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Achieving and Maintaining Cognitive Vitality With Aging

      Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.
      AAMI (age-associated memory impairment), AD (Alzheimer disease), apoE4 (apolipoprotein E4), BDNF (brain-derived neurotrophic factor), CREB (cyclic adenosine monophosphate response element binding protein), FDA (Food and Drug Administration), MCI (mild cognitive impairment), MMSE (Mini-Mental State Examination), MRI (magnetic resonance imaging), NGF (nerve growth factor), NSAID (nonsteroidal anti-inflammatory drug), PET (positron emission tomography), SPECT (single-photon emission computed tomography)
      The “longevity revolution” has increased the focus on many aspects of health in aging. The older population is growing rapidly, and individuals are typically living longer, more active lives.
      • Rowe JW
      • Kahn RL
      However, most older individuals still face late life with changes in cognitive function that affect quality of life
      and increase mortality.
      • Bosworth HB
      • Schaie KW
      Survival effects in cognitive function, cognitive style, and sociodemographic variables in the Seattle Longitudinal Study.
      Cognitive vitality in old age is impaired by both “normal cognitive aging” and diseases that cause dementia, primarily Alzheimer disease (AD) and vascular dementia. Although the cognitive impairments associated with normal aging have been defined and may impair quality of life,
      • Petersen RC
      • Smith GE
      • Waring SC
      • Ivnik RJ
      • Tangalos EG
      • Kokmen E
      Mild cognitive impairment: clinical characterization and outcome [published correction appears in Arch Neurol. 1999;56:760].
      • Crook T
      • Bartus RT
      • Ferris SH
      • Whitehouse P
      • Cohen GD
      • Gershon S
      Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change: report of a National Institute of Mental Health Work Group.
      • Schaie KW
      The course of adult intellectual development.
      • Schaie KW
      The hazards of cognitive aging.
      cognitive decline with aging is not inevitable, and many older adults, including some centenarians, appear to avoid cognitive decline even into the 11th decade of life.
      • Silver MH
      • Jilinskaia E
      • Perls TT
      Cognitive functional status of age-confirmed centenarians in a population-based study.
      • Schaie KW
      Variability in cognitive function in the elderly: implications for societal participation.
      Recent research has resulted in new information identifying clinical risk factors for cognitive aging that are potentially modifiable. These new data support an emerging basis for primary and secondary prevention efforts to achieve and maintain cognitive vitality in late life. In this review, we discuss research that associates various risk factors with normal cognitive aging. Because most of these risk factors are potentially modifiable or manageable, such research should be of interest to physicians who provide preventive care counseling to older persons hoping to maintain cognitive vitality with aging.

      COGNITIVE AGING

      Neuropsychology

      Cognitive decline, although a relatively common occurrence, cannot be considered an inevitable part of aging. Nature provides clear examples of elderly people who maintain cognitive vitality, even in extreme old age. Many older adults who live into their ninth decade retain high cognitive function,
      • Berkman LF
      • Seeman TE
      • Albert M
      • et al.
      High, usual and impaired functioning in community-dwelling older men and women: findings from the MacArthur Foundation Research Network on Successful Aging.
      and centenarians who maintain their intellect negate the myth of the inevitability of cognitive decline.
      • Perls TT
      • Morris JN
      • Ooi WL
      • Lipsitz LA
      The relationship between age, gender and cognitive performance in the very old: the effect of selective survival.
      • Silver M
      • Newell K
      • Hyman B
      • Growdon J
      • Hedley-Whyte ET
      • Perls T
      Unraveling the mystery of cognitive changes in old age: correlation of neuropsychological evaluation with neuropathological findings in the extreme old.
      The aging brain remains capable of adapting to stimuli, and although declines in specific cognitive functions occur, some cognitive functions increase with age and can compensate for those functions that may decline. In addition, normal older persons and even those with mild cognitive deficits can benefit from cognitive training.
      • Willis SL
      • Schaie KW
      Training the elderly on the ability factors of spatial orientation and inductive reasoning.
      • Willis SL
      • Nesselroade CS
      Long-term effects of fluid ability training in old-old age.
      • Verhaeghen P
      • Marcoen A
      • Goossens L
      Improving memory performance in the aged through mnemonic training: a meta-analytic study [published correction appears in Psychol Aging. 1993;8: 338].
      People who reach old age with greater stores of knowledge may show increased adaptivity.
      Some cognitive functions, such as vocabulary, improve with age.
      • Birren JE
      • Morrison DF
      Analysis of WAIS subtests in relation to age and education.
      Older people who are socially interactive and use additional information resources in solving everyday problems also show adaptivity.
      Taken together, these findings suggest that individuals have varying degrees of “functional reserve” in their brains. Persons with high functional reserve may have increased capacity to keep learning and adapting despite age-related changes.
      • Baltes PB
      • Baltes MM
      Psychological perspectives on successful aging: the model of selective optimization with compensation.
      Increasing this functional reserve should promote cognitive vitality with aging.

      Neurobiology

      The underpinning of this functional reserve is likely to be brain plasticity, the ability of the brain to change structurally in response to stimuli. Recent neuroscience research shows that plasticity occurs via several mechanisms. In young animals, complex experience results in an angiogenic effect to increase vascular supply to the brain.
      • Black JE
      • Sirevaag AM
      • Greenough WT
      Complex experience promotes capillary formation in young rat visual cortex.
      • Sirevaag AM
      • Black JE
      • Shafron D
      • Greenough WT
      Direct evidence that complex experience increases capillary branching and surface area in visual cortex of young rats.
      Long-term enhancement of hippocampal synaptic connections occurs with acquisition of knowledge, although this process occurs more slowly in older animals than in young animals.
      • Barnes CA
      • McNaughton BL
      An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses.
      Synaptogenesis and angiogenesis also occur in the cerebellar cortex of the adult rat in response to stimuli.
      • Black JE
      • Isaacs KR
      • Anderson BJ
      • Alcantara AA
      • Greenough WT
      Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats.
      The number of synapses per neuron may increase in rats exposed to more stimulatory vs less stimulatory environments.
      • Turner AM
      • Greenough WT
      Differential rearing effects on rat visual cortex synapses, I: synaptic and neuronal density and synapses per neuron.
      In old rats, a stimulating environment helps reverse age-related gliosis in the hippocampus, which is associated with damage.
      • Soffié M
      • Hahn K
      • Terao E
      • Eclancher F
      Behavioural and glial changes in old rats following environmental enrichment.
      Finally, the widely held belief that the adult brain cannot make new neurons (neurogenesis) has been challenged recently by a growing body of new data. Animal studies have demonstrated that neuronal precursors in the dentate gyrus of the hippocampus, an area of the brain associated with learning and memory, continue to produce new neurons in adulthood.
      • Cameron HA
      • Gould E
      Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus.
      • Eriksson PS
      • Perfilieva E
      • Bjork-Eriksson T
      • et al.
      Neurogenesis in the adult human hippocampus.
      Studies in rats and mice show that a stimulatory environment,
      • Kempermann G
      • Kuhn HG
      • Gage FH
      Experience-induced neurogenesis in the senescent dentate gyrus.
      • Kempermann G
      • Kuhn HG
      • Gage FH
      More hippocampal neurons in adult mice living in an enriched environment.
      estrogen,
      • Tanapat P
      • Hastings NB
      • Reeves AJ
      • Gould E
      Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat.
      and aerobic exercise (running) also stimulate such new neuron production.
      • van Praag H
      • Christie BR
      • Sejnowski TJ
      • Gage FH
      Running enhances neurogenesis, learning, and long-term potentiation in mice.
      Neurogenesis has also been observed in the neocortex of adult primates.
      • Eriksson PS
      • Perfilieva E
      • Bjork-Eriksson T
      • et al.
      Neurogenesis in the adult human hippocampus.
      • Gould E
      • Reeves AJ
      • Graziano MS
      • Gross CG
      Neurogenesis in the neocortex of adult primates.
      The decline in cognitive function seen with apparently normal aging is associated with structural changes in the brain. Even early in the aging process, changes such as cerebral atrophy, ventricular enlargement, and hippocampal atrophy may be evident in some, but not all, individuals.
      • Meyer JS
      • Rauch GM
      • Crawford K
      • et al.
      Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia.
      • Coffey CE
      • Wilkinson WE
      • Parashos IA
      • et al.
      Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging.
      Ultimately, the underlying pathologic basis of cognitive decline must be loss of synapses, neurons, neurochemical inputs and neuronal networks.
      • Honig LS
      • Rosenberg RN
      Apoptosis and neurologic disease.
      • Hof PR
      • Cox K
      • Morrison JH
      Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease, I: superior frontal and inferior temporal cortex.
      However, neuronal loss is no longer thought to be a characteristic and inevitable feature of normal brain aging.
      • Morrison JH
      • Hof PR
      Life and death of neurons in the aging brain.
      In normal aging, some disruptions in neural networks occur, but cell death is not as common as it is in dementia.
      • West MJ
      • Coleman PD
      • Flood DG
      • Troncoso JC
      Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease.
      Indeed, as noted previously, neurogenesis, the production of new neurons, appears to continue throughout life, including old age.
      • Eriksson PS
      • Perfilieva E
      • Bjork-Eriksson T
      • et al.
      Neurogenesis in the adult human hippocampus.
      • Kempermann G
      • Kuhn HG
      • Gage FH
      Experience-induced neurogenesis in the senescent dentate gyrus.
      The cause of changes in brain structure and function with aging is unknown. Some processes required for maintaining normal neural function may become dysregulated with aging, causing neural damage.
      Dysregulated inflammation (activation of microglia, cytokine release, and acute-phase response) may contribute to neuronal damage.
      • Mackenzie IR
      • Munoz DG
      Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging.
      • Selkoe DJ
      Translating cell biology into therapeutic advances in Alzheimer's disease.
      Oxidative stress, an imbalance between oxidative and antioxidant processes, may also cause neuronal damage in the aging brain.
      • Sayre LM
      • Zagorski MG
      • Surewicz WK
      • Krafft GA
      • Perry G
      Mechanisms of neurotoxicity associated with amyloid beta deposition and the role of free radicals in the pathogenesis of Alzheimer's disease: a critical appraisal.
      • McDonald DR
      • Brunden KR
      • Landreth GE
      Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia.
      The pathologic changes associated with AD differ substantially from normal brain aging. Although some minor deposition of ß-amyloid peptide and neurofibrillary tangles may occur in the aging brain, the amount and distribution of these deposits are greatly increased in AD. Deposition of ß-amyloid is thought to be a primary factor in causing AD,
      • Selkoe DJ
      Translating cell biology into therapeutic advances in Alzheimer's disease.
      resulting in neuronal cell death and disruption of neural networks in AD. Tangles are believed to either contribute to and/or to be a sign of neuronal cell dysfunction and death and are associated with an abnormally phosphorylated form of a brain protein called tau. In tangles, tau twists into paired helical filaments that form intracellular occlusions associated with disruption of microtubules. The precise mechanism underlying the aberrant assembly of tau into tangles is unknown, but the available evidence suggests that hyperphosphorylation of tau is involved.
      • Jenkins SM
      • Zinnerman M
      • Garner C
      • Johnson GVW
      Modulation of tau phosphorylation and intracellular localization by cellular stress.
      • Gong C-X
      • Lidsky T
      • Wegiel J
      • Zuck L
      • Grundke-Iqbal I
      • Iqbal K
      Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain: implications for neurofibrillary degeneration in Alzheimer's disease.

      Clinical and Investigational Paradigms

      Many investigators have studied the characteristics of normal cognitive aging. Cognition is a combination of skills, including attention, learning, memory, language, and praxis, and executive functions, such as decision making, goal setting, planning, and judgment. A hallmark of normal cognitive aging is slowed speed of processing.
      • Birren JE
      • Fisher LM
      Aging and speed of behavior: possible consequences for psychological functioning.
      • Salthouse TA
      The processing-speed theory of adult age differences in cognition.
      This slowed speed of processing may be the “bottleneck” that causes other deficits in cognitive function. Researchers hypothesize that slow speed of processing impairs cognition because simultaneous cognitive operations cannot be successfully executed and the products of early processing are not available when later processing is completed (“simultaneity”).
      • Salthouse TA
      The processing-speed theory of adult age differences in cognition.
      Slowed speed of processing may contribute to declines in visual and verbal memory, abstraction, naming, verbal fluency, and recall.
      • Craik FIM
      • Anderson ND
      • Kerr SA
      • Li KZH
      Memory changes in normal ageing.
      • MacKay DG
      • Abrams L
      Age-linked declines in retrieving orthographic knowledge: empirical, practical, and theoretical implications [published correction appears in Psychol Aging. 1999;14: 76].
      • Antonelli Incalzi R
      • Capparella O
      • Gemma A
      • Marra C
      • Carbonin PU
      Effects of aging and of Alzheimer's disease on verbal memory.
      • Cullum CM
      • Butters N
      • Tröster AI
      • Salmon DP
      Normal aging and forgetting rates on the Wechsler Memory Scale-Revised.
      • Huppert FA
      • Kopelman MD
      Rates of forgetting in normal ageing: a comparison with dementia.
      • Mayr U
      • Kliegl R
      Sequential and coordinative complexity: age-based processing limitations in figural transformations.
      As a result, older individuals may have difficulty performing tasks that require holding and integrating multiple items in memory (eg, remembering a telephone number that one just looked up after being distracted by a question).
      From a clinical and an investigational perspective,
      • Bosworth HB
      • Schaie KW
      Survival effects in cognitive function, cognitive style, and sociodemographic variables in the Seattle Longitudinal Study.
      types of cognitive decline with aging have been recognized: age-associated memory impairment (AAMI),
      • Crook T
      • Bartus RT
      • Ferris SH
      • Whitehouse P
      • Cohen GD
      • Gershon S
      Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change: report of a National Institute of Mental Health Work Group.
      mild cognitive impairment (MCI),
      • Petersen RC
      • Smith GE
      • Waring SC
      • Ivnik RJ
      • Tangalos EG
      • Kokmen E
      Mild cognitive impairment: clinical characterization and outcome [published correction appears in Arch Neurol. 1999;56:760].
      and dementia. Age-associated memory impairment is a clinical paradigm that attempts to describe changes in cognition that occur with normal aging.
      • Goldman WP
      • Morris JC
      Evidence that age-associated memory impairment is not a normal variant of aging.
      Although age-associated memory impairment is a commonly used term for older persons with complaints of memory loss, other concepts and terms, such as age-related cognitive decline
      • McEntee WJ
      • Larrabee GJ
      Age-associated memory impairment.
      and cognitive impairment-no dementia,
      • Di Carlo A
      • Baldereschi M
      • Amaducci L
      • et al.
      Cognitive impairment without dementia in older people: prevalence, vascular risk factors, impact on disability: the Italian Longitudinal Study on Aging.
      have also been used to describe persons with mild memory loss. People experiencing AAMI complain of memory loss but generally have normal scores on psychometric testing for their age group.
      • Crook T
      • Bartus RT
      • Ferris SH
      • Whitehouse P
      • Cohen GD
      • Gershon S
      Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change: report of a National Institute of Mental Health Work Group.
      This syndrome has been variously termed benign senescent forget- fulness and aging-related cognitive decline. For persons older than 50 years who complain of subjective memory loss, AAMI is defined as cognitive function that is 1 SD below the mean for young individuals on at least 1 psychometric memory test.
      • Crook T
      • Bartus RT
      • Ferris SH
      • Whitehouse P
      • Cohen GD
      • Gershon S
      Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change: report of a National Institute of Mental Health Work Group.
      • Sherwin BB
      Mild cognitive impairment: potential pharmacological treatment options.
      Most data indicate that patients with AAMI do not progress to dementias such as AD. In addition, most data indicate that AAMI is not a prodromal state for MCI because less than 1% of people with AAMI will develop dementia. However, certainly some individuals with very early dementia may complain of mild memory loss akin to AAMI as their first symptom.
      • Bartres-Faz D
      • Junque C
      • Lopez-Alomar A
      • et al.
      Neuropsychological and genetic differences between age-associated memory impairment and mild cognitive impairment entities.
      Nevertheless, more studies of rates of progression of AAMI to MCI or dementia are needed.
      Mild cognitive impairment describes older persons with subjective complaints of memory loss and objective psychometric measures of memory impairment compared with individuals of the same age.
      • Petersen RC
      • Smith GE
      • Waring SC
      • Ivnik RJ
      • Tangalos EG
      • Kokmen E
      Mild cognitive impairment: clinical characterization and outcome [published correction appears in Arch Neurol. 1999;56:760].
      However, these individuals do not have pronounced impairments in daily function and generally do not have impairment of other cognitive functions such as language or abstract thinking. Therefore, by definition, they do not have dementia. In a study of MCI, subjects performed 1.5 SDs below the mean for age- matched adults on memory tests, whereas other cognitive functions appeared relatively unaffected.
      • Petersen RC
      • Smith GE
      • Waring SC
      • Ivnik RJ
      • Tangalos EG
      • Kokmen E
      Mild cognitive impairment: clinical characterization and outcome [published correction appears in Arch Neurol. 1999;56:760].
      At least in some patients, MCI may be a prodromal syndrome of dementia. Up to 15% of individuals with MCI develop dementia each year, and 50% with MCI will develop dementia within 3 years of diagnosis. However, whether MCI is a separate entity or an early prodromal stage of dementia remains a matter of debate
      • Petersen RC
      Mild cognitive impairment or questionable dementia? [editorial].
      because all individuals with MCI do not inevitably have progression to AD.
      • Petersen RC
      Mild cognitive impairment: transition between aging and Alzheimer's disease.
      A recent study found that older patients with memory complaints who convert to AD differ by at least 1.5 SDs from normal older patients on 3 of 17 cognitive tests. Based on these studies, selected clinical interview questions may be useful to identify such converters, particularly questions related to delayed recall.
      • Daly E
      • Zaitchik D
      • Copeland M
      • Schmahmann J
      • Gunther J
      • Albert M
      Predicting conversion to Alzheimer disease using standardized clinical information.
      Dementia can be broadly defined as a syndrome of progressive global cognitive impairment severe enough to affect daily function.
      • Shumaker SA
      • Reboussin BA
      • Espeland MA
      • et al.
      The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia.
      The term dementia is reserved for chronic, progressive, irreversible, global cognitive impairment. Dementia is common in old age, with up to 25% of people older than 75 years and 40% of people older than 80 years having the illness.
      • Evans DA
      • Funkenstein HH
      • Albert MS
      • et al.
      Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported.
      The most common causes are clearly AD and vascular dementia. Other causes of dementia include Parkinson disease, Lewy body disease, and other more rare neurodegenerative conditions.
      • Paist III, SS
      • Martin JR
      Brain failure in older patients: uncovering treatable causes of a diminished ability to think.
      • Rockwood K
      • Bowler J
      • Erkinjuntti T
      • Hachinski V
      • Wallin A
      Subtypes of vascular dementia.
      As discussed previously, at present there is no known neuro- pathogenic relationship between cognitive aging and AD. Alzheimer disease is not considered an accelerated form of cognitive aging, but rather a disease primarily of old persons.

      STRATEGIES TO PROMOTE COGNITIVE VITALITY WITH AGING

      Emerging research has resulted in a growing understanding of the potentially modifiable risk factors associated with cognitive decline in late life, and several interventions are being evaluated in research studies to prevent cognitive decline and dementia in older persons (Table 1).
      • Fillit HM
      • Butler RN
      Table 1Possible Strategies to Promote Cognitive Vitality With Aging
      • Early detection of individuals at risk
        • Neuropsychological testing
        • Neuroimaging
        • Biomarkers
        • Genetic markers
      • Lifestyle management
        • Build “cognitive reserve” by remaining intellectually and socially active
          • Continue lifelong learning
          • Engage in regular mental exercise
          • Maintain active social networks
          • Remain involved in the community by occupational or voluntary activity
        • Engage in regular physical exercise
        • Reduce or minimize the effects of stress
        • Ensure appropriate nutrition and avoid nutritional deficiencies
      • Manage medical comorbidities
        • Hypertension
        • Diabetes
        • Hyperlipidemia
        • Depression
        • Sleep disorders
        • Polypharmacy
        • Sensory impairments
        • Avoid alcohol, smoking, and illicit drug abuse
      • Pharmaceutical approaches
        • Cognitive enhancers
        • Neurotrophins
        • Anti-inflammatory agents
        • Antioxidants
        • Hormones

      Early Detection

      Early detection is essential to implementation of strategies to prevent cognitive decline. General approaches to early detection of cognitive impairment are neuropsychological testing, imaging, and use of biomarkers and genetic markers. At present, most of these strategies, particularly brain imaging, are being evaluated primarily for use in the early detection of MCI or dementia.

      Neuropsychological Testing

      Neuropsychological testing is clearly the most practical method of evaluation of cognitive decline with normal aging. Because there is considerable interindividual variation in cognitive decline with normal aging, neuropsychometric examination could potentially evaluate an individual's cognitive strengths and weaknesses and potentially lead to an intervention plan of cognitive training that is tailored to that individual's needs. Indeed, clinical programs along these lines are evolving in clinical practice, often using computer-based technology to expedite the process of both evaluation and training. Although neuropsychological approaches have the advantage of measuring the actual function of interest (ie, cognitive function), neuropsychometrics are time-consuming, and considerable effort is required to detect subtle neuropsy- chological impairments that can be compared with age- matched norms. Several studies
      • Shulman KI
      Clock-drawing: is it the ideal cognitive screening test?.
      • Semenza C
      • Borgo F
      • Mondini S
      • Pasini M
      • Sgaramella T
      Proper names in the early stages of Alzheimer's disease.
      • Jacobs DM
      • Sano M
      • Dooneief G
      • Marder K
      • Bell KL
      • Stern Y
      Neuropsychological detection and characterization of preclinical Alzheimer's disease.
      have investigated neu- ropsychological testing paradigms for early detection of cognitive impairment in individuals with early AD, MCI, or AAMI. However, routine neuropsychological testing for the evaluation of normal cognitive aging cannot be recommended at this time.
      Many brief and practical mental status tests are available in clinical practice to screen and assess cognitive function in older persons, but these are primarily geared toward the detection of more severe cognitive impairment due to dementia. The Mini-Mental State Examination (MMSE)
      • Mendiondo MS
      • Ashford JW
      • Kryscio RJ
      • Schmitt FA
      Modelling Mini Mental State Examination changes in Alzheimer's disease.
      is probably the most widely used and has been validated for screening for cognitive impairment in older persons in a community setting. Because the MMSE and instruments like it were primarily developed to detect dementia, they are not sensitive enough to detect the mild cognitive changes associated with normal aging. In clinical practice, patients who complain of memory impairment and who may have AAMI or MCI will generally score normally on screening instruments such as the MMSE. When indicated or desired, these individuals may be given more extensive psychometric testing by an expert neuro- psychologist to distinguish patients with AAMI or MCI from those with dementia.
      Specifically with regard to screening for cognitive impairment due to dementia, the US Preventive Services Task Force found in 1996 that evidence was insufficient to recommend for or against cognitive screening for dementia in asymptomatic older people in routine clinical practice because not enough data had been accumulated to gauge the benefit of such screening for preventing the medical, psychological, and social consequences of dementia.
      • U.S. Preventive Services Task Force
      However, with Food and Drug Administration (FDA) approval of modestly effective and safe cholinesterase inhibitors and advances in the understanding of AD care management, the impetus for screening and early detection may have changed considerably.
      • Fillit H
      • Knopman D
      • Cummings J
      • Appel F
      Opportunities for improving managed care for individuals with dementia, part 1: the issues.
      • Fillit H
      • Cummings J
      Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting, part I: early detection and diagnosis.
      Early detection means that people can receive new treatments and effective care management, which are crucial to promoting cognitive, emotional, and functional health during a time of cognitive frailty and in preserving the health of the caregiver. As the prevalence of cognitive impairment increases to approach 25% of individuals older than 75 years, it may be effective to screen these individuals on some regular basis (eg, every 2 years) for cognitive impairment. With ongoing clinical trials of the cholinesterase inhibitors and other drugs for the treatment of AAMI and MCI, the paradigm for screening for cognitive impairment may change even more in the future. One could envision a future in which treatments for normally aging individuals with slowed speed of processing and mild short-term memory impairment may be available and would justify routine neuropsychological assessment as part of an annual “health in aging” examination. Clearly, however, that day has not yet arrived.

      Brain Imaging Techniques

      As with neuropsycho- logical evaluations, brain imaging techniques, such as computed tomography, magnetic resonance imaging (MRI), functional MRI, positron emission tomography (PET) scanning, and single-photon emission computed tomography (SPECT), have been primarily investigated as methods for the early, preclinical detection of dementia. These imaging techniques show considerable promise as methods to detect the early brain changes that occur before the clear clinical expression of MCI and AD.
      • Bottino CM
      • Almeida OP
      Can neuroimaging techniques identify individuals at risk of developing Alzheimer's disease?.
      • Small GW
      Differential diagnosis and early detection of dementia.
      • Small GW
      • Leiter F
      Neuroimaging for diagnosis of dementia.
      • Small GW
      • Ercoli LM
      • Silverman DHS
      • et al.
      Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.
      • Bookheimer SY
      • Strojwas MH
      • Cohen MS
      • et al.
      Patterns of brain activation in people at risk for Alzheimer's disease.
      In particular, MRI measurements of hippocampal atrophy appear to be sensitive enough to detect individuals with MCI at risk for subsequent progression to AD.
      • Convit A
      • De Leon MJ
      • Tarshish C
      • et al.
      Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease.
      • Jack Jr, CR
      • Petersen RC
      • Xu YC
      • et al.
      Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment.
      Ongoing longitudinal studies are evaluating this technology. In the future, this technology may be able to detect early hippocampal atrophy before the onset of clinically apparent dementia. PET scanning also shows promise for the early detection of metabolic changes in the temporal-parietal cortex that are associated with subsequent progression to AD.
      • McGeer EG
      • McGeer PL
      • Kamo H
      • Tago H
      • Harrop R
      Cortical metabolism, acetylcholinesterase staining and pathological changes in Alzheimer's disease.
      In addition, PET scanning may be useful for the early detection of plaques and tangles associated with AD.
      • Small GW
      Differential diagnosis and early detection of dementia.
      Recent work in mice suggests that radioligands and use of SPECT and PET may allow the detection of brain deposits of ß-amyloid in living patients with AD. These radioligands may be useful to identify individuals at risk of developing AD and for monitoring disease progression and to show the effect of a therapeutic intervention.
      • Skovronsky DM
      • Zhang B
      • Kung MP
      • Kung HF
      • Trojanowski JQ
      • Lee VM
      In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease.
      However, other than identifying individuals at risk for AD, imaging currently has no application in those experiencing normal cognitive aging, other than as investigational tools. In the future, imaging (particularly PET and functional MRI) might be useful for identifying cognitive strengths and weaknesses of the aging brain.

      Biomarkers

      As with brain imaging, the primary purpose of current research regarding the development of biomarkers is targeted for early detection of individuals at high risk for AD who might benefit from intensive prevention programs. For example, low levels of ß-amyloid and high levels of tau-related antigens in cerebrospinal fluid have been reported to correlate with AD.
      • Motter R
      • Vigo-Pelfrey C
      • Kholodenko D
      • et al.
      Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.
      • Tamaoka A
      • Sawamura N
      • Fukushima T
      • et al.
      Amyloid β protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.
      • Scheuner D
      • Eckman C
      • Jensen M
      • et al.
      Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
      • Arai H
      • Nakagawa T
      • Kosaka Y-I
      • et al.
      Elevated cerebrospinal fluid tau protein level as a predictor of dementia in memory-impaired individuals.
      • Trojanowski JQ
      • Clark CM
      • Arai H
      • Lee VM-Y
      Elevated levels of tau in cerebrospinal fluid: implications for the antemortem diagnosis of Alzheimer's disease.
      • Hampel H
      • Buerger K
      • Kohnken R
      • et al.
      Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231 [letter].
      Blood levels of ß-amyloid have also been correlated with AD in some studies.
      • Scheuner D
      • Eckman C
      • Jensen M
      • et al.
      Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
      However, the potential role of biomarkers for the preclinical detection of sporadic AD remains undefined.
      • Ronald and Nancy Reagan Research Institute of the Alzheimer's Association
      • The National Institute on Aging Working Group
      Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer's Disease” [published correction appears in Neurobiol Aging. 1998;19:285].
      At present, because the actual biological basis of normal cognitive aging remains unknown, there are no clinically valuable or relevant biomarkers that would be useful in the context of normal cognitive aging, and careful psychometric testing remains the most relevant and sensitive test for these purposes.

      Genetic Markers

      Although genetic factors are not currently potentially modifiable, they may play a role in risk for cognitive decline with aging. Although the apolipoprotein E4 (apoE4) genotype
      • Bookheimer SY
      • Strojwas MH
      • Cohen MS
      • et al.
      Patterns of brain activation in people at risk for Alzheimer's disease.
      • Prince M
      • Lovestone S
      • Cervilla J
      • et al.
      The association between APOE and dementia does not seem to be mediated by vascular factors.
      is associated with increased risk of dementia, there is no evidence that the apoE4 genotype is associated with an increased risk of cognitive decline with aging. Because not all persons with the apoE4 genotype develop dementia, apoE4 is probably a susceptibility factor that interacts with other factors (such as head trauma and cholesterol)
      • Katzman R
      • Galasko DR
      • Saitoh T
      • et al.
      Apolipoprotein-ɛ4 and head trauma: synergistic or additive risks? [letter].
      to cause dementia.
      • Notkola I-L
      • Sulkava R
      • Pekkanen J
      • et al.
      Serum total cholesterol, apolipoprotein E ɛ4 allele, and Alzheimer's disease.
      • González C
      • Martín T
      • Cacho J
      • et al.
      Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4 apolipoprotein E allele carriers.
      • Tang M-X
      • Jacobs D
      • Stern Y
      • et al.
      Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease.
      More recently, loci have been identified that are associated with extreme longevity in pedigrees of humans. Of note, individuals in these families appear to be protected from cognitive decline well into the 10th and 11th decades of life. A gene loci located on chromosome 4 associated with extreme longevity has been identified among centenarians with intact cognitive function.
      • Silver MH
      • Jilinskaia E
      • Perls TT
      Cognitive functional status of age-confirmed centenarians in a population-based study.
      Ultimately, the identification of such protective genes could lead to new therapeutic targets to promote cognitive vitality in late life.

      Lifestyle Factors

      Promoting Brain Reserve: Lifelong Learning, Social Engagement, and Occupational Complexity

      Some studies
      • Callahan CM
      • Hall KS
      • Hui SL
      • Musick BS
      • Unverzagt FW
      • Hendrie HC
      Relationship of age, education, and occupation with dementia among a community-based sample of African Americans.
      • Cobb JL
      • Wolf PA
      • Au R
      • White R
      • D'Agostino RB
      The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study.
      • Farmer ME
      • Kittner SJ
      • Rae DS
      • Bartko JJ
      • Regier DA
      Education and change in cognitive function: the Epidemiologic Catchment Area Study.
      • Snowdon DA
      • Kemper SJ
      • Mortimer JA
      • Greiner LH
      • Wekstein DR
      • Markesbery WR
      Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study.
      have shown that low education and poor linguistic ability are correlated with cognitive decline in late life, although others have not found this association.
      • Evans DA
      • Beckett LA
      • Albert MS
      • et al.
      Level of education and change in cognitive function in a community population of older persons.
      Other studies
      • Cobb JL
      • Wolf PA
      • Au R
      • White R
      • D'Agostino RB
      The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study.
      • Chibnall JT
      • Eastwood R
      Postsecondary education and dementia risk in older Jesuit priests.
      • Colsher PL
      • Wallace RB
      Longitudinal application of cognitive function measures in a defined population of community-dwelling elders.
      • Stern Y
      • Gurland B
      • Tatemichi TK
      • Tang MX
      • Wilder D
      • Mayeux R
      Influence of education and occupation on the incidence of Alzheimer's disease.
      have found a similar association of these factors with dementia in late life. Although education may be a marker of socioeconomic status, the association of education with cognitive decline and dementia appears to be independent of socioeconomic status. However, the association of low education with cognitive decline may also be related to selection bias in studies. Clearly, more research needs to be done, and prospective trials will likely be almost impossible to design and conduct.
      Social disengagement is an independent risk factor for cognitive decline among cognitively intact older persons.
      • Bassuk SS
      • Glass TA
      • Berkman LF
      Social disengagement and incident cognitive decline in community-dwelling elderly persons.
      Berkman
      • Berkman LF
      Which influences cognitive function: living alone or being alone?.
      suggests that social engagement most likely challenges individuals to communicate and participate in exchanges that stimulate cognitive capacities. Other studies
      • Fabrigoule C
      • Letenneur L
      • Dartigues JF
      • Zarrouk M
      • Commenges D
      • Barberger-Gateau P
      Social and leisure activities and risk of dementia: a prospective longitudinal study.
      • Friedland RP
      • Fritsch T
      • Smyth K
      • et al.
      Participation in nonoccupational activities in midlife is protective against the development of Alzheimer's disease: results from a case control study [abstract].
      • Helmer C
      • Damon D
      • Letenneur L
      • et al.
      Marital status and risk of Alzheimer's disease: a French population-based cohort study.
      have suggested that individuals who have rich and satisfying social engagement patterns and who engage in continuing complex nonoccupational activities may be protected against dementia in late life. These data suggest that maintenance of social engagement and avoidance of social isolation may be important in maintaining cognitive vitality in old age. Considerable animal data indicate that environmental enrichment and stimulation increase capillary formation, synaptogenesis, and neurogenesis, even in older animals.
      • Black JE
      • Sirevaag AM
      • Greenough WT
      Complex experience promotes capillary formation in young rat visual cortex.
      • Sirevaag AM
      • Black JE
      • Shafron D
      • Greenough WT
      Direct evidence that complex experience increases capillary branching and surface area in visual cortex of young rats.
      • Soffié M
      • Hahn K
      • Terao E
      • Eclancher F
      Behavioural and glial changes in old rats following environmental enrichment.
      • Eriksson PS
      • Perfilieva E
      • Bjork-Eriksson T
      • et al.
      Neurogenesis in the adult human hippocampus.
      • Kempermann G
      • Kuhn HG
      • Gage FH
      Experience-induced neurogenesis in the senescent dentate gyrus.
      • Kempermann G
      • Kuhn HG
      • Gage FH
      More hippocampal neurons in adult mice living in an enriched environment.
      • van Praag H
      • Christie BR
      • Sejnowski TJ
      • Gage FH
      Running enhances neurogenesis, learning, and long-term potentiation in mice.
      Complex intellectual work increases the cognitive functioning of older workers.
      • Schooler C
      • Mulatu MS
      • Oates G
      The continuing effects of substantively complex work on the intellectual functioning of older workers.
      Work may also increase social interactions and a sense of self-efficacy, both of which may be important to maintenance of cognitive vitality.
      • Rowe JW
      • Kahn RL
      These findings may have important implications for the structure of retirement in old age and support the common wisdom that volunteerism and continued participation in the workforce may play a role in maintaining cognitive reserve and vitality in aging.
      These animal and human data suggest that lifelong learning and maintenance of occupational and social engagement may contribute to cognitive vitality in late life perhaps by promoting biological “cognitive reserve” through increased synaptic complexity and neurogenesis. However, definitive research studies, such as prospective randomized clinical trials, to support this possibility have not been performed.

      Cognitive Training

      Studies
      • Willis SL
      • Schaie KW
      Training the elderly on the ability factors of spatial orientation and inductive reasoning.
      • Willis SL
      • Nesselroade CS
      Long-term effects of fluid ability training in old-old age.
      • Verhaeghen P
      • Marcoen A
      • Goossens L
      Improving memory performance in the aged through mnemonic training: a meta-analytic study [published correction appears in Psychol Aging. 1993;8: 338].
      • Ball KK
      • Beard BL
      • Roenker DL
      • Miller RL
      • Griggs DS
      Age and visual search: expanding the useful field of view.
      • Baron A
      • Mattila WR
      Response slowing of older adults: effects of time-limit contingencies on single- and dual-task performances.
      • Kramer AF
      • Hahn S
      • Gopher D
      Task coordination and aging: explorations of executive control processes in the task switching paradigm.
      • Ball K
      • Sekuler R
      Improving visual perception in older observers.
      • Ball K
      Attentional problems and older drivers.
      • Owsley C
      Clinical and research issues on older drivers: future directions.
      have shown that training can improve various cognitive functions in older adults, including reasoning, memory storage and retrieval, visual perception, attention, and skill coordination. Indeed, a small but growing body of evidence suggests that skills learned during training can be transferred to similar tasks. However, training is often specific to the skills trained and learned (eg, training for memory enhancement does not transfer to tasks that rely on the rapid scanning of the environment). Therefore, training interventions need to be tailored to the cognitive problems exhibited by the individual, generally determined by neuropsychometrics testing. The effect of training on prevention of cognitive decline is an area of research interest.
      Although older adults with mild cognitive deficits can be trained to improve certain cognitive functions, there is a paucity of such resources and programs in clinical practice, and the effectiveness of existing “mental exercise” programs has not been shown.

      Physical Exercise

      Animal models clearly show a beneficial effect of physical exercise on cognitive function.
      • van Praag H
      • Christie BR
      • Sejnowski TJ
      • Gage FH
      Running enhances neurogenesis, learning, and long-term potentiation in mice.
      This effect may be mediated, in part, through increased levels of brain-derived neurotrophic factor (BDNF),
      • Widenfalk J
      • Olson L
      • Thoren P
      Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain.
      • Neeper SA
      • Gomez-Pinilla F
      • Choi J
      • Cotman C
      Exercise and brain neurotrophins [letter].
      a neurotrophin involved with learning, long- term potentiation, cell health and survival, and protection from injury.
      • Cotman CW
      Homeostatic processes in brain aging: the role of apoptosis, inflammation, and oxidative stress in regulating healthy neural circuitry in the aging brain.
      Although several studies
      • Yaffe K
      • Barnes D
      • Nevitt M
      • Lui LY
      • Covinsky K
      A prospective study of physical activity and cognitive decline in elderly women: women who walk.
      • Albert MS
      • Jones K
      • Savage CR
      • et al.
      Predictors of cognitive change in older persons: MacArthur studies of successful aging.
      • Bunce DJ
      • Barrowclough A
      • Morris I
      The moderating influence of physical fitness on age gradients in vigilance and serial choice responding tasks.
      • Rikli RE
      • Edwards DJ
      Effects of a three-year exercise program on motor function and cognitive processing speed in older women.
      • Kramer AF
      • Hahn S
      • Cohen NJ
      • et al.
      Ageing, fitness and neurocognitive function [letter].
      show improvement in cognitive function with physical exercise or better cognitive function in older persons who exercise, some do not.
      • Hill RD
      • Storandt M
      • Malley M
      The impact of long-term exercise training on psychological function in older adults.
      • Madden DJ
      • Blumenthal JA
      • Allen PA
      • Emery CF
      Improving aerobic capacity in healthy older adults does not necessarily lead to improved cognitive performance.
      These discrepancies among studies may be related to differences in the types of exercise promoted (aerobic, anaerobic, strenuous) and in the general health of the participants at baseline.
      • Blumenthal JA
      • Emery CF
      • Madden DJ
      • et al.
      Long-term effects of exercise on psychological functioning in older men and women.
      Determining direct beneficial cognitive effects of exercise from its effects on mood and other factors such as stress is difficult. In addition to these neurobiologic mechanisms, physical exercise also ameliorates vascular risk factors and medical comorbidities that contribute to cognitive decline.
      • Black JE
      • Isaacs KR
      • Anderson BJ
      • Alcantara AA
      • Greenough WT
      Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats.
      Although more human research is clearly needed in this area, these new data support the notion that engaging in physical exercise, including enjoyable leisure-time activities, can contribute to maintaining cognitive vitality and preventing cognitive decline in late life, either directly or through the avoidance of medical comorbidities such as vascular disease.

      Stress Reduction

      Animal models and some human studies
      • Sapolsky RM
      • Krey LC
      • McEwen BS
      Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging.
      show that chronic stress results in hippocampal atrophy through a glucocorticoid-mediated mechanism. Studies
      • Lupien SJ
      • de Leon M
      • de Santi S
      • et al.
      Cortisol levels during human aging predict hippocampal atrophy and memory deficits [published correction appears in Nat Neurosci. 1998;1:329].
      • Fuchs E
      • Uno H
      • Flugge G
      Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew.
      • Mabry TR
      • Gold PE
      • McCarty R
      Age-related changes in plasma catecholamine responses to acute swim stress.
      in humans suggest that it is how stress is perceived that is critical and that it is the sense of being overwhelmed by stress that influences brain structures and may result in associated memory defects. Acute stress is also associated with impaired cognitive functioning,
      • Chambers RA
      • Bremner JD
      • Moghaddam B
      • Southwick SM
      • Charney DS
      • Krystal JH
      Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation.
      especially in older adults. Posttraumatic stress disorder is a good example of the short- and long-term effects of acute stress on the human brain.
      • Bremner JD
      Does stress damage the brain?.
      The long-term effects of chronic stress on cognitive function may result in decreased cognitive reserve, resulting from neurotoxicity, neuroendocrine changes, or other factors.
      These data indicate that stress contributes to cognitive decline. Cognitively frail, elderly individuals with decreased brain reserve may be particularly at risk. Clinical strategies for stress reduction may include activities that have other health benefits (eg, exercise). Training in stress reduction, including adaptive (as opposed to maladaptive) methods for responding to stress, may be useful as a means to promote cognitive vitality for selected individuals. Clinical studies are needed to show that stress reduction improves cognitive function in elderly individuals.

      Sleep

      Cognitive vitality may be compromised substantially by sleep disorders, and older persons are especially susceptible to this effect. Biological alterations in sleep patterns occur with age.
      • Dykierek P
      • Stadtmuller G
      • Schramm P
      • et al.
      The value of REM sleep parameters in differentiating Alzheimer's disease from old-age depression and normal aging.
      As a result, older persons often experience sleep fractionation and other changes. Sleep fractionation may adversely affect cognitive function and is associated with poor memory and learning.
      • Stone WS
      • Gold PE
      Sleep and memory relationships in intact old and amnestic young rats.
      In addition, older individuals are at increased risk for sleep apnea and hypopnea and for the adverse cognitive effects of sedatives and hypnotics, which are frequently prescribed to treat sleep disorders in older persons. Older patients complaining of cognitive impairment should be questioned about their sleep patterns. Strategies to promote sleep hygiene and avoidance of daytime napping are often effective in improving sleep, whereas some older patients may require evaluation and treatment for sleep disorders.

      Nutrition

      Some studies
      • Means LW
      • Higgins JL
      • Fernandez TJ
      Mid-life onset of dietary restriction extends life and prolongs cognitive functioning.
      • Mattson MP
      Impact of dietary restriction on brain aging and neurodegenerative disorders: emerging findings from experimental and epidemiological studies.
      suggest that caloric restriction early in life has a beneficial effect on cognition with aging, but other studies
      • Bellush LL
      • Wright AM
      • Walker JP
      • Kopchick J
      • Colvin RA
      Caloric restriction and spatial learning in old mice.
      do not show such an association. Caloric restriction in older persons is not recommended because of the risk of malnutrition. Malnutrition can cause long-term cognitive impairment.
      • Levitsky DA
      • Strupp BJ
      Malnutrition and the brain: changing concepts, changing concerns.
      Isolated vitamin deficiencies, particularly B12 deficiency, are associated with cognitive disorders (including dementia) in elderly individuals that may be attributed to “normal cognitive aging” but, in fact, represent a potentially reversible disorder.
      • Freter S
      • Bergman H
      • Gold S
      • Chertkow H
      • Clarfield AM
      Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort.
      Antioxidants, such as vitamin E and vitamin C, may be important in protecting the brain from oxidant injury. Some studies
      • Paleologos M
      • Cumming RG
      • Lazarus R
      Cohort study of vitamin C intake and cognitive impairment.
      • Perrig WJ
      • Perrig P
      • Stähelin HB
      The relation between antioxidants and memory performance in the old and very old.
      suggest a protective effect of these antioxidants against cognitive decline. Other studies
      • Prasad KN
      • Hovland AR
      • Cole WC
      • et al.
      Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale.
      • Grundman M
      Vitamin E and Alzheimer disease: the basis for additional clinical trials.
      • Morris MC
      • Beckett LA
      • Scherr PA
      • et al.
      Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease.
      suggest an association of antioxidant intake with protection against the risk of dementia. However, there are no prospective randomized, controlled studies showing that antioxidants promote cognitive vitality or protect against dementia. Although several of these studies are ongoing, more research is needed to determine the benefits of dietary antioxidant
      • Rowe JW
      • Kahn RL
      interventions in both short- and long-term clinical trials.
      • Grundman M
      Vitamin E and Alzheimer disease: the basis for additional clinical trials.
      In older individuals taking antioxidants, clinicians should caution against excess vitamin intake as a means of promoting cognitive vitality. The use of a daily multivitamin is probably prudent, provided the recommendations of the Institute of Medicine's Food and Nutrition Board regarding the levels of vitamins C and E for older persons are adhered to.

      Managing Medical Comorbidities

      Accumulating data also show that many medical conditions, particularly those identified as risk factors for cardiovascular disease, are also risk factors for cognitive decline with aging and dementia in older individuals. Potentially reversible medical illnesses may also cause cognitive impairment in older individuals. These include adverse drug reactions; depression; metabolic, nutritional, and endocrine disturbances; tumors; normal-pressure hydrocephalus; trauma, including subarachnoid hemorrhage; alcoholism and other forms of substance abuse; sensory loss (vision and hearing problems); and infection.
      • Paist III, SS
      • Martin JR
      Brain failure in older patients: uncovering treatable causes of a diminished ability to think.
      During the early stages of these disorders, memory disturbances and other cognitive dysfunction may be attributed to “cognitive aging”; eventually they may cause delirium or dementia. Clearly, many older individuals may have more than one of these medical comorbidities, which may increase their risk of cognitive impairment.

      Hypertension

      Data indicating a relationship between blood pressure and late-life cognitive function in the absence of dementia suggest that hypertension is a risk factor for impaired cognitive function in late life.
      • Glynn RJ
      • Beckett LA
      • Hebert LE
      • Morris MC
      • Scherr PA
      • Evans DA
      Current and remote blood pressure and cognitive decline.
      Several studies
      • Tatemichi TK
      • Desmond DW
      • Prohovnik I
      Strategic infarcts in vascular dementia: a clinical and brain imaging experience.
      • Tatemichi TK
      How acute brain failure becomes chronic: a view of the mechanisms of dementia related to stroke.
      • Butler RN
      • Ahronheim J
      • Fillit H
      • Rapoport SI
      • Tatemichi TK
      Vascular dementia: how to make the diagnosis in office practice.
      have also identified hypertension as a risk for vascular dementia, presumably through the occurrence of both large and small strokes. Launer et al
      • Launer LJ
      • Ross GW
      • Petrovitch H
      • et al.
      Midlife blood pressure and dementia: the Honolulu-Asia aging study.
      have shown that elevated levels of blood pressure in middle age increase the risk for late-life dementia in men never treated with antihypertensive medication.
      Small (lacunar) strokes causing cognitive impairment are often “strategic” strokes that are not clinically apparent and may not be associated with motor or sensory deficits. In counseling middle-aged and older persons regarding the importance of compliance with hypertension treatment, clinicians can inform them that control of hypertension is a means of reducing stroke and, therefore, the cognitive decline associated with cerebrovascular disease. In addition, effective management of hypertension may also prevent clinically nonapparent lacunar strokes and “strategic” strokes in localized regions that affect cognition alone without affecting motor function.

      Diabetes

      Diabetes at midlife is a risk for cognitive decline,
      • Knopman DS
      • Boland LL
      • Folsom AR
      • et al.
      Cardiovascular risk factors and longitudinal cognitive changes in middle-aged adults [abstract].
      and older women with diabetes have lower levels of cognitive function than do women without diabetes.
      • Gregg EW
      • Yaffe K
      • Cauley JA
      • Study of Osteoporotic Fractures Research Group
      • et al.
      Is diabetes associated with cognitive impairment and cognitive decline among older women?.
      Poor metabolic control (sustained hyperglycemia) in people with diabetes has been linked to reduced cognitive functioning.
      • Wändell PE
      • Tovi J
      The quality of life of elderly diabetic patients.
      The relationship between diabetes and cognitive impairment is complicated. Glucose is needed for all types of cognition.
      • Stone WS
      • Rudd RJ
      • Gold PE
      Amphetamine, epinephrine, and glucose enhancement of memory retrieval.
      However, the relationship between glucose and cognitive function follows an inverted U-shaped curve,
      • Parsons MW
      • Gold PE
      Glucose enhancement of memory in elderly humans: an inverted-U dose-response curve.
      with impaired cognitive function occurring as a result of both acute hyperglycemia and hypoglycemia.
      • Strachan MW
      • Deary IJ
      • Ewing FM
      • Frier BM
      Recovery of cognitive function and mood after severe hypoglycemia in adults with insulin-treated diabetes.
      • Messier C
      • Gagnon M
      Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes.
      Therefore, the long-term health risks and benefits of tight glucose control on cognition must be carefully considered in older individuals. In addition, diabetes is associated with other comorbid conditions, such as hypertension, atherosclerosis, and altered insulin concentrations,
      • Kumari M
      • Brunner E
      • Fuhrer R
      Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory.
      • Kalaria RN
      The role of cerebral ischemia in Alzheimer's disease.
      that may also affect cognitive function through various mechanisms.
      These data indicate that diabetes is a risk factor for cognitive decline.
      • Gregg EW
      • Yaffe K
      • Cauley JA
      • Study of Osteoporotic Fractures Research Group
      • et al.
      Is diabetes associated with cognitive impairment and cognitive decline among older women?.
      The failure to control diabetes adequately may contribute to cognitive decline through several mechanisms. More research is needed to determine the risks of tight glucose control on cognitive function. More studies of treatments for diabetes need to include their impact on cognitive outcomes in older persons.

      Hyperlipidemia and Atherosclerosis

      Hyperlipidemia has been associated with cerebral atrophy.
      • Meyer JS
      • Rauch GM
      • Crawford K
      • et al.
      Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia.
      Atherosclerosis at middle age increases the prevalence of cerebral white matter lesions in late life.
      • de Leeuw FE
      • De Groot JC
      • Oudkerk M
      • et al.
      Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly.
      In addition, a moderate association exists between carotid atherosclerosis and poor cognitive function in men aged 59 to 71 years.
      • Auperin A
      • Berr C
      • Bonithon-Kopp C
      • EVA Study Group
      • et al.
      Ultrasonographic assessment of carotid wall characteristics and cognitive functions in a community sample of 59- to 71-year-olds.
      Hyperlipidemia has also been identified as a risk factor for dementia.
      • Pappolla M
      • Bozner P
      • Soto C
      • et al.
      Inhibition of Alzheimer beta-fibrillogenesis by melatonin.
      Recent data in animal models indicate that hyperlipidemia increases ß-amyloid deposition in the brain and that cholesterol-lowering treatment reduces amyloid accumulation,
      • Refolo LM
      • Pappolla MA
      • LaFrancois J
      • et al.
      A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.
      • Refolo LM
      • Malester B
      • LaFrancois J
      • et al.
      Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model [published correction appears in Neurobiol Dis. 2000;7(6, pt B):690].
      one of the hallmarks of AD.
      • Perls TT
      Acute care costs of the oldest old.
      In a population-based study,
      • Breteler MM
      • Bots ML
      • Ott A
      • Hofman A
      Risk factors for vascular disease and dementia.
      all markers of atherosclerosis were associated with both AD and vascular dementia. These recent data suggest that cholesterol and atherosclerosis are risk factors for cognitive decline due to dementia and indicate that lowering cholesterol may prevent cognitive decline. Several studies currently under way are investigating the effects of lipid-lowering agents (3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors) in AD (www.aging-institute.org/gs18.htm). However, at present, there are no data that prospectively show that lowering cholesterol prevents cognitive decline in normally aging individuals.

      Depression

      Persons who have a high sense of self- efficacy are more likely to maintain cognitive function over time.
      • Rowe JW
      • Kahn RL
      • Albert MS
      • Jones K
      • Savage CR
      • et al.
      Predictors of cognitive change in older persons: MacArthur studies of successful aging.
      Depression, which is common in older persons, clearly has important deleterious effects on cognitive function
      • Sheline YI
      • Sanghavi M
      • Mintun MA
      • Gado MH
      Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.
      and is the most common cause of reversible cognitive impairment and dementia in older individuals. Clinicians need to have a high index of suspicion for depression in older persons and must be particularly aware of the effects of depression on cognitive function. In individuals complaining of cognitive dysfunction, depression should be considered as a possible reversible and treatable cause.

      Polypharmacy

      Many older people take medications that may impair cognitive function. Multiple medications have adverse central nervous system effects for which older persons with decreased cognitive reserve are especially at risk.
      • Hanlon JT
      • Schmader KE
      • Ruby CM
      • Weinberger M
      Suboptimal prescribing in older inpatients and outpatients.
      Adverse drug reactions are a common cause of reversible cognitive decline in elderly patients. A careful medication review can eliminate medications that may adversely affect cognitive function. Several classes of medications cause cognitive adverse effects more commonly than others, such as anxiolytics, hypnotic-sedative agents, antipsychotics, antihistamines, and anticholinergics.
      Sensory Impairments.—Visual and auditory deficits are common in older persons. Sensory impairments can be a cause of isolation, loss of mental stimulation, and even depression. Common treatable causes of sensory impairments, such as glaucoma, cataracts, and impacted cerumen, should be treated with a view to their importance for maintaining cognitive function, particularly in frail, older persons. By encouraging the use of technological aids, cognitive function in older persons can be optimized through improved ability to sense environmental information and more effectively interact with the environment.
      • Fisher DL
      Cognitive aging and adaptive technologies.

      Head Trauma

      Head trauma is an important source of brain damage that often goes unrecognized.
      • NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury
      Consensus conference: rehabilitation of persons with traumatic brain injury.
      Repeated low-level head trauma may also contribute to cognitive decline in apparently normal aging. Chronic head trauma in professional soccer players has been associated with impaired performance in memory, planning, and visuoperceptual tasks compared with a control group of noncontact sport athletes.
      • Matser JT
      • Kessels AG
      • Jordan BD
      • Lezak MD
      • Troost J
      Chronic traumatic brain injury in professional soccer players.
      Cognitive performance of professional soccer players was inversely related to the number of concussions incurred and the frequency of “heading” the ball while playing soccer. Dementia pugilistica from boxing is another example of the impact of chronic head trauma on cognitive function. An early case-control study
      • Mortimer JA
      • French LR
      • Hutton JT
      • Schuman LM
      Head injury as a risk factor for Alzheimer's disease.
      found head injury to be a significant risk factor for AD, although a recent study
      • Launer LJ
      • Andersen K
      • Dewey ME
      • EURODEM Incidence Research Group and Work Groups
      • et al.
      Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses.
      did not corroborate these findings. Individuals with the apoE4 genotype may be at greater risk for cognitive decline after head trauma.
      • Katzman R
      • Galasko DR
      • Saitoh T
      • et al.
      Apolipoprotein-ɛ4 and head trauma: synergistic or additive risks? [letter].
      Older persons who fall are at risk for subarachnoid hemorrhage that may cause reversible cognitive decline.

      Substance Use and Abuse: Smoking, Alcohol, and Illicit Drugs

      Nicotine may have a beneficial effect on cognition by enhancing attention.
      • Baron JA
      Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious.
      Nicotinic agonists remain an active area of research in drug discovery and drug development as cognitive enhancers.
      • Lewis R
      • Wake G
      • Court G
      • et al.
      Non-ginsenoside nicotinic activity in ginseng species.
      • Wake G
      • Court J
      • Pickering A
      • Lewis R
      • Wilkins R
      • Perry E
      CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory.
      We are aware of no studies on the relationship between smoking and cognitive decline associated with normal aging or of studies of the effect of smoking on cognition in normally aging indi viduals. One case-control study
      • Graves AB
      • van Duijn CM
      • Chandra V
      • EURODEM Risk Factors Research Group
      • et al.
      Alcohol and tobacco consumption as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies.
      found an inverse relationship between smoking and AD, but later studies
      • Friedland RP
      • Fritsch T
      • Smyth K
      • et al.
      Participation in nonoccupational activities in midlife is protective against the development of Alzheimer's disease: results from a case control study [abstract].
      • Launer LJ
      • Andersen K
      • Dewey ME
      • EURODEM Incidence Research Group and Work Groups
      • et al.
      Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses.
      • Doll R
      • Peto R
      • Boreham J
      • Sutherland I
      Smoking and dementia in male British doctors: prospective study.
      found that smoking does not positively affect the onset or severity of AD. Smoking is associated with increased vascular disease, particularly stroke, which may cause vascular dementia.
      • Gorelick PB
      • Erkinjuntti T
      • Hofman A
      • Rocca WA
      • Skoog I
      • Winblad B
      Prevention of vascular dementia.
      Clearly, smoking should not be recommended because of potential nicotine effect on cognition in elderly individuals. Given the relationship of smoking with pulmonary and vascular comorbidities, particularly stroke, smoking may contribute to cognitive decline in older persons, but prospective data to demonstrate this are lacking.
      The Baltimore Epidemiologic Catchment Area survey of the National Institute of Mental Health showed that alcoholism is highly prevalent among people older than 65 years.
      • Neumark YD
      • Van Etten ML
      • Anthony JC
      “Alcohol dependence” and death: survival analysis of the Baltimore ECA sample from 1981 to 1995.
      In mice, alcohol abuse has been shown to cause brain deficits and reduced cognitive performance.
      • Beracochea DJ
      • Tako AN
      • Jaffard R
      Accelerated rates of forgetting of spatial information during aging and long-term ethanol consumption in mice: evidence for two distinct forms of amnesia.
      However, investigators have shown an inverted U- or J-shaped relationship between alcohol consumption and cognitive performance that suggests that very moderate alcohol consumption might positively affect cognitive function, perhaps mediated by a favorable effect on vascular comorbidities.
      • Dufouil C
      • Ducimetière P
      • Alpérovitch A
      • EVA Study Group
      Sex differences in the association between alcohol consumption and cognitive performance.
      However, the effect may vary from person to person. In non-apoE4 carriers, moderate drinking was found to protect against cognitive decline, but apoE4 carriers who drank moderately experienced an increased risk.
      • Dufouil C
      • Tzourio C
      • Brayne C
      • Berr C
      • Amouyel P
      • Alpérovitch A
      Influence of apolipoprotein E genotype on the risk of cognitive deterioration in moderate drinkers and smokers.
      Excessive, long-term alcohol consumption is associated with dementia.
      • Kasahara H
      • Karasawa A
      • Ariyasu T
      • Thukahara T
      • Satou J
      • Ushijima S
      Alcohol dementia and alcohol delirium in aged alcoholics.
      Despite some health benefit claims for very moderate alcohol consumption, we believe the cognitive tolerance of older individuals to alcohol is low, and the danger of alcohol abuse is high. In older individuals with decreased cognitive reserve, even very moderate long-term alcohol consumption may impair cognition. Older individuals complaining of memory loss and cognitive decline should be queried about their alcohol consumption and a trial of abstinence recommended if appropriate in an attempt to regain optimal cognitive function.
      Contrary to popular belief, substance abuse with illicit drugs occurs in elderly individuals and can contribute to cognitive decline. Long-term marijuana abuse has been associated with subtle impairment of memory, attention, and information processing,
      • Hall W
      • Solowij N
      Adverse effects of cannabis.
      • Block RI
      Does heavy marijuana use impair human cognition and brain function? [editorial].
      • Court JM
      Cannabis and brain function.
      • Hall W
      • Solowij N
      Long-term cannabis use and mental health [editorial].
      although the degree of cognitive impairment is less than that seen with long-term alcohol abuse.
      • Hall W
      • Solowij N
      Adverse effects of cannabis.
      • Block RI
      Does heavy marijuana use impair human cognition and brain function? [editorial].
      The psychoactive drug 3,4-methylene- dioxymethamphetamine (ecstasy) has also been associated with memory impairment.
      • Morgan MJ
      Memory deficits associated with recreational use of “ecstasy” (MDMA).
      Impairment of cognitive function has not been as clearly shown with other hallucinogens such as lysergic acid diethylamide.
      • Morgan MJ
      Memory deficits associated with recreational use of “ecstasy” (MDMA).
      • Halpern JH
      • Pope Jr, HG
      Do hallucinogens cause residual neuropsychological toxicity?.
      Persons who consume stimulants such as cocaine or crack-cocaine experience pronounced brain pathologic conditions and cognitive impairment.
      • Di Sclafani V
      • Clark HW
      • Tolou-Shams M
      • et al.
      Premorbid brain size is a determinant of functional reserve in abstinent crack-cocaine and crack-cocaine-alcohol-dependent adults.
      • Strickland TL
      • Miller BL
      • Kowell A
      • Stein R
      Neurobiology of cocaine-induced organic brain impairment: contributions from functional neuroimaging.
      Additional research is needed to investigate the long-term effects of drug use on cognitive vitality in later life, particularly because many baby boomers who may have experimented with drugs in the 1960s remain intermittent or continuous users of marijuana and other drugs and are now entering their later years.

      PHARMACEUTICAL APPROACHES

      Although most pharmaceutical research to date has focused on the development of drugs to prevent or treat dementia, interest is growing in the development of pharmacologic agents for cognitive enhancement in older persons experiencing normal cognitive aging.
      • Whitehouse PJ
      • Juengst E
      • Mehlman M
      • Murray TH
      Enhancing cognition in the intellectually intact.
      Some agents are being evaluated for AAMI and MCI.
      • Sherwin BB
      Mild cognitive impairment: potential pharmacological treatment options.

      Drugs That Enhance Cognition

      The basal forebrain cholinergic system plays a key role in normal memory and learning.
      • Selkoe DJ
      Translating cell biology into therapeutic advances in Alzheimer's disease.
      Currently, there are 4 FDA-approved cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galanthamine) for treatment of cognitive impairment in AD.
      • Francis PT
      • Palmer AM
      • Snape M
      • Wilcock GK
      The cholinergic hypothesis of Alzheimer's disease: a review of progress.
      • Knopman DS
      Current pharmacotherapies for Alzheimer's disease.
      These drugs have been shown to significantly improve or maintain cognitive function and daily function in about 60% of patients with mild to moderate AD.
      • Rösler M
      • Anand R
      • Cicin-Sain A
      • et al.
      Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial [published correction appears in BMJ. 2001;322:1456].
      • Rogers SL
      • Doody RS
      • Mohs RC
      • Friedhoff LT
      • Donepezil Study Group
      Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study.
      • Tariot PN
      • Solomon PR
      • Morris JC
      • Kershaw P
      • Lilienfeld S
      • Ding C
      • Galantamine USA-10 Study Group
      A 5-month, randomized, placebo-controlled trial of galantamine in AD.
      These cholinesterase inhibitors are currently being investigated for the treatment of cognitive impairment in patients with MCI and AAMI. Some preliminary data indicate that cholinesterase inhibitors may have value in the treatment of cognitive disorders associated with normal aging.
      • Schredl M
      • Weber B
      • Leins ML
      • Heuser I
      Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons.
      There is no evidence that these medications play a role in the prevention of cognitive decline or AD.
      Muscarinic agonists
      • Avery EE
      • Baker LD
      • Asthana S
      Potential role of muscarinic agonists in Alzheimer's disease.
      target postsynaptic muscarinic M1 receptors and have been shown to improve cognitive function in animal models and humans.
      • Growdon JH
      Muscarinic agonists in Alzheimer's disease.
      Although these agents have shown some improvement in cognitive function in patients with AD, agents in this class have been severely limited because of their adverse effects. Continued research on these agents may yet result in an approved drug.
      • Fox RI
      Sjögren's syndrome: current therapies remain inadequate for a common disease.
      Another approach to address impaired cholinergic transmission is to target nicotinic cholinergic receptor ligands to allosterically potentiate submaximal neurotransmission.
      • Maelicke A
      • Albuquerque EX
      Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.
      Glutamate modulators are also being evaluated as cognitive enhancers. Glutamate neurotransmission plays a role in cognition and is affected in AD.
      • Francis PT
      • Palmer AM
      • Snape M
      • Wilcock GK
      The cholinergic hypothesis of Alzheimer's disease: a review of progress.
      Memantine is a noncompetitive N-methyl-d-aspartate modulator that interacts with N-methyl-d-aspartate receptors. This agent is currently in phase 3 clinical trials for vascular dementia and severe AD. In a recent study,
      • Winblad B
      • Poritis N
      Memantine in severe dementia: results of the 9M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine).
      memantine improved function and reduced care dependency in AD patients with severe dementia. Ampakines, a novel class of agents, augment glutaminergic pathways and increase the production of BDNF and nerve growth factor (NGF) in brain areas involving memory, which also makes them potential disease-modifying agents. The ampakine CX516 enhances short-term memory in rats through a synaptic mechanism
      • Hampson RE
      • Rogers G
      • Lynch G
      • Deadwyler SA
      Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance.
      • Lauterborn JC
      • Lynch G
      • Vanderklish P
      • Arai A
      • Gall CM
      Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons.
      and is currently undergoing clinical evaluation for early AD and MCI.
      Cyclic adenosine monophosphate response element binding protein (CREB) has been linked with long- term memory formation in animals.
      • Yin JC
      • Tully T
      CREB and the formation of long-term memory.
      Indeed, blocking CREB expression blocks long-term memory formation,
      • Yin JC
      • Wallach JS
      • Del Vecchio M
      • et al.
      Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.
      whereas enhancing CREB expression potentiates long- term memory.
      • Yin JC
      • Del Vecchio M
      • Zhou H
      • Tully T
      CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila.
      These results suggest that agents that promote CREB expression may be promising for promoting long-term memory formation, even in normally aging individuals.
      Other products that are available as alternative medicines purport to enhance cognition in normally aging individuals. Huperzine A is a cholinergic agent available as a neutraceutical.
      • Cheng DH
      • Ren H
      • Tang XC
      Huperzine A, a novel promising acetylcholinesterase inhibitor.
      One recent clinical trial suggested that gingko biloba may be of benefit in patients with AD.
      • Le Bars PL
      • Katz MM
      • Berman N
      • Itil TM
      • Freedman AM
      • Schatzberg AF
      • North American EGb Study Group
      A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia.
      Phosphatidylserine has also been investigated as a treatment for AAMI with some benefit in clinical trials.
      • Crook TH
      • Tinklenberg J
      • Yesavage J
      • Petrie W
      • Nunzi MG
      • Massari DC
      Effects of phosphatidylserine in age-associated memory impairment.
      Several other strategies for improving cognition in patients with AAMI have also been investigated.
      • McEntee WJ
      • Larrabee GJ
      Age-associated memory impairment.
      Cholinesterase inhibitors, muscarinic agonists, nicotinic agonists, glutamate modulators, CREB activators, and alternative medicines are an exciting new group of therapeutics that may be useful in the future for the treatment of cognitive decline in individuals experiencing normal cognitive aging. However, these agents require further study for their use in normal aging and are either not available or not indicated for healthy individuals at this time.

      Protective Agents

      Neurotrophins

      Because various neuronal insults occur with normal aging, promoting the survival of neurons could be useful in preventing or treating normal cognitive aging. Neurotrophins such as BDNF and NGF are protein growth factors that control the survival, growth, or differentiation of neurons and other cells derived from neuroectoderm. Modulation of neutrophin activity may be approached by targeting local neurotrophin synthesis, neurotrophin receptors, or signal transduction pathways associated with neurotrophin activity.
      • Saragovi HU
      • Gehring K
      Development of pharmacological agents for targeting neurotrophins and their receptors.
      The purine derivative AIT-082 promotes NGF-induced neurite extension in cell culture by activating transcription of neu- rotrophic factors in regions of the brain associated with learning and memory.
      • Middlemiss PJ
      • Glasky AJ
      • Rathbone MP
      • Werstuik E
      • Hindley S
      • Gysbers J
      AIT-082, a unique purine derivative, enhances nerve growth factor mediated neurite outgrowth from PC12 cells.
      AIT-082 has also been shown to improve working memory in mice.
      • Glasky AJ
      • Melchior CL
      • Pirzadeh B
      • Heydari N
      • Ritzmann RF
      Effect of AIT-082, a purine analog, on working memory in normal and aged mice.
      This agent is currently in phase 2 clinical trials for AD. A second agent, CEP-1347, is a small molecule that rescues neurons from apoptosis. CEP-1347 has been shown to promote motor neuron survival.
      • Maroney AC
      • Glicksman MA
      • Basma AN
      • et al.
      Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway.

      Anti-inflammatory Agents

      There is no evidence that inflammation plays a role in normal cognitive aging. However, inflammation is recognized as an important component of the neuropathology of AD. Several epidemiologic studies
      • McGeer PL
      • McGeer E
      • Rogers J
      • Sibley J
      Anti-inflammatory drugs and Alzheimer disease [letter].
      have shown that patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) have a lower incidence of AD. Indeed, patients taking NSAIDs have only about a third of the activated microglia seen in other patients with senile plaques.
      • Mackenzie IR
      • Munoz DG
      Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging.
      In animal models using transgenic mice, amyloid deposition is suppressed by NSAIDs.
      • Lim GP
      • Yang F
      • Chu T
      • et al.
      Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease.
      A pharmacologic rationale exists for the use of aspirin to prevent cognitive impairment because aspirin may play a role in preventing strokes and, therefore, vascular dementia.
      • Stürmer T
      • Glynn RJ
      • Field TS
      • Taylor JO
      • Hennekens CH
      Aspirin use and cognitive function in the elderly.
      However, only limited data are available on the use of aspirin to prevent cognitive decline.
      • Stürmer T
      • Glynn RJ
      • Field TS
      • Taylor JO
      • Hennekens CH
      Aspirin use and cognitive function in the elderly.
      • Peacock JM
      • Folsom AR
      • Knopman DS
      • Mosley TH
      • Goff Jr, DC
      • Szklo M
      Association of nonsteroidal anti-inflammatory drugs and aspirin with cognitive performance in middle-aged adults.
      Studies testing the value of NSAIDs in the prevention of AD are currently in progress. A recent trial of the corticosteroid prednisone failed to show any effect in slowing the rate of progression of existing AD.
      • Aisen PS
      • Davis KL
      • Berg JD
      • et al.
      Alzheimer's Disease Cooperative Study. A randomized controlled trial of prednisone in Alzheimer's disease.
      At this time, anti-inflammatories should not be taken as a means to prevent cognitive aging or dementia.

      Antioxidants

      Oxidative stress is a rational target for slowing cognitive aging. However, to our knowledge, no studies of antioxidants in normal cognitive aging have been performed. One study showed that vitamin E in high doses (presumably required to achieve therapeutic levels within the brain) and selegiline, a monoamine oxidase inhibitor, both delayed time to institutionalization in patients with moderate AD.
      • Sano M
      • Ernesto C
      • Thomas RG
      • Alzheimer's Disease Cooperative Study
      • et al.
      A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease.
      Newer, more potent central nervous system-specific antioxidants are currently being investigated.
      • Pappolla MA
      • Chyan YJ
      • Poeggeler B
      • et al.
      An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease.
      • Bachurin S
      • Oxenkrug G
      • Lermontova N
      • et al.
      N-acetylserotonin, melatonin and their derivatives improve cognition and protect against beta-amyloid-induced neurotoxicity.

      Hormones

      Decreased estrogen levels after menopause have been associated with the cognitive decline that occurs in older women. Estrogen has both neurotrophic and neuroprotective effects.
      • McEwen BS
      Clinical review 108: the molecular and neuroanatomical basis for estrogen effects in the central nervous system.
      Animal studies
      • Wu X
      • Glinn MA
      • Ostrowski NL
      • et al.
      Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats.
      show a clear benefit of estrogen or selective estrogen receptor modulators on cognitive function. Estrogen stimulates formation of neurons in the dentate gyrus of the rat.
      • Tanapat P
      • Hastings NB
      • Reeves AJ
      • Gould E
      Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat.
      Some cross-sectional and longitudinal studies
      • Matthews K
      • Cauley J
      • Yaffe K
      • Zmuda JM
      Estrogen replacement therapy and cognitive decline in older community women.
      • Tang MX
      • Jacobs D
      • Stern Y
      • et al.
      Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease.
      • Yaffe K
      • Sawaya G
      • Lieberburg I
      • Grady D
      Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.
      • Mulnard RA
      • Cotman CW
      • Kawas C
      • Alzheimer's Disease Cooperative Study
      • et al.
      Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial.
      have shown that use of oral estrogen replacement therapy may protect against age-related decline in cognitive function and dementia in older women. The Women's Health Initiative Memory Study
      • Shumaker SA
      • Reboussin BA
      • Espeland MA
      • et al.
      The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia.
      is investigating the effects of estrogen on the prevention of dementia. Estrogen is also being considered for treatment of MCI
      • Sherwin BB
      Mild cognitive impairment: potential pharmacological treatment options.
      because it has other health benefits for the younger cohort of the aged population. Estrogen may improve subclinical cognitive changes in recently postmenopausal women.
      • Sherwin BB
      Sex hormones and psychological functioning in postmenopausal women.
      A recent trial failed to show efficacy of estrogen therapy for older women with existing AD.
      • Wang PN
      • Liao SQ
      • Liu RS
      • et al.
      Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study.
      Use of estrogen replacement therapy should be considered by the clinician in the context of overall patient risks and benefits. No recommendation can be made at this time on using estrogen to prevent or treat cognitive decline.
      Testosterone has been suggested to have some benefit in improving cognitive function in men. Men who are hypogonadal may have cognitive and emotional changes that respond to testosterone replacement.
      • Alexander GM
      • Swerdloff RS
      • Wang C
      • et al.
      Androgen-behavior correlations in hypogonadal men and eugonadal men, II: cognitive abilities.
      • Alexander GM
      • Swerdloff RS
      • Wang C
      • et al.
      Androgen-behavior correlations in hypogonadal men and eugonadal men, I: mood and response to auditory sexual stimuli.
      Ongoing trials are evaluating the possible risks and benefits of testosterone therapy for older men with cognitive decline and dementia.
      Several agents that have been historically marketed for general health benefits are now being touted for cognitive vitality. Dehydroepiandrosterone is a natural precursor of estrogen and testosterone that has been advertised as a supplement to boost memory and to cure many ills of aging. Melatonin, another over-the-counter substance, may have a mild hypnotic effect.
      • Brzezinski A
      Melatonin in humans.
      Melatonin levels may decrease with age, which may be associated with insomnia in some older people. Because lack of sleep is implicated in memory dysfunction, marketers are promoting melatonin to increase cognitive vitality. Human growth hormone levels also decline with age,
      • Rudman D
      • Feller AG
      • Nagraj HS
      • et al.
      Effects of human growth hormone in men over 60 years old.
      and cognitive benefits of treatment with human growth hormone have been proposed.
      More research is needed to evaluate these hormonal agents
      • Rowe JW
      • Kahn RL
      • Hermann M
      • Berger P
      Hormone replacement in the aging male?.
      because they are unproven therapies for preventing and treating cognitive decline. Until more clinical trial data are obtained, clinicians should not recommend these hormonal agents for the treatment of cognitive decline, particularly because these hormones may have serious adverse effects.

      CONCLUSION

      Cognitive vitality is essential to quality of life and survival in older persons. Research on cognitive aging indicates that cognitive decline is not an inevitable part of aging. Studies in animals have clearly shown considerable plasticity in the aging brain. Recent studies have identified several risk factors for cognitive decline that are modifiable, including lifestyle factors and medical comorbidities. These emerging scientific data have important implications for preventing and managing cognitive decline with aging. In addition, therapeutic strategies in development may contribute substantially to the practice of prevention and treatment of cognitive decline in older persons.
      Nevertheless, more research is clearly needed to advance our knowledge of the prevention and treatment of cognitive aging.
      Additional studies are needed to define the specific changes that occur with normal cognitive aging at the molecular, cellular, organ system, and individual levels. Research on biomarkers associated with cognitive impairment and advanced brain imaging techniques is also needed. Better animal models of cognitive aging must be developed for descriptive studies and the design of proof- of-concept prevention studies. Primary and secondary prevention trials for delaying cognitive aging in older persons, such as the ongoing cognitive aging studies within the Women's Health Initiative funded by the National Institute on Aging, are clearly needed. Further research is also needed with regard to behavioral interventions (such as cognitive training and physical exercise) that may promote cognitive vitality in older individuals.
      Health in aging is a key issue in the longevity revolution. However, most efforts to date with regard to healthy aging have focused on medical and physical functional aspects of health. Unfortunately, the maintenance of cognitive health has not been a primary public policy issue. Perhaps, given the emerging data described herein, policy initiatives can now begin to advance the goal of achieving and maintaining cognitive vitality. Recent research on the effect of lifestyle factors and medical comorbidities on cognitive vitality could become the basis for population- based programs to increase awareness among the general population and among clinicians about the real potential to achieve cognitive vitality in old age. In the future, with continuing research and better clinical care, we may expect that, for an increasing percentage of aging individuals, it is possible to set the goal that cognitive function might change little, if at all, from its level in middle age.
      Cognitive vitality is crucial to optimal aging. This has been known for thousands of years. In the words of Marcus Tullius Cicero (106-43 bce), “To live is to think.” Although we still have much to learn, data are now beginning to form the scientific basis for achieving and maintaining cognitive vitality in late life through primary and secondary prevention in clinical practice.

      Acknowledgments

      We thank Dennis Evans, MD, Neil Buckholz, PhD, and Marcelle Morrison-Bogorad, PhD, for their participation and contributions to this work. We are also grateful to Tonya Lee, Nora O'Brien, MA, and Sue Reynolds-Foley, MHA, for their invaluable help.

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