilateral oophorectomy before the menopause had a significantly increased risk of MCI or dementia, the risk increasing with younger age at oophorectomy. Women treated with estrogen from the time of oophorectomy to the age of 50 years had no increased risk.

In the Cache County prospective study of 1357 men (average age: 73.2 years) and 1889 women (average age: 74.5 years), the incidence of dementia in women over the age of 80 years exceeded the risk in men. Women who had used MHT had a reduced risk compared with nonusers, and those who had used MHT for 10 years had the same incidence as men.

The development of the pathological changes of AD follows a similar time course to that of atherosclerosis and cardiovascular disease. MHT may have a beneficial effect in the prevention of both AD and VaD.

Current trials of MHT may provide further evidence of the ‘window of opportunity‘, which, if proven, will have a profound effect on the assessment of the benefits of MHT and the care of menopausal women.

Many measures may help to prevent or retard the development of AD and VaD in both men and women and should be strongly encouraged.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Alzheimer'S Disease,Dementia,Mild Cognitive Impairment and the Menopause: A ‘Window of Opportunity’?

Abstract

Keywords

Epidemiology

Pathology of AD & dementia

Etiology of AD

Diagnosis

Effect of age on cognition

Gender & AD

Menopause & cognition

Effect of MHT on cognition

Effect of bilateral oophorectomy & MHT

Effect of different estrogen/progestin combinations & of different routes of administration

Timing & duration of MHT: a ‘window of opportunity’?

A ‘window of opportunity’ to prevent AD & VaD?

Measures that may prevent or reduce the incidence of AD, VaD & dementia in both women & men

Diet

Vitamin D

Sleep deprivation

Depression

Cognitive interventions

Treatment of hypertension & hypercholesterolemia to prevent CVD

Conclusion & future perspective

Footnotes

References