Sex Differences in Alzheimer’s Disease

Introduction

Alzheimer’s disease (AD) dementia is one of the most common types of dementia in older adults. As the population ages, the number of patients who are concerned about cognitive decline and who have AD is dramatically increasing. Barriers to successful diagnosis and care include the failure to properly diagnose dementia early in the course of AD, underestimation by both healthcare professionals and the public of the morbidity associated with AD, and the inconsistent use of appropriate medications for treatment. The links between diverse sets of risk factors for cognitive decline and dementia have long been recognized in the literature, and more recently, research interest in potential sex differences in disease risk and prevention has emerged. In this chapter, the latest epidemiological evidence that supports sex differences in AD, clinical and diagnostic considerations, and the role of co-morbidities associated with AD are reviewed.

Epidemiology

An estimated 5.7 million Americans live with AD, and an additional 11.6 million Americans are thought to have mild cognitive impairment (MCI). [1, 2] Alzheimer’s disease is the most common cause of dementia, accounting for 60%–80% of cases. It is the sixth leading cause of death in the United States. The incidence and prevalence of AD increases dramatically with age; it affects approximately 80% of patients aged ≥ 75 years. Incidence rates increase from 2 per 1,000 at age 65–74 to 37 per 1,000 at age ≥ 85 [3]. By 2050, the number of patients with AD in the US is projected to triple, with the greatest increase among those aged ≥ 85 years [4].

The number of individuals with AD is expected to increase more in women than men over the coming years, which reflects increased longevity for women as well as biological influences [4]. The overall lifetime risk of acquiring AD for those aged 65 is 21.2% for females and 11.6% for males. [1, 5] Projected survival varies between four and eight years across studies and is impacted by multiple factors, including age at diagnosis, sex, behavioral features, motor system involvement, and medical co-morbidities [6].

Considerations: Sex-Specific Risk Factors

Sex differences in risk factors fall into two categories:

1. diseases or conditions that are specific to one sex; and

2. diseases or conditions that have distinct causes, manifestations, outcomes (morbidity or mortality), or responses to treatments for one sex compared to the other.

Sex-specific risk factors of dementia for women include pregnancy and menopause. For example, multiple studies have reported that a history of preeclampsia is associated with an increased risk of mild cognitive impairment, vascular dementia, and Alzheimer’s disease [7–9].

In addition, early menopause (natural or surgery-induced), especially before the age of 45 years, is associated with an increased risk of mild cognitive impairment and dementia [10–13].

Influence of Sex Hormones

The Women’s Health Initiative Memory Study (WHIMS) remains the only randomized, placebo-controlled trial on menopausal hormone therapy for the primary prevention of dementia [14, 15]. This study enrolled females > 65 years with a uterus who were randomized to receive oral conjugated equine estrogen (CEE) (0.625 mg/day) plus medroxyprogesterone acetate (MPA) (2.5 mg CEE/MPA) or a placebo, and females without a uterus (n = 4,532) were randomized to receive oral CEE (0.625 mg/day) or a placebo. Important results from this study suggested that the risk of all-cause dementia was double in the combined CEE/MPA group compared to the group that received only CEE and that these findings were not modified by smoking, cardiovascular disease (CVD) risk factors, stroke, or statin or aspirin use.

In addition, CVD risk factors did not modify the effects of hormone therapy on a composite measure of global cognitive function. MRI brain imaging also showed that for the WHIMS patients, ischemic brain volume did not differ between the hormone therapy and placebo groups. However, the rates of accumulation of white matter lesions and total brain lesion volumes were higher among females with a history of CVD treated with hormone therapy versus a placebo. More recent randomized clinical trial studies have identified the timing and initiation of menopausal hormone therapy as important factors in cognitive decline, with data suggesting that initiating menopausal hormone therapy within five years of menopause does not have detrimental effects on cognition [16–18]. However, long-term menopausal hormone therapy use of 5 or more years may be associated with an increased risk. There continues to be relatively little research investigating the effect of declining male sex hormones on cognitive function with age. However, of the studies conducted, one noted that males experience an approximately 2%–3% decline in testosterone levels per year after the age of 30 [19].

It remains unclear whether low testosterone levels are associated with the risk of dementia among males [20]. However, androgen deprivation therapy, a common therapy for prostate cancer, has been associated with a risk of cognitive impairment and dementia [21].

Genetic Contributions

Late-onset AD is a complex genetic disorder with an estimated heritability of 60%–80%. The strongest genetic risk factor for late-onset AD remains the apolipoprotein E (APOE) genotype. APOE encodes the brain’s major cholesterol transporter and has three common alleles: e2 (with an estimated frequency of 8.4% in the population), e3 (77.9%), and e4 (13.7%) [22, 23].

APOE e4 is associated with an increased risk of developing AD compared to the e3/e3 genotypes [24], and each APOE e4 allele reduces the average age of symptom onset by a decade. Female carriers of APOE e4 are at a greater risk than male carriers, particularly those aged 65–75 years [25].

APOE e4 contributes to AD risk via a multitude of mechanisms, including enhanced aggregation and decreased clearance of the amyloid-β polypeptide, increased tau phosphorylation, neuronal hyperexcitability, reduced glucose metabolism and vascular function, and neurodevelopment differences [24, 25]. As APOE represents a risk factor but is not considered a deterministic gene, APOE genotyping is currently not recommended in the clinical evaluation of patients with suspected AD [26].

The APOE4 allele has, however, been associated with an increased risk of amyloid-related imaging abnormalities (ARIA) in individuals treated with plaque-lowering mAbs (e.g., aducanumab) [27], and guidelines regarding the appropriate use of genetic testing in patients considering starting an mAB have been developed [28].

Other genetic investigations, such as genome-wide association studies, have identified more than 20 additional common genetic variants that modify the risk of late-onset AD [22, 29]. These genes converge in biological pathways involving lipid metabolism, immunity, and endocytosis. The effect of each gene on AD risk is small (with an OR of 0.8–0.9 for protective alleles and 1:1–1:2 for risk alleles), with no known sex differences; thus, these results are not clinically meaningful.

Finally, polygenic hazard scores that attempt to assess the overall burden of AD risk alleles could theoretically enhance the ability to predict at-risk individuals; however, they are still rarely used, and at this time, no specific sex difference considerations are involved in developing these scores. Likewise, mutations in the amyloid-β precursor proteins presently 1 and 2, which lead to familial early-onset AD, remain rare and do not currently exhibit sex-specific differences [22].

Sex Differences in Risk Factors

Multiple environmental, behavioral, and lifestyle factors have been associated with AD, and the relationships between many of these risk factors and dementia vary by sex and gender [30]. Traumatic brain injury is a potentially modifiable risk factor for AD and other neurodegenerative disorders [31]. Many of the adverse psychosocial risk factors for TBI disproportionally affect women, whereas sports and occupations, two of the biggest risk factors for TBI, differentially impact men. There is also evidence that, for any given severity of TBI, women are likely to have poorer outcomes, including Alzheimer’s disease related dementias (ADRD) [32, 33].

Women have been reported to have twice the risk of depression compared to men, and this worsens during the menopausal transition [34, 35]. Some studies have reported that elevated rates of depressive symptoms were associated with a stronger risk of AD in men compared to women [36, 37]. However, another study that reported a stronger increase in AD risk for women, late-life depression was also associated with an increased risk of cognitive decline [38], although it is still unclear whether this constitutes a risk factor or is the consequence of early AD neuropathology in serotonergic and noradrenergic brainstem nuclei [39].

Conversely, increased years of formal education, physical activity, and social engagement across one’s lifespan moderate the risk of late-life dementia [30]. Historically, women have had less access to education, so more women are affected by this socioeconomic factor.

Common neuropsychiatric symptoms of AD include depression, anxiety, mild apathy, irritability, and sleep disturbances (e.g., insomnia or disrupted circadian rhythm) [40]. In a meta-analysis, female sex was associated with a higher prevalence and greater severity of depressive symptoms, aberrant motor behavior, and psychotic symptoms in AD dementia, whereas male sex was associated with an increased severity of apathy [41].

Complaints of sleep disturbances in both sexes are commonly seen with neuropsychiatric behavior symptoms and have known sex differences [42]. These sleep disturbances are linked to late-life cognitive decline and AD [43–45]. Observational studies indicate that sleep quality is related to cognitive function in both early and late life, while disordered breathing is associated with an increased risk of dementia [45]. Sleep disruption in patients with AD is a common complaint, and disruption to slow-wave sleep (Stage 3) has been linked to an increase in A beta levels [45]. Women are especially vulnerable to sleep disruption at or around the transition to menopause; however, whether sex differences affect AD risk is still under investigation [46, 47].

Multiple studies have identified a strong association between physical activity (PA) and cognitive function. Participation in PA may reduce the risk of dementia by increasing oxygen saturation and neurogenesis, minimizing vascular risk factors, and reducing inflammation and depressive symptoms [48]. A meta-analysis of prospective studies in older adults without dementia found that all levels of PA (low, moderate, and high) were associated with protection against cognitive decline compared to none at all [49]. In addition, PA was associated with beneficial effects on the brain’s structures [50]. Multiple studies suggest that sex modifies the association between PA and cognition. Older women undergoing aerobic training showed greater cognitive gains than older men [51, 52], and PA maintenance over 10 years predicted fewer declines in multiple cognitive domains among women compared to men in the Health, Aging, and Body Composition study [53].

Increasing evidence suggests that diet and nutrient intake are related to dementia risk. Studies have investigated the effects of a variety of specific nutrients, including B vitamins, antioxidants, and fatty acids, on late-onset dementia [54]. While many studies have demonstrated a strong association between nutrient deficits and cognitive function, the findings of most randomized controlled trials on single-nutrient supplements have not been positive [55]. Dietary requirements vary by sex, and some studies have reported that a diet low in vitamin B12 [56], western dietary patterns [57], and high in fat and red meat is associated with an increase in AD in men but not women [58].

The prevention of dementia through dietary intervention and the analysis of specific dietary patterns may be more effective than traditional therapies to treat dementia once it has emerged. The Mediterranean diet is associated with a lower risk of mild cognitive impairment and AD, and the MIND diet is thought to reduce the incidence of AD and slow cognitive decline in older adults [59–63]. Adherence to other healthy dietary patterns has been demonstrated to have a similar association with cognitive function [64]. This is supported by preliminary cross-sectional data obtained from investigations into dietary patterns pertaining to total cerebral brain volume and white matter hyperintensity volumes [65].

Cardiometabolic and cardiovascular risk factors are an important group of associations that exhibit known sex differences. The risk of developing AD and related forms of dementia is increased in patients with vascular risk factors, and growing evidence suggests that the aggressive treatment of risk factors as early as midlife can attenuate the risk of developing cognitive impairment at an older age [66, 67]. In addition, vascular risk factors are associated with a faster rate of cognitive decline after a diagnosis of AD, further emphasizing the importance of adequate treatment [68].

Several cardiovascular risk factors have been demonstrated to have a strong relationship with cognitive decline and dementia, including hyperlipidemia, hypertension, obesity, and diabetes mellitus. Several mechanisms are implicated, including disruption to insulin signaling, an increase in the accumulation of advanced glycation end-products, and interference with amyloid-β clearance [69].

In addition, diabetic women had a higher risk of diabetic complications, myocardial infarction, and coronary artery disease than men in studies that assessed the impact of cardiovascular risk factors on older men and women [70, 71].

Echoing the cognitive studies demonstrating the importance of the timing of hormonal influences and replacement therapy across one’s lifespan, similar trends are emerging for cardiovascular risk factors. Studies that have closely evaluated the association between metabolic syndrome and cognitive function across the human lifespan [72] note that midlife hypercholesterolemia, hypertension, and obesity are consistently associated with the risk of late-life dementia [73, 74].

In contrast, there are less consistent relationships between late-life vascular risk factors and late-life cognition or dementia [75]. More specifically, some studies suggest that low blood pressure, low cholesterol, and weight loss are associated with dementia risk in later life [76–78]. These findings are likely due to the effects of the underlying disease process even before a diagnosis is obtained and, in the case of hypotension, of reduced cerebral blood flow. The data regarding potential sex differences in these relationships are also inconsistent. For example, we know that men have a higher prevalence of vascular risk factors and conditions up to about the age of 80. However, a recent study suggested that despite the higher prevalence of these conditions in midlife for men, women who had vascular risk factors were at the greatest risk of cognitive decline [79].

Over the past few years, efforts of the American Heart Association (AHA) and others involved in clinical trials have focused on the management of blood pressure to prevent cognitive decline and dementia. The AHA published recommendations for the management of vascular cognitive impairment, which include the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression (which can occur with cerebrovascular disease) and the aggressive management of CVD risk factors [80].

Findings from the Systolic Hypertension in Europe trial noted that aggressive blood pressure (BP) management was associated with a reduced risk of developing dementia compared to a placebo [81]. More recently, the SPRINT MIND randomized trial evaluated the cognitive effects of intensively lowering BP (to a systolic BP goal of < 120 mmHg) versus the traditional BP-lowering goal of < 140/90 mmHg. In adults aged ≥ 50 years without diabetes mellitus or prior stroke, intensive BP lowering significantly reduced the rate of MCI (14.6 versus 18.3 cases per 1,000 person-years; HR of 0.81; 95% confidence interval [CI]: 0.69–0.95) as well as the combined rate of MCI or probable dementia (20.2 versus 24.1 cases per 1,000 person-years; HR of 0.85; 95% CI: 0.74–0.97) [82].

Furthermore, a brain MRI sub-study documented a significant reduction in the development of white matter lesions [82] with this intensive blood pressure control. This study, along with others that evaluated BP reduction, pointed to possible pathways that link vascular dementia to AD (known as mixed dementia), which may further help explain varying patterns in cognitive function between the sexes [83–85].

Variations in the course of CVD between women and men suggest that the interaction between sex and age is an important consideration relative to cognitive impairment. Finally, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability investigated a multimodal diet, physical activity, cognitive intervention that included vascular risk factor monitoring and demonstrated a decrease in cognitive decline over two years in the multidomain intervention group. Presently, the data from this study’s outcomes are being examined for potential sex differences through an extension of the study [86].

Given the association between hyperlipidemia or hypertension and dementia, multiple clinical trials have assessed whether statin or antihypertensive use reduce the risk of cognitive decline and dementia [87]. Although these studies have not systematically examined sex differences in response to therapy through stratified analyses, one study did find that statins were similarly associated with reduced dementia risk for both women and men [88]. Thus, whether there were demonstrable sex differences in responses to therapy could not be determined.

Sex Differences in Clinical Presentation

Individuals with AD present with early and prominent involvement of episodic memory and mild impairment of other cognitive domains. The clinical history is usually suggestive of classic AD features, which include cognitive changes that are slow and progressive and appear insidiously. Frustration over the inability to remember recent information, sleep disturbances, and a family history of a cognitive disorder are all suggestive of AD, and research suggests that there may be some important sex differences in complaints and presentation.

The topic of subjective memory complaints (SMC) has garnered recent attention because older patients so commonly report them, yet physicians are not quite sure whether to take these complaints seriously and evaluate them further. Some studies have shown a higher prevalence of SMC in women compared to men [89, 90], whereas others have noted that SMC may be associated more closely with objective memory performance in woman than men [91].

Prior to a full cognitive battery, screening with rapid cognitive tests, such as the Mini Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA), is often administered. The MoCA is increasingly used as a foundation test to assess the capacity for attention, the components of executive function, language, and memory because it can do so in greater detail than the MMSE. One small study of 70-year old community-dwelling patients found women performed better than men on delayed recall on the MoCA whereas men scored better on visuoconstruction and serial subtraction [92]. Presently, however, there limited studies regarding sex-specific norms for MoCA scores.

Late-onset AD most commonly manifests as an amnestic disorder characterized by episodic memory with varying degrees of executive language and visual spatial impairment [93]. Patients often show a gradient of memory impairment, with the greatest deficit being their ability to recall recent events, while remote memory is relatively less affected. Patients who undergo memory testing (e.g., word lists or story learning) show impaired learning, sudden memory loss, and poor, delayed recall [94]. On average, women perform better on tests of verbal memory and processing speed, whereas men perform better on visual-spatial tests [95]. Sex differences in cognitive testing profiles indicate that women often have more difficulty with language and confrontational naming tests [96, 97]. Longitudinally, women may also have difficulty with memory tests and, in particular, delayed recall of verbal information [98].

Clinical Evaluation

In evaluations to address cognitive concerns, it is important to obtain corroborative information from an additional source, such as a family member or close friend, since patient recall or insight may be limited. Patients with acquired cognitive impairment that represents a decline from their previous level of performance and that has been objectively corroborated by history and examination but does not interfere with daily function are considered to have MCI [99].

When cognitive decline interferes with independent function, patients meet the criteria for dementia. Equivalent categories of mild and major neurocognitive disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [100]. With advances in the field, these categories represent a continuum of cognitive decline that begins with subjective changes and culminates in dementia.

Laboratory Data

The American Academy of Neurology (AAN) guidelines recommend that the following laboratory tests should be ordered in the routine evaluation of patients with cognitive decline: a complete blood cell count, serum electrolytes, liver and renal function tests, thyroid function tests, and serum vitamin B₁₂ [26]. Additional tests may be appropriate in patients with systemic disorders.

Blood-based tests indicative of AD pathology, including tests of amyloid-beta or phosphorylated tau (P-tau) and neurofilament light (NfL) for neurodegeneration, are now available for clinical use [101]. However, these tests are generally not covered by insurance or Medicare.

The Alzheimer’s Association recently released appropriate use recommendations for blood-based biomarkers in AD [102]. It was cautiously stated that these blood-based biomarkers could be used in specialized memory clinics as part of a diagnostic workup of patients with cognitive symptoms, but the results should be confirmed with cerebrospinal fluid (CSF) or PET. Moreover, blood biomarkers should not be utilized in primary care or in isolation to determine a diagnosis. A primary reason for this is that blood biomarkers have not been adequately examined in older, diverse populations, who typically present in primary care with multiple comorbidities and cognitive impairment. Sex differences in blood biomarker levels have not been systematically examined.

Cerebrospinal Fluid

A low CSF ratio of amyloid-beta 42/40 and elevated levels of P-tau are indicative of AD pathology and can aid in the diagnosis of AD dementia. Lumbar punctures and CSF assays are reimbursable in the US. In addition, CSF NfL is a promising marker of neurodegeneration but is nonspecific to the type of disease. Studies have not found sex differences in levels of CSF amyloid-beta 42 or P-tau. However, CSF NfL has consistently been reported to be higher for men than for women across the clinical disease spectrum [103, 104].

Neuroimaging

Diagnosis of AD are still based on charting a detailed clinical history of cognitive decline and conducting a clinical evaluation to eliminate any reversible causes. The AAN guidelines support the use of brain imaging, either computed tomography (CT) or magnetic resonance imaging (MRI), in the initial assessment of dementia to rule out the possibility of space-occupying lesions (i.e., neoplasms), stroke, subdural hematomas, or, rarely, normal pressure hydrocephalus [33]. CT and MRI can also inform the differential diagnosis of neurodegenerative disease by identifying characteristic brain atrophy patterns and ischemia for vascular injury.

The main findings on MRI are changes that include atrophy of the hippocampus and medial temporal lobes, temporoparietal cortical atrophy, and ventricular enlargement [46]. Patients may also show varying degrees of white matter hyperintensities on T2-weighted/fluid-attenuated inversion recovery (FLAIR) sequences, which are nonspecific but most often associated with small vessel ischemic disease [48]. Notably, cognitively unimpaired women typically have significantly greater white matter hyperintensities compared to men [105].

Cortical, but not deep, microbleeds correlate with cerebral amyloid angiopathy and amyloid burden. They can be measured using susceptibility-weighted imaging and extensive white matter lesions on T2-weighted/FLAIR sequences [106]. Men have a higher prevalence of cerebral microbleeds than women from mid- to late-life [107].

Despite the reported MRI findings and knowledge surrounding structural brain differences in women and men, there are limited longitudinal data on sex differences. Data from large-scale neuroimaging databases suggest that women with MCI have increased total brain volume loss and hippocampal volume loss compared to men [108]. Functional MRI and amyloid PET imaging studies are underway to examine potential sex differences in cognitive function and dementia. However, their use is still limited to clinical research.

Treatment Plan

For both sexes, a comprehensive care plan includes treatment with AD-specific medications and the management of vascular risk factors, sleep and mood disorders, and other comorbid conditions. Acetylcholinesterase inhibitors (AChEIs) remain the mainstay of pharmacologic therapy for AD [109]. As AD is associated with the loss of cholinergic neurons in the basal forebrain, these medications enhance cholinergic transmission by inhibiting the hydrolysis of acetylcholine in the synaptic cleft.

The typical approach to drug treatment of AD includes the initiation of an AChEI in early AD and the addition of memantine when patients enter the moderate stage of the disease. Memantine, a non-competitive N-methyl-D-aspartate receptor antagonist has been approved for the treatment of moderate to severe AD dementia but has not been found to be beneficial for mild dementia or MCI. Although subtle differences exist in the biological effects of different AChEIs, their efficacy is similar across agents. Of the few studies examining AChEI efficacy and longitudinal treatment effects, some have suggested a sex difference, with men exhibiting a greater chance of responding to treatment than women [110] and a lower rate of progression [111]. The possible sex differences reported in that review were small and exhibited large individual variations; thus, this subject requires further investigation.

In the past decade, drug discovery has been directed at ‘disease modifying drugs’ that are able to counteract the progression of AD via neuropathological processes. The amyloid cascade hypothesis suggests that increased amyloid-β (Aβ)42 production, decreased degradation, and aggregation leads to synaptic changes that causes deposition of Aβ42 in diffuse plaques. Three main therapeutic intervention strategies aimed at reducing, facilitating clearance or preventing Aβ aggregation have been tested in clinical trials: and include γ- and β-secretases, or monoclonal antibodies (mAbs) to stimulate clearance of Aβ. Recently two mAB’s, aducanumab and lecanemab, have been shown to remove beta amyloid, with variable effects on clinical cognitive outcomes. Unfortunately, for both trials, no data has been reported regarding potential sex differences in clinical outcomes or adverse event profiles to date. The lack of this type of reporting only adds to the dearth of sex-stratified clinical drug data on efficacy, drug dosing, and the type and rate of adverse events [112].

Conclusions

AD impacts both sexes in several unique ways. (Table 1) First, women have a higher risk of AD. Second, the clinical risk factor profile for the development of AD differs between men and women. Third, the clinical presentation and cognitive testing profiles also differ between the sexes. Finally, treatment and biomarker (blood, CSF, and neuroimaging) profiles have been shown to differ by sex. Current research efforts are continuing to better define sex differences in AD with the goal of identifying the underlying biological mechanisms of these differences.

Table 1.

Summary of Sex Differences in Alzheimer’s Dementia

	Women and Females	Men and Males
Age of onset	Increased for all age strata compared to men 65–74 75–84 85 +
Symptoms	Increased changes in mood: depression as an early symptom
Physical Examination Cognitive Profiles	No consistent differences More difficulty with more difficulty with language, confrontational naming tests, delayed recall of verbal information
Laboratory Findings	Blood based biomarkers: No consistent differences	CSF biomarkers: Nfl increased
Radiographic Findings	Neuroimaging biomarkers: Increased total brain atrophy and hippocampal volume loss in MCI Greater white matter hyperintensity volumes
Treatment	No consistent differences
Co-morbidities	Increased CV risk factor prevalence / severity > 65 years Increased diabetes Increased depression

Key Points

• Overall, women are two to three times likelier to develop Alzheimer’s dementia than men across all age strata after the age of 65.

• Multiple lifestyle factors are known to impact cognitive decline, and modification of these factors may favorably impact women more than men.

• Compared to men, women may initially present with complaints of verbal memory and word-finding difficulties rather than episodic memory in the early stages of cognitive impairment.

• Sex differences in biomarkers (blood, cerebrospinal fluid, and neuroimaging) may help identify the underlying biological mechanisms of these differences.

Synopsis

Reviewing the research presented in this chapter, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex and gender differences in Alzheimer’s dementia (AD) are due to differences in longevity, survival bias and comorbidities. Medical, genetic, psychosocial, and behavioral factors, in addition to hormonal factors can differentially affect the risk and progression of AD in women versus men. Further, evaluation of sex differences in AD progression and the trajectory of change in cognitive function, neuroimaging, cerebrospinal fluid (CSF), and blood-based biomarkers of AD is needed. Finally, identifying sex differences in AD biomarkers and change across the life span is critical for the planning of prevention trials to reduce the risk of developing AD.