Midlife risk and protective factors of AD

AD is nowadays considered as a continuum of disease which begins well before the appearance of any clinical symptoms (McKhann et al., 2011). As a result, various protective and risk factors of AD have been recognized which operate throughout the individual’s life-span especially during midlife, thus affecting his/her likelihood of developing AD. Some of the protective and risk factors of AD pertaining to lifestyle and sociodemographic are listed in Figure 2 (Solomon et al., 2014a).

Risk factors of AD can be categorized into two main categories; modifiable and unmodifiable factors. Age, genetic constitution (APOE status) and family history of AD fall into the unmodifiable group of risk factors.

Age is the strongest predictor of AD, i.e. the risk of AD increases exponentially as the individual gets older. The presence of the APOE Ɛ4 allele is another well-established genetic risk factor for sporadic AD and >60% of AD cases carry at least one APOE Ɛ4 allele (Riedel et al., 2016). Women carrying one APOE Ɛ4 allele had similar risk of AD as men homozygous for APOE Ɛ4 (Farrer et al., 1997). The APOE gene encodes a protein which acts as a major component for central nervous system lipoproteins and is thus involved in lipid transport in brain (Manaye et al., 2013). The APOE ε4 isoform increases the risk of AD through increased production of amyloid Aβ, and a decrease in dendritic spine density (Rodriguez et al. 2013, Dumanis et al., 2009).

Another important determinant with respect to APOE ε4 status is its interaction with female sex steroid hormones. APOE is a biological factor which associates with sex, genetic, and lifestyle related factors (education, physical activity, smoking, occupation status, and job situation) to alter AD-related pathology (Rocca et al., 2014b). Women homozygous for APOE Ɛ4 were found to have lower CSF Aβ levels in a dose response manner in late onset AD but not in early onset AD (Mehrabian et al. 2015). In females, the influence of APOE Ɛ4 presence was more pronounced on the neuropsychiatric symptoms of AD (Xing et al., 2015), and APOE Ɛ4 carriers showed more severe amyloid pathology on positron emission tomography than was present in non-carriers (Jack et al., 2015).

The modifiable risk factors of AD include cerebrovascular and cardiovascular risk factors, such as obesity, smoking, alcohol intake, and high fat diet (Solomon et al., 2014a) with higher education, social and physical activity, and doing a mentally stimulating job being associated with a decreased risk of dementia (Wilson et al., 2007). The mechanisms through which higher education, higher socioeconomic status, being socially active and doing a mentally stimulating job protect from AD are possibly mediated through the increase in cognitive and brain reserve (Wilson et al., 2010, Fotenos et al., 2008). A higher brain reserve would enable a brain to better withstand pathological insults due to the presence of the larger number of healthy neurons, while cognitive reserve denotes the brain’s ability to exploit alternative networks of brain to combat the developing pathology, such as in AD (Sperling et al., 2011). Both cognitive and brain reserve enable the brain to tolerate the initial symptoms of dementia without showing any clinical symptoms for a longer duration of time, but it may also lead to a more rapid decline once compensatory mechanisms stop functioning (Fotenos et al., 2008). APOE Ɛ4 and education influence the onset of dementia

independently as well as interactively i.e. the risk of dementia is halved among APOE Ɛ4 carriers with high education in comparison to APOE Ɛ4 carriers with low education (Wang et al., 2012).

Smoking, alcohol intake, low physical activity, and high fat diet etc. predispose to higher risk of AD. These habits may promote accelerated aging of brain through metabolic and glucose dysregulation, oxidative stress and chronic inflammation, all of which are factors that increase the risk of AD either independently or operate through increasing the risk of cardiovascular and cerebrovascular diseases (Arvanitakis et al., 2004, Yaffe et al., 2009, Schmidt et al., 2002). Volunteering in any task has been associated with decreased mortality among older people, and the underlying reason can be that volunteerism stems from emotional wellbeing and as well as the social interactions gained by this activity (Harris and Thoresen et al., 2005). Obesity itself is an important predictor of AD. Midlife BMI of >30 in conjunction with high systolic blood pressure and higher total cholesterol increase the risk of AD either through the inflammation associated with obesity or increasing the risk of the metabolic syndrome (Kivipelto et al., 2005). Diabetes mellitus is another risk factor acting either independently or in combination with obesity to increase the risk of AD via insulin resistance and microvascular disease in brain. Brain insulin production may be inhibited by peripheral hyperinsulinemia, which in turn may decrease the clearance of amyloid from the brain (Barnes and Yaffe 2011). Moreover, adipocytes are known to secrete various hormones (leptin, cortisol) and cytokines (tumor necrosis factor-alpha and interleukin 6) which collectively increase the risk of AD by inducing inflammation in brain and by altering brain beta amyloid levels (Profenno et al., 2009). An elevated serum cholesterol level is a well-established risk factor for AD since it promotes the formation of amyloid beta in neuronal cell membranes through the formation of cholesterol rich areas which preferentially process APP into Aβ (Casserly and Topol 2004). High blood pressure in midlife is associated with a higher risk of late-life dementia. Hypertension increases the risk of developing white matter lesions, small and large vessel disease, and brain atrophy, all of which may converge and thus link the higher risk of dementia with high blood pressure (Launer et al., 2000).

Hypertension also affects the endothelial lining of blood vessels, altering their permeability and inducing proinflammatory and procoagulant responses in cell membranes, which in turn may trigger the formation of neuritic plaques, a hallmark of AD (Hallenbeck 1994). A decline in the incidence of dementia with antihypertensive drugs among older people support the view that hypertension is a modifiable risk factor for dementia (Forette et al., 2002, Feigin et al., 2005).

Other important factors associated with a decreased risk of AD are higher intellectual activity, being in a relationship (marriage), which also delays AD through increasing cognitive reserve (Vemuri et al. 2014, Sundstrom et al., 2016). In summary, preventing or delaying the onset of AD clearly demands monitoring and modifying of midlife risk and protective factors for AD (Solomon et al., 2013).

With regard to the several protective factors, hormone therapy (HT) holds a special place as a potential therapeutic to prevent or delay onset of dementia in women. Considering the longer life span of women, the menopause also marks a midlife event (mean age 51 years) as more than one third of a woman’s life span is spent in the postmenopausal state. Thus,

the higher risk of AD among females than males can be associated biologically with the decline in the amounts of sex steroid hormones (estrogen and progesterone) at menopause (Vest and Pike 2013). The use of conjugated equine estrogens was not associated with a cognitive decline in a recent meta-analysis, but this report did not consider other formulations of estrogens such as estradiol. In the same meta-analysis, cognitive training was associated with a decreased risk of cognitive decline, while current smoking and APOE Ɛ4 genotype were associated with an increased risk of AD (Plassman et al., 2010). The biological effectiveness of estrogen is reduced in the presence of the APOE Ɛ4 allele (Manaye et al., 2013). It has been reported that estrogen conferred protection against cognitive decline among APOE Ɛ4 negative women but not in APOE Ɛ4 positive women (Yaffe et al., 2000a).

This concept may also explain the higher risk of AD among women which might be mediated through the APOE interaction with female sex per se.

Though no clear guidelines are available whether or not to use HT among postmenopausal women as a means to prevent dementia or AD, much research has been conducted in this field during the past two decades; there is evidence of a neuroprotective potential of HT emerging from experiments conducted in animals as well as in observational trials. Some discrepancies have also been seen with respect to the clinical trial findings; these will be discussed in detail in the following chapters.

Figure 2: Risk and protective factors of AD (Solomon et al., 2014) 2.3.4 Sex based dimorphism in brain and AD

Of the 5.2 million people with AD in United States, 3.3 million (two thirds) are women (Alzheimer's Association 2016). Similarly, in global terms, more than 60% of patients with AD are women (Riedel et al., 2016). The higher risk of AD among women than men can be simply attributed to their longer life span (Gao et al., 1998) but it may also be linked to

gender have emerged as separate entities recently, where sex defines biological characteristics such as chromosomal constitution (XX or XY), gonadal and hormonal differences, while gender refers to cultural, psychological and social differences (access to education, occupation) between men and women (Ristvedt 2014, Mielke et al., 2014). Thus, identification of both sex- and gender- based risk and protective factors are critical in understanding a chronic illness such as AD. Sexual dimorphism is driven by the levels of the sex-specific hormones prevailing during prenatal period, adolescence, puberty, and adulthood (Li et al., 2014) and these are governed by hormone dependent gene activations in a sex specific manner (Nugent et al., 2012). One such example is the sex hormone mediated language development which differs depending on whether the postnatal hormonal surge is mediated by estrogen or testosterone (Schaadt et al., 2015).

The distinctive distributions of estrogen and androgen receptors in brain account for differences in performance in brain tasks (Li and Singh 2014); this has been linked with certain pathological variants; long term estrogen depletion was reported to be associated with cognitive decline (Mielke et al., 2014); excess hormone exposure results in polycystic ovarian syndrome in females (Nugent et al., 2012); and X-inactivation is associated with an increased AD risk among females (Ferrari et al., 2013).

All of these mechanisms suggest that sex-specific hormones affect an individual’s likelihood of developing AD in a variety of ways. It can be mediated through down-regulation of estrogen receptors in hippocampus in the case of long term-estrogen depletion, thus affecting the main area of the brain involved in neuroprotection and cognitive enhancement (Mielke et al., 2014). There are also possible indirect pathways e.g. the higher risk of AD among women with polycystic ovarian disease, who also have a higher risk of developing the metabolic syndrome due to insulin resistance, higher BMI and cholesterol levels. These metabolic changes predispose women with polycystic ovaries to a higher risk of AD (Nugent et al. 2012). Similarly, genetic mechanisms may be involved in the higher prevalence of AD among women, such as inactivation of the X-chromosome during embryogenesis since this chromosome mainly carries neuroprotective genes, or it can be due to unknown non-genetic and epigenetic mechanisms (Ferrari et al. 2013).

Moreover, sexual dimorphism in brain is associated with a higher incidence of AD among women through sex-specific white matter lesions (Gallart-Palau et al., 2016) and an increased rate of cognitive decline among females than males (Laws et al., 2016, Koran et al., 2016). These sex-specific associations involve a complex interplay between hormonal, genetic, and environmental factors (Carter et al., 2012).