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Menopause: The Journal of The North American Menopause SocietyVol. 19, No. 7, pp. 724/734DOI: 10.1097/gme.0b013e31825a28f2 * 2012 by The North American Menopause Society 2011 NAMS/PFIZER V WULF H. UTIAN ENDOWED LECTURE History and experience: the direction of Alzheimer's disease William E. Reichman, MD1 and Nathan S. Rose, PhD2 As the global population is projected to age substantially in coming decades, the number of individuals who will develop Alzheimer disease (AD) is expected to rise dramatically. We have come to understand that AD islikely to be multidetermined through interactions between heritable causal and susceptibility genes, environmentalexposures, midlife health status, and lifestyle choices. In addition, mounting evidence suggests that the neuro-pathological processes characteristic of AD can be detected several years before the onset of clinical symptoms.
Thus, AD is now considered to have presymptomatic, prodromal (mild cognitive impairment), and dementia phases.
Through cerebrospinal fluid biomarkers, volumetric neuroimaging, functional neuroimaging, and cognitive stresstests, individuals at significant risk for developing dementia can now be identified with greater sensitivity andspecificity. Consequently, there is growing attention to identify interventions to halt or delay the onset of AD. Thebiological capacities of neurogenesis and neuroplasticity and the related concepts of brain and cognitive reserveprovide a rationale for developing techniques to maintain or enhance the cognitive abilities of older persons tosufficiently prevent dementia. This has led to the emergence of a new Bbrain fitness[ commercial industry in whichBproducts[ are being marketed and sold to consumers to Bkeep your brain sharp.[ However, most available brainfitness products have scant scientific evidence to support their effectiveness. Nevertheless, ongoing research advancesdo support the potential for memory and other intellectual functions to be strengthened and maintained through cog-nitive training, physical exercise, dietary choices, social engagement, and psychological stress reduction.
Key Words: Alzheimer disease Y Dementia Y History Y Prevention Y Brain fitness.
With the projected aging of the global population, order,AD,isthemajorcauseofthesyndromehasespecially the prevalence of dementia is anticipated to rise come to light during the last 40 years.
from nearly 40 million persons today to approx- imately 118 million by 2050.1 Today, Alzheimer disease (AD), the preeminent cause of dementia, is as much a part of the It was little more than a century ago that Dr. Alois Alzhei- public health lexicon as cancer, stroke, and heart disease. With mer (b. 1864-1915), a German physician, publically shared unusual exception when directly queried, adults from all walks his original case of the disorder that, shortly thereafter, would of life will remark that indeed, they have known or loved an endure to bear his name. In 1906, Alzheimer specifically individual who had this disorder. However, this was not our reported on his treatment and the subsequent postmortem brain experience through most of the 20th century. The public's examination of a female patient, Frau Auguste Deter (Auguste recognition of the remarkable frequency with which dementia D), who had dementia in midlife. She presented to Alzheimer accompanies advancing age and that a neurodegenerative dis- as a 51-year-old married woman who expressed delusionaljealousy and manifested depressive symptoms. She was con- Received February 1, 2012; revised and accepted April 12, 2012.
fined to the state asylum in Frankfurt, where Alzheimer was From the 1Baycrest Centre, Department of Psychiatry, Faculty of Medi- then working. Her clinical syndrome was found to include hal- cine, University of Toronto, Toronto, Ontario, Canada; and 2Rotman lucinations, paranoid ideation, and a tendency toward screaming Research Institute, Baycrest Centre, Toronto, Ontario, Canada.
and to be hostile. Enmeshed within this presentation of insanity Funding/support: The content of this article was presented by Dr. Reichmanat the NAMS/Pfizer Wulf H. Utian Endowed Lecture last September 23, was severe memory impairment along with other abnormalities 2011, in Washington, DC at the Annual Meeting of The North American in cognitive ability, including language disturbance.
Menopause Society (NAMS). An endowment to NAMS from Pfizer The patient continued to rapidly deteriorate in the asylum established this annual lectureship, with faculty selected by the NAMSScientific Program Committee.
and became bedridden and incontinent and was in a com- Financial disclosures/conflicts of interest: Dr. Reichman is president and pletely helpless state. After her death and when Alzheimer had chief executive officer of Baycrest, which has a major equity stake in a new already moved to Munich to continue his work under the brain fitness company called Cogniciti, Inc., in which he is also a director.
tutelage of the prominent psychiatrist Emil Kraepelin, his col- Address correspondence to: William E. Reichman, MD, Baycrest, 3560 leagues in Frankfurt sent him Auguste D's brain for postmor- Bathurst Street, Toronto, Ontario, Canada M6A 2E1. E-mail: [email protected] tem examination. Alzheimer's public lecture about the case 724 Menopause, Vol. 19, No. 7, 2012 Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ALZHEIMER'S DISEASE and the subsequent written report identify the presence of dra- of these seemingly disparate clinical disorders were actually matic brain atrophy and abnormal microscopic deposits in indistinguishable from one another. This argument was further and around the patient's neurons. These pathological findings supported by an epidemiological study published by Neumann included neuronal death, arteriosclerotic changes, extracellular and Cohn6 in 1963, who reported on the incidence of AD in a plaques, and intracellular tangles of fibrils. Alzheimer reported large psychiatric hospital. Within a decade, AD would become BIscattered through the entire cortex, especially in the upper recognized as the principal cause of senile dementia through layers, one found miliary foci that were caused by the deposi- the research findings of Blessed et al.7 In a significant cohort of tion of a peculiar substance in the cerebral cortex.[2 elderly individuals who had died with diagnoses of dementia Alzheimer was not the first to have identified plaques, or as and went on to postmortem brain examination, they were the it was termed then, miliary sclerosis, as present in the brains of first to demonstrate a significant correlation between the level individuals with senile dementia. However, the unique nature of of cortical burden of senile plaques and neurofibrillary tangles Auguste D's case, including the relatively early age of onset and the severity of dementia.
before 65 years (presenile), the rapid progression of cognitive These findings were followed by a seminal editorial pub- deficit with behavioral change, and the severity of the neuro- lished in April 1976 in the Archives of Neurology by Robert pathological alterations that were evident, led Alzheimer to Katzman,8 entitled BThe Prevalence and Malignancy of Alz- believe that he was describing a novel neurological condition.
heimer's Disease: A Major Killer.[ Through this article, the Other cases of this presenile dementia with similar neuropath- major public health impact of the disorder became more ological features of plaques and tangles subsequently appeared widely appreciated. In the United States, in the 1980s, the in the literature over the next few years.
National Institutes of Health, through the National Institute It was in 1910 that Kraepelin,3 in his Handbook of Psy- on Aging, launched a concerted scientific effort in AD, in- chiatry, 8th Edition, stated BIa particular group of cases cluding the creation of a specialized network of university- with extremely serious cell alterations was described by Alz- based research and care centers. During this historic period heimerIthe clinical interpretation of this Alzheimer's disease of increasing public awareness, the Alzheimer's Disease and is still unclear. Although the anatomical findings suggest Related Disorders Association (ADRDA) was formed to sup- that we are dealing with a particularly serious form of senile port affected families across the nation and to garner more dementia, the fact is that this disease sometimes starts as early resources to advance research into the causes and treatments as in the late forties.[ This statement by Kraepelin is widely of the illness. The association ultimately was rebranded as the regarded to have been the first time that this specific neuro- degenerative disorder causing senile dementia was named for As federally funded neuroscience research continued to progress through the especially fertile period of the 1980s to After 1910 and through most of the next half century, senile advance our understanding of the pathogenesis of AD and dementia was widely thought to be caused by atheromatous to thus identify potential therapeutic targets, important strides degeneration of blood vessels with accompanying stroke and were also being made to establish greater precision in the was a distinct condition from AD.4 It was generally believed diagnosis of the disorder. In the fall of 1983, a workgroup that Bsenility[ was a distinct disorder from either AD or senile was convened by the National Institute of Neurological and dementia and represented an expected, age-related deteriora- Communicative Disorders and Stroke (NINCDS) and the tion in cognitive functioning. As more individuals, especially in ADRDA to develop standardized diagnostic criteria and to Western societies, were living to advanced ages, the preva- more fully describe the clinical presentation of AD. In 1984, lence of cognitive failure was increasing. Notably, however, the group published what was to become the dominant ap- senile dementia was rarely mentioned as a cause of death in proach for the diagnosis of AD over the subsequent 27 years, the elderly population. AD as the major cause of both cogni- the NINCDS-ADRDA criteria.9 These criteria defined the tive failure and subsequent mortality was largely ignored.
diagnosis of AD as either Bdefinite[ (the most typical clinical Adding to a lack of clarity throughout the first half of the 20th syndrome, confirmed by either biopsy or postmortem histo- century were studies reporting that intraneuronal tangle path- pathological confirmation), Bprobable[ (the most frequently ology was found across a number of different neurological encountered clinical presentation including memory loss, at disorders and that seemingly cognitively healthy elderly indi- least two cognitive deficits, insidious onset and gradual pro- viduals older than 65 years had postmortem pathological evi- gression of the severity of deficits, and the absence of other dence of cerebral plaques and tangles.
significant plausible causes in the setting of functionaldecline), or Bpossible[ (an atypical or mixed etiological pre- Public recognition and advocacy sentation). In addition, age of onset was described to be be- In 1948, Newton5 published an article entitled BThe Iden- tween 40 to 90 years of age.
tity of Alzheimer's Disease and Senile Dementia and TheirRelationship to Senility,[ in which he argued that both AD Major late 20th century discoveries on pathogenesis and senile dementia were progressive conditions with a cluster Cholinergic depletion of similar clinical features that are indistinguishable from one As the field progressed toward an enhanced understanding another. He posited that the postmortem pathological hallmarks of the pathogenesis, diagnosis, and treatment of AD, several Menopause, Vol. 19, No. 7, 2012 Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
REICHMAN AND ROSE especially noteworthy scientific developments occurred during early-onset AD (with onset before 65 y of age). Although this the same period. In 1981, Whitehouse and colleagues10 reported gene was associated with an atypical version of AD, its func- that the cholinergic basal forebrain (the nucleus basalis of tion to code for the amyloid precursor protein (APP), the parent Meynert) had all but disappeared in the brains of patients who molecule from which amyloid-A is formed, represented a major had died of AD.
advance in furthering our understanding of the disorder's po- This finding would ultimately lead to the cholinergic deple- tential genetic influences on pathogenesis.14 tion hypothesis of ADVthat loss of cells in the cholinergic Two additional causative gene mutations would eventually basal forebrain and diminished cholinergic neurotransmission be reported over the next few decades, presenilin 1 and pre- were fundamentally responsible for the cognitive impairment senilin 2. These genetic mutations would also ultimately be associated with AD. However, subsequent research has sug- implicated in amyloidogenesis and the development of auto- gested that this hypothesis was overly simplistic and failed somal dominant, early-onset familial AD.15 The link between to explain the early symptoms of the disorder.
AD and genetic mutations affecting the processing of APPwould ultimately provide some of the strongest evidence sup- porting the amyloid hypothesisVthe notion that some aspect In 1984, Glenner and Wong11 reported on the purification of the protein's metabolism initiates a cascade of pathological and characterization of a novel cerebrovascular amyloid pro- events resulting in the characteristic plaques, tangles, and cog- tein. They stated, in what was to be a landmark article, that nitive dysfunction associated with AD.16 Bthis protein may be derived from a unique serum precursor In 1993, the first major susceptibility gene for the most which may provide a diagnostic test for Alzheimer's disease typical form of the disorder, sporadic (late-onset) AD, the and a means to understand its pathogenesis.[11 Although the apolipoprotein D 4 (APOE-e4) allele, was reported by Corder specific diagnostic test they had hoped for has yet to materi- and colleagues.17 This allele has been consistently demon- alize, their critical work did indeed help to establish cerebral strated during the intervening years to be a strong risk factor for amyloid metabolism, deposition, and clearance as perhaps the development of AD in later life such that up to nearly 50% the most vital areas of AD pathogenesis for continued study.
of affected patients are carriers. Possessing one copy of the Arguably, the presumed early and central role of amyloid allele increases the lifetime risk of AD by 3- to 4-fold; having in the cascade of pathological changes characteristic of AD two copies (homozygous condition) increases lifetime risk by would be seen by many to overly dominate the next quarter 9- to 10-fold.
century of basic research efforts in the disorder.
In 1986, other research teams focused on characterizing During this same period in the 1980s, in the first multisite the biological origin of paired helical filaments, which were clinical trial of an AD-specific therapy, the cholinesterase known at the time to form neurofibrillary tangles, the most inhibitor tacrine was collaboratively launched by the Warner- common intraneuronal abnormality of the cytoskeleton found Lambert pharmaceutical company and the National Institute in AD. The research groups of Grundke-Iqbal and colleagues12 on Aging. The drug would eventually prove to have sufficient and Kosik et al13 reported within a month of each other on the but modest efficacy and with acceptable levels of tolerabil- association of the hyperphosphorylated microtubuleYassociated ity and safety to come to market in 1993 as the inaugural T protein as a major component of Alzheimer paired helical AD therapy, Cognex. Its indication was limited to mild- to filaments. It was surmised at the time, and is still believed by moderate-stage clinical disease. Widespread use of the drug was many today, that the progressive accumulation of abnormal T significantly limited by its required four times per day dosing protein in Alzheimer affected neurons may lead to instability regimen; cholinergic side effect profile, especially gastrointes- of the microtubular structure and the consequent loss of effec- tinal upset; and the observation of hepatic enzyme elevation in tive intracellular transport, and ultimately, neuronal death.12,13 a significant number of treated patients.
As the years progressed, a number of other major areas of As the search for effective pharmacological interventions basic AD research activity emerged, including, but not lim- continued, donepezil hydrochloride (Aricept) became the ited to, neurochemical alterations, especially of the cholinergic second cholinesterase inhibitor introduced for the treatment system; inflammation; oxidative cell damage; apoptosis; mito- of mild to moderate AD in 1996. It required an improved chondrial dysfunction; gene expression; and the role of herita- once per day dosing regimen and had a significantly better ble factors.
tolerability profile than Cognex did. In 2000, rivastigmine(Exelon) and, in 2001, galantamine (Reminyl/Razadyne) were Genetic mutations and the amyloid hypothesis introduced as alternative cholinesterase inhibitors for the treat- In 1987, the first causative Alzheimer gene mutation was ment of mild to moderate AD. In 2003, memantine (Namenda), reported by St George-Hyslop and colleagues.14 This gene, with a noncholinergic mechanism of action affecting the glu- located on chromosome 21, was associated with a com- tamatergic system, was approved for the treatment of moderate paratively rare, early-onset, familial form of the disease, to severe AD. Since that time, no new medications have been which is now frequently called autosomal dominant AD or approved in the United States for treatment of the condition, 726 Menopause, Vol. 19, No. 7, 2012 * 2012 The North American Menopause Society Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ALZHEIMER'S DISEASE although the indication for donepezil was subsequently broad- ment (MCI) and normal cognitive performance. These condi- ened to include moderate to severe AD.
tions are now seen along a clinical continuum in which AD Unfortunately, as a group, studies examining the effective- also exists in a pathological, but preclinical, state. As stated ness of cholinesterase inhibitors in improving the symptoms earlier, we have come to understand that AD neuropatho- or slowing the rate of decline in AD have shown relatively logical change may begin several years and perhaps at least a modest benefits of this drug class.18 decade before the onset of cognitive deficits.21 These changesnow have the potential to be detected preclinically through Antiamyloid and other treatments innovations in brain imaging and the identification of periph- Currently, more than 80 drugs are being investigated for AD eral biomarkers.22,23 therapy in various preclinical and clinical trial stages. Thesedrugs vary in their main therapeutic properties. Many of the agents in development target amyloid-A, with some aiming to Advances in structural imaging, particularly volumetric mea- decrease its production, others targeted to limiting its aggre- surement of especially vulnerable brain regions in AD, such gation, and others designed to increase the brain's ability to as the mesial temporal area including the hippocampus, may clear it (via immunotherapy). Another class of drugs in devel- herald the development of the disease in the preclinical state.
opment is designed to decrease the aggregation or phosphor- Positron emission tomography (PET) imaging demonstrations ylation of T. Still, other classes of drugs involve a combination of impaired glucose utilization in critical neocortical areas for of these therapeutic properties or target some other mechanism cognitive function also have the potential to identify the dis- such as mitochondrial dysfunction, apoptosis, inflammation order in preclinical states. This technique can also be ultimately and oxidative cell damage.
used to confirm AD in the setting of MCI or overt dementia.
Given the limited effectiveness of current pharmacological Imaging is now increasingly being used in research studies to therapies in treating AD once clinical symptoms are apparent directly detect the presence of amyloid deposition using PET (tertiary prevention), many research groups have increasingly tracers such as Pittsburgh compound B (PIB).24 focused their efforts on the early identification of individuals inthe early, preclinical stages of AD (secondary prevention) or Cerebrospinal fluid markers even earlier in healthy individuals in middle adulthood who Over the last decade, as imaging advances have been made, have an elevated risk for developing AD (primary prevention).
similar efforts have continued to identify reliable and valid Specifically, many now believe that the limited effectiveness serum and cerebrospinal fluid (CSF) markers indicative of AD of AD therapies to date may be because clinical trials have pathology. Recently, results from the multisite Alzheimer's targeted individuals already showing symptoms of dementia, Disease Neuroimaging Initiative were released to show that clinical features that are probably emerging after several years there is a typical AD CSF biomarker profile. As compared with of amyloid accumulation and the other pathological changes controls, patients with AD had decreased levels of CSF AA42 underlying the disorder.19,20 protein and increased levels of CSF total T and phosphorylated As a result, an increasing view in the field is that the onset T. In reporting these results, De Meyer and colleagues25 dem- of dementia can be conceptualized as a relatively advanced onstrated that the AD CSF profile appeared in 90% of AD form of brain failure that generally occurs after the patho- patients diagnosed by clinical criteria, 39% of normal controls, logical burden of AD, and neurofibrillary tangle formation and 73% of research subjects meeting diagnostic criteria for is very well established in the affected brain with resulting MCI. After 5 years of follow-up, 100% of the MCI group that neuronal dysfunction and cellular loss. Therefore, much work had the AD CSF profile went on to develop dementia, pre- has commenced in recent years to better understand how to sumably due to AD. It is posited that the cognitively normal identify the disease in its earliest possible expression and then group showing the AD profile may be in a preclinical stage to target therapies before the clinical onset of dementia. It is of the disorder and at risk for eventually developing MCI or hoped that this approach to treatment will yield improved dementia.25 Work continues to develop greater reliability, val- results over the failures that have largely characterized AD idity, and standardization of these approaches before they will clinical drug development since the introduction of the cholin- be readily available, through the creation of diagnostic algo- esterase inhibitors and memantine.
rithms, for routine clinical use.
Revision of diagnostic criteria Since the time of the originally published NINCDS-ADRDA In addition, there are other reasons that have been posited criteria in 1984, a number of vital research advances have led to support the need for a revision of the 1984 NINCDS- to what has recently been proposed as the need for a signifi- ADRDA criteria. For example, other forms of dementia, such cant revision to the diagnosis of AD. The factors necessitating as dementia with Lewy bodies, primary progressive aphasia, the revision include the increased appreciation that the histo- behavioral variant frontotemporal dementia, and vascular de- pathology that has characterized AD can occur across a broader mentia, are now more accurately clinically characterized and can clinical spectrum than previously understood to include persons be better distinguished from AD. New diagnostic criteria can with not only frank dementia but also mild cognitive impair- also incorporate genetic factors including causative mutations.
Menopause, Vol. 19, No. 7, 2012 Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
REICHMAN AND ROSE Revised criteria would also acknowledge that although mem- versible at this stage. In contrast, the changes associated with ory impairment is most commonly the central cognitive deficit subsequent stages of disease progression are less likely to be of AD, other nonamnestic presentations can rarely but do occur reversible. These include degradation in the microstructure of with AD histopathology (eg, posterior cortical atrophy). Lastly, white matter tracts during the beginning signs of MCI and accumulated observations over the past few decades no longer macrostructural changes such as volumetric brain atrophy that support an arbitrary age cutoff for the probability of an accurate is evident on MRI in the final stage that qualifies as a pro- premortem diagnosis of AD.
gressive clinical dementia syndrome.28 As such, a body ofwork has been conducted over the past several years to better Diagnosis of AD in 2011 understand the risk factors for the development of AD and In response to the growing need for a more comprehen- putative strategies targeting primary, secondary, and tertiary sive consideration of the full clinical continuum and biologi- prevention of the disorder.
cal spectrum of AD, a series of articles were published by the Through the use of CSF biomarkers (low AA42, elevated T), National Institute on AgingYAlzheimer's Association work- PET (AA deposition), volumetric neuroimaging, functional groups that detailed the recommendations for revised diag- neuroimaging, genetic testing, and cognitive stress tests, indi- nostic guidelines for AD.15,21,26,27 The recommendations viduals at significant risk for developing dementia due to AD incorporate many of the 1984 NINCDS-ADRDA criteria and can now be identified with greater sensitivity and specificity still propose classification criteria for probable AD and pos- and at earlier ages than has been previously possible. The sible AD based on behavioral indicators of cognitive func- emerging ability to detect the disorder much earlier in its course tion and objectively measured change in cognitive function.
has increasingly demanded more research emphasis on pre- In addition, the recommendations also include categories vention and early intervention.
intended for research purposes that incorporate biomarkersof ADVprobable AD or possible AD with evidence of the AD pathophysiological processs.27 Evidence of the AD path- Over the past few decades, great attention has been paid ophysiological process include biomarkers of amyloid-A de- to identifying potentially important AD risk factors, with in- position (low CSF AA42 or positive results on PET amyloid creasing efforts underway to identify potential targets for the imaging) and neuronal degeneration or injury (elevated CSF prevention of age-related cognitive decline and dementia. A T, decreased fluorodeoxyglucose uptake on PET in the temporal- variety of factors have been shown to impact the likelihood parietal cortex, or disproportionate atrophy on structural mag- that an individual will develop AD, including genetic load, netic resonance imaging [MRI] in the medial-parietal cortex hormonal status, cognitive stimulation, social engagement, body and medial-, basal-, and lateral-temporal cortex). A positive weight, cardiovascular health, diet, and exercise. As discussed result for one of these biomarkers is indicative of intermediate in more depth below, some AD risk factors that may influence probability of AD etiology; a positive result on both biomarkers the risk of developing AD are associated with an assortment of is indicative of high probability of AD etiology.
disorders, including type 2 diabetes mellitus, atherosclerosis, However, McKhann and colleagues27 noted that although hyperlipidemia, hypertension, cardiac disorders, cerebrovascu- Bbiomarker evidence may increase the certainty that the basis lar pathology, and body mass index.29 of the clinical dementia syndrome is the AD pathophysiologi-cal processIwe do not advocate the use of AD biomarker tests for routine diagnostic purposes at the present time.[ That As discussed earlier, gene studies and observational or healthy older individuals without dementia can have both pos- epidemiological studies have revealed a number of factors itive biomarkers and evidence of amyloid (PIB) burden under- associated with increased risk of developing AD that vary in mines the use of these methods for clinical diagnosis of AD.
their degree of potential modifiability. Relative to factors likeone's genetic profile and sex, many risk factors that have been Toward earlier identification of preclinical AD and identified have the potential to be altered by experience, in- cluding educational/occupational attainment, diet, a variety of As repeatedly argued above, there is increasing acceptance leisure activities (cognitive stimulation, social engagement, phys- that AD probably exists in preclinical and prodromal phases ical exercise), and health status.
(eg, MCI). Even during the preclinical asymptomatic stage,there are mechanistic neuronal changes taking place, such as a functional disconnect between critical regions in large-scale A recent meta-analysis of studies predicting progression neural networks (eg, the default mode network) that can be from MCI to AD with APOE-e4 genotyping found that distinguished from healthy aging. Notably, a diagnosis of MCI Bthe APOE-e4 allele is a moderately strong predictor of pro- due to AD (with possible or probable certainty) may be con- gression from MCI to AD-type dementia. The risk is twice sidered given evidence of change from an individual's previ- as high for APOE-e4 heterozygotes and four times as high ous level of cognitive function, as indicated by a clinician, an for APOE-e4 homozygotes compared with non-carriers.[30 informant (eg, spouse, caregiver), or the patient.
However, the authors concluded that, to date, there is limited Importantly, the subtle cognitive and/or neuropathological value in using APOE genotyping for predicting progres- changes in preclinical or prodromal AD are still plausibly re- sion to AD in clinical practice, as sensitivity and positive 728 Menopause, Vol. 19, No. 7, 2012 * 2012 The North American Menopause Society Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ALZHEIMER'S DISEASE predictive value were low (half of those without an APOE-e4 inergic neuronal growth and survival and, further, the me- allele progressed to AD and 40% of those with an APOE-e4 tabolism of APP. Early observational studies suggested that did not progress to AD over a 3-y period).30 women treated with hormone therapy (HT) had a reduced risk A family history of AD is a risk factor over and above the of AD compared with those who were not. However, the ef- presence of APOE-e4 alleles as well. For example, even in fect of estrogen on cognitive functioning is less consistent cognitively normal, middle-aged adults who are APOE-e4 across observational/epidemiological studies and clinical trials noncarriers, a family history of the disorder is associated of HT (see Janicki and Schupf 32 for a review). In observational with several putative preclinical AD CSF and neuroimaging studies, there may be confounding variables that influence the biomarkers (levels of AA42 and T in CSF, PIB mean cortical choice of women to use HT, such as a higher education level binding potential, and decreased fractional anisotropy from and better access to health care. In addition, the inconsistency diffusion tensor imaging in the genu and splenium of the of the research findings to date may be caused by the timing corpus callosum).31 This suggests that those with a family of HT, with benefits observed for previous use and/or when history of AD may have biological evidence of the disease initiated early in menopause but with no benefit of current use that is identifiable even in middle adulthood and in the ab- in postmenopausal women unless initiated more than 10 years sence of cognitive or behavioral symptoms. Although the num- before cognitive assessment (or before the approximate age ber of known AD risk genes is growing rapidly, Bup to 50% of the heritability of AD remains unexplained.[28 Rather than Importantly, clinical trials of HT have generally shown a individual genes having a strong impact on susceptibility, it is neutral effect of estrogen-only treatment and a negative effect more probable that the combination of multiple genes and of estrogen-progestogen treatment on verbal memory. For environmental factors determines the risk of developing AD.28 example, the Women's Health Initiative Memory study foundthat postmenopausal women 65 years or older assigned to HT (combined estrogen and progestin) had impaired general Some early investigations showed a greater risk of AD cognitive function relative to those assigned to a placebo.35 for women than for men, such as the European Studies of Moreover, the study showed that HT resulted in a twofold Dementia (EURODEM) Incidence Research Study (adjusted increase in the diagnosis of dementia relative to a placebo.36 relative risk, 1.54; 95% CI, 1.21-1.96) and a Swedish cohort Because HT is also associated with increased risk for stroke, study, where the association was particularly notable for those it was assumed that the declines in cognition and increased older than 90 years. However, it is important to consider the risk of dementia associated with this intervention were caused earlier mortality and greater morbidity rates in men than in by an increase in subclinical cerebrovascular lesions. How- women. Studies that considered age-specific incidence, such as ever, Coker et al37 recently reported that neither the number the Monongahela Valley Independent Elders Survey (MoVIES) of brain vascular lesions nor their volumes were substantially study, the Rochester study, the Framingham study, the Bal- increased among women assigned to HT. However, this same timore Longitudinal Study of Aging, the East Boston Study, group of researchers also reported that frontal cortex and hip- and the Adult Changes in Thought (ACT) cohort study, found pocampal volumes were generally smaller in women prescribed no difference between women and men in the incidence of HT relative to those given placebo.38 dementia or AD.32 Thus, it appears that the potential of HT to reduce risk of In the Study of Osteoporotic Fractures, cognitive function AD or to improve cognition relies on the type of treatment (Mini-Mental State Examination [MMSE]) was assessed in (with estrogen-only treatment being preferable to combined 9,704 women over 6, 8, 10, and 15 years (mean age, 72 y at estrogen-progestogen) and initiating treatment within a Bcriti- baseline and 85 y at follow-up).33 Nine percent of the women cal window[Vearly perimenopause or just after the onset of maintained optimal cognitive function (slope Q0), 58% expe- rienced minor decline (slope G0 but 9 lowest tertile), and 33%experienced major decline (slope elowest tertile). Adjusted Education and occupation for confounding factors (age, education, baseline cognitive In 1994, Stern and colleagues39 reported on nearly 600 function, and study site), the factors that were most predictive individuals of whom 106 developed AD during their study.
of maintaining optimal cognitive function as opposed to minor A higher level of educational and occupational attainment cognitive decline included lack of comorbid medical condi- was associated with a reduced risk of AD (2.02; 95% CI, tions (diabetes mellitus, hypertension), presence of healthy 1.33-3.06). Several other studies have also found a reduced behaviors (nonsmoking, moderate alcohol consumption), lack risk of cognitive decline and/or dementia associated with of difficulty with instrumental activities of daily living, and greater amounts of educational attainment, complexity of work, lack of poor social network.33 and cognitive activity that is broadly defined (see Reichmanet al40 for a review). Interestingly, some research has revealed that although higher educational and occupational attainment Hundreds of in vitro and animal studies have shown estro- may confer a reserve that delays the onset of clinical symptoms, gen to have beneficial effects on neurotrophism and neuronal once dementia develops, these same factors may be associated functioning. For example, estrogen is known to promote chol- with a faster rate of decline.39 Although it is plausible that Menopause, Vol. 19, No. 7, 2012 Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
REICHMAN AND ROSE achieving higher educational attainment and pursuing more to consumers to promote brain fitness, with a few exceptions, complex occupations provide cognitive stimulation that may most of these methods have scant scientific evidence to sup- confer benefits to cognitive functioning in later life, it is im- port their effectiveness.40 portant to note that there are potential confounds associated Despite the relative paucity of proven techniques to strengthen with such variables, such as socioeconomic status.
cognitive function that translates into better daily function orthe prevention of dementia, the biological capacities of neuro- genesis and neuroplasticity and the related concepts of brain Another factor that is emerging as a potent moderator of or cognitive reserve provide a firm rationale for serious efforts cognitive aging is bilingualism. Bilingualism requires exe- to continue in this area.40 Neurogenesis and neuroplasticity cutive control to coordinate the selection of the appropriate refer to the brain's ability to generate new cells and reorganize language to use in a particular context and monitoring of the its physical structure (eg, neuronal networks) and function in situation to control switching between languages. Some evi- response to environmental experience.46 For example, animals dence suggests that bilinguals have slower rates of cognitive living in Benriched environments[ with greater cognitive stim- decline than monolinguals do.41 Incredibly, lifelong bilin- ulation display an increase in brain synaptic density and num- gualism appears to delay the onset of dementia by approx- bers of synapses, enlarged dendritic length, increased dendritic imately 4 years.42 Schweizer et al43 compared a group of branching, and the creation (neurogenesis) and maturation of bilingual AD patients with a group of monolingual AD pa- new neurons and connections.47 tients who were matched on level of cognitive function. The The concept of reserve refers to a threshold model of bilinguals showed more atrophy in the medial temporal lobes vulnerability to the cumulative effects of aging. That is, the yet equivalent memory and executive functioning as mono- ability to deal with pathological burden within the brain when lingual controls. In addition, bilinguals have both enhanced it arises depends on the initial integrity of the central nervous white matter integrity in the corpus callosum extending to system and the potential to use existing neural pathways and/or the superior and inferior longitudinal fascicule and anterior to recruit new pathways that are not typically used to accom- to posterior functional connectivity.44 This pattern suggests a link between bilingualism and brain reserve (see below)whereby enhanced frontal connectivity can compensate for Cognitive training age-related volumetric reductions in medial temporal lobes.
Observational studies have shown that engaging in cogni- Critically, whereas other variables that have been sug- tive stimulating activities related to education and occupation gested to promote brain reserve (eg, diet, education, occupa- is associated with superior memory and cognitive function tion) have some degree of self-selection and an association and a reduced risk of dementia in later life; however, the with socioeconomic status, bilingualism is not necessarily results of cognitive interventions in healthy aging have largely associated with these confounds. In the great majority of cases, people become bilingual because they or their parents Two meta-analyses have been conducted on randomized move to another country, so they must learn a second lan- controlled trials of cognitive training interventions in healthy guage to surviveVit is not simply because they are bright or older adults (one on 10 studies50 and one on 7 studies47). The are Bgood at languages.[42 cognitive training interventions have varied widely, consist-ing of piano lessons, memory or reasoning strategy instruc- Summary of risk factors tions, or practice at discriminating auditory tones, to name The great hope for the Bbaby boom[ and subsequent gen- just a few. It is difficult to extract generalities from the lim- erations as they age is that lifestyle interventions may prove ited number of studies that have been conducted, particularly to protect against cognitive decline associated with AD in given the vast differences in design characteristics (in total later life. Based on observational and epidemiological studies, time spent training, outcome measures, longitudinal follow-up, the most promising targets for the prevention of dementia type of control group, and sample size). Nonetheless, Papp are cognitive, physical, and social activity, as well as diet.44 et al50 reported a small but significant overall mean weighted Perhaps, not surprisingly, interest among today's consumer effect size of 0.16 favoring cognitive training over controls; public in learning how to prevent cognitive loss and how to Valenzuela and Sachdev47 reported a larger effect sizeVa strengthen such abilities in mid and later life appears to be weighted mean difference score of 1.07. The authors of both steadily growing. It has given rise to what is now termed the articles noted that the effect sizes of individual studies were brain fitness movement.
largest when the outcome measures were closely related to thetype of training (ie, near transfer).
Brain Fitness Movement Some studies have examined the effectiveness of cog- The interest in finding methods to Bkeep our brains sharp[ nitive training on improving cognitive function in individuals by maintaining or enhancing cognitive performance has led with mild severity AD and vascular dementia. In an early to the emergence of a new global commercial industry. Al- review of six randomized clinical trials comparing cogni- though numerous cognitive training and related Bproducts,[ tive training interventions with control conditions, none demon- such as nutritional supplements, are being marketed and sold strated statistically significant effects of cognitive training in any 730 Menopause, Vol. 19, No. 7, 2012 * 2012 The North American Menopause Society Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ALZHEIMER'S DISEASE domain.51 The authors of this review concluded that their low MMSE score at baseline). Not only were cognitive gains findings did not provide Bstrong support[ for the use of cog- found in executive inhibitory processes, but also intervention- nitive training interventions for patients with early-stage AD specific increases in brain activity were observed in the pre- or vascular dementia; however, the number of well-controlled frontal and anterior cingulate cortex at 6-month follow-up studies and the numbers of participants were limited at the using functional MRI.
time of their analysis.
In a more recent review, Sitzer and colleagues52 conducted a meta-analysis on controlled trials of cognitive training in As discussed earlier, the combination of factors that pose individuals with AD. The authors reported a significant effect a risk for cardiovascular disease and type 2 diabetesVthe (Cohen d = 0.47) for cognitive training strategies in general but so-called metabolic syndromeValso elevates one's risk for significant difference across specific domains ranging from MCI and the development of vascular dementia and/or AD.
2.16 for verbal and visual learning to j0.38 for visuospatial High body mass index, atherosclerosis, hyperlipidemia, hyper- functioning. These results suggest that cognitive training does tension, cerebrovascular pathology, and cardiac disorders all demonstrate some potential promise in the treatment of AD.
increase the risk of developing cognitive impairment that may However, as with the cognitive training studies on healthy result in vascular dementia and/or AD. For example, older adults older adults, most studies report small sample sizes and use (mean age, 74 y) with the metabolic syndrome (n = 1,016) were of neuropsychological test measures instead of performance- more likely to develop cognitive impairment (indexed by a based measures of daily functioning to determine the effec- drop in at least 5 points on the MMSE) over 5 years than were tiveness of the training intervention. In addition, the studies those without the metabolic syndrome (n = 1,616).56 Current have used a wide range of treatment strategies that varied in smokers were more likely than former smokers or nonsmokers duration, which makes it difficult to draw definitive conclu- to exhibit cognitive decline (MMSE) over at least 1 year (rel- sions about their overall effectiveness.
ative risk, 1.41; 95% CI, 1.16-1.71).57 Individuals with type 2 As previously discussed, it is quite important to distinguish diabetes were more likely than nondiabetic individuals to show between different types of cognitive training interventions cognitive decline (MMSE; odds ratio, 1.2; 95% CI, 1.05-1.4) (compensatory or strategy-based training and restorative or over 2 to 6 years.58 In concert with these findings, a great deal process-based training) and between the effectiveness of such of research has been increasingly focused on the potential for trainings on different outcome measures (near transfer to tasks modifications in diet and exercise to protect against vascular similar to the trained tasks and far transfer to everyday cogni- risk factors associated with cognitive decline and dementia.
tive functioning). However, although the effectiveness of cog-nitive training interventions in AD remains equivocal, it is important to note that there is no evidence of any negative side Several observational studies have shown that a diet rich in effects of participating in cognitive training interventions.
nuts, fish, fruits, and vegetablesVthe so-called MediterraneandietVis associated with a reduced risk of dementia and Social engagement AD.59,60 For example, Gu et al61 categorized the reported food In addition to benefiting one's psychological well-being, consumption of 2,148 older adults based on the composition of greater social engagement seems to also be associated with a specific nutrients in their diet (ie, saturated fatty acids, mono- reduced risk of dementia. Those with a larger social network unsaturated fatty acids, omega-3 and omega-6 polyunsaturated had reduced incident dementia relative to a control sample in fatty acids [PUFAs], folate, and vitamins E and B12). The at least one observational study.53 Although no clinical trials authors assessed the association between nutrient intake from have investigated the potential benefits of social engagement whole dietary patterns and risk of developing AD after ap- for the prevention of cognitive decline or development of proximately 4 years. The dietary pattern that was significantly dementia, some intriguing research has been conducted on the associated with reduced AD risk was a diet rich in omega-3 benefits of volunteering activities on cognitive functioning and and omega-6 PUFAs, vitamin E, and folate and low in satu- mental health in seniors. For example, the Experience Corps rated fatty acids and vitamin B12. The protective dietary pattern program consists of older volunteers working for a minimum was positively correlated with intake of dark and green leafy of 15 hours per week within a school for grades K-3.54 The vegetables, salad dressing, nuts, fish, tomatoes, poultry, cru- work involves special areas of need within the school: literacy ciferous vegetables, and fruits and negatively associated with tutoring, management of behaviors in the children, and library intake of high-fat dairy, red meat, organ meat, and butter.
use. In an 8-month follow-up study, Carlson and coworkers55 Importantly, the association between this dietary pattern and found that active volunteer participants with impaired baseline AD risk remained even after controlling for factors such as age, executive functions showed the greatest degree of improve- education, ethnicity, sex, smoking, alcohol consumption, use of ment in executive and memory functioning, whereas the sim- nutrient supplements, and APOE status. Moreover, a healthy ilarly impaired controls declined in executive function ability diet (consisting of a similar dietary pattern) at midlife has been (P G 0.05). Carlson and colleagues55 subsequently assessed the associated with a decreased risk of dementia/AD in late life.62 benefits of Experience Corps in Bat risk[ volunteers (ie, African Unsurprisingly, there has been increasing consumer inter- American women with low level of education, low income, and est in the consumption of dietary supplements containing Menopause, Vol. 19, No. 7, 2012 Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
REICHMAN AND ROSE antioxidants and/or PUFAs. However, most randomized con- Some research has suggested that the beneficial effects of trolled studies comparing nutrient supplementation with pla- exercise may be particularly robust for women. In a 6-month cebo have not consistently found an association between use of randomized control trial, Klusmann and colleagues71 assessed supplements such as vitamin E and omega-3 fatty acids and the effects of mental and physical activity on cognitive per- cognitive outcomes.45 Plassman et al63 reviewed observational formance in older women 70 to 93 years of age. Study par- and randomized controlled trials on nutrient supplementation ticipants were randomly assigned to an exercise group, a and concluded that there was little evidence to suggest that computer course group, or a control group. At follow-up, taking dietary supplements protects against cognitive decline.
women in the computer group and the exercise group showed Current research on supplementation is focusing on the possi- improvements in episodic memory and maintenance in work- ble benefits of statins and homocysteine-lowering supplements ing memory compared with the control group, which showed on cognitive functioning.16,64<66 However, many researchers a decline in cognitive performance. In another study, those are beginning to acknowledge the importance of considering who participated in 45 to 60 minutes of aerobic exercise three one's whole dietary pattern because of potential interactions to four times a week over 6 months demonstrated improved or synergistic effects among different components of a diet.
executive functioning relative to a stretching and balance train- Encouragingly, diet interventions have fared better than sup- ing control group; the findings were notable particularly for plement interventions. For example, a 4-week high-fat, high- women in the exercise group.72 glycemic index diet versus a low-fat, lowYglycemic index diet Some research has suggested that there may be synergistic had dramatic effects on AD biomarkers including CSF levels effects of physical exercise and other factors such as diet and of AA42, APOE (which is important for AA clearance), and HT. For example, the researchers of the aforementioned diet F2-isoprostanes (which are indicative of neuronal injury). The intervention who showed the impact of high- versus low-fat high-fat diet moved CSF AA42 levels in a direction consistent diet on CSF AA42 levels in healthy older adults and individ- with amplified AD-related pathology, whereas the low-fat diet uals with MCI subsequently revealed that the effects were moved levels in the opposite direction; the low-fat diet in- moderated by participant's level of physical activity. For creased levels of APOE and reduced levels of F2-isoprostanes, healthy adults, high amounts of physical activity minimized whereas the high-fat diet increased F2-isoprostane concen- the negative effect of a high-fat diet on CSF AA42 levels, trations. The low-fat diet also increased delayed visual recall.67 whereas for individuals with MCI, high physical activity had Although the small, restricted sample of this study limits the enhanced the effects of the low-fat diet on AA42 levels.73 generalizability of these findings, it hints at the possibility Some studies have even combined physical exercise inter- of even short-term dietary interventions to prevent or reverse ventions with other interventions with the hope that physical some aspects of the pathophysiological process and/or cogni- exercise might potentiate the effects of other factors. For ex- tive outcomes of AD.
ample, Scarmeas et al74 have shown additive effects of physi-cal exercise and diet interventions. Erickson and colleagues70 Physical exercise examined the effects of both HT and level of physical fitness Observational studies have generally shown that greater in postmenopausal women and found significant interaction amounts of physical activity, broadly defined, over the course effects. Regardless of whether the elderly women had been of one's lifetime are associated with a reduced risk of demen- treated with HT, physically fitter women demonstrated en- tia.68 Encouragingly, the positive effects of exercise train- hanced cognitive performance and increased measures of brain ing interventions in later life have also revealed benefits to volume. In addition, shorter term HT (G10 y) was associated memory and cognitive function.49 For example, Lautenschlager with greater gray matter volumes in the prefrontal and temporal et al69 conducted a randomized controlled trial on 138 adults cortex and enhanced executive control performance relative to older than 50 years with memory complaints. Participants longer term HT (916 y). However, higher levels of aerobic fit- were randomly assigned to either a 6-month exercise program ness negated the relatively negative effects of long-term HT.
or education classes and standard care. Whereas those in the Although these studies focused on individuals without de- exercise group had improved scores on the Alzheimer's Dis- mentia, exercise interventions in patients with AD have re- ease Assessment ScaleYCognition, those in the control group vealed benefits as well. Rolland and colleagues75 conducted a had declining scores, an advantage that was maintained at the randomized controlled trial of an exercise program with 134 18-month follow-up. In a study conducted by Erickson et al,70 nursing home residents with AD. Residents either received the participants, 120 older adults without dementia, were ran- standard care or participated in 1 hour of strength, balance, domly assigned to either an aerobic exercise training group flexibility training, or walking twice a week for 12 months.
(mean age, 67.7 y) that engaged in approximately 30 minutes Those in the intervention group had a slower rate of decline of walking, three times per week, for 1 year or a stretching in activities of daily living than did those who received rou- control group (mean age, 65.5 y) that engaged in the same tine nursing and medical care. Heyn and colleagues76 con- number of sessions.70 Strikingly, exercise training increased ducted a meta-analysis of 12 randomized controlled trials that hippocampal volumes and memory scores; in contrast, hippo- examined the effects of a physical exercise intervention on campal volumes and memory scores declined over the 1-year the cognitive function of individuals with dementia. Most study period in the control group.
studies showed a medium to large effect size (mean effect size, 732 Menopause, Vol. 19, No. 7, 2012 * 2012 The North American Menopause Society Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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