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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Ann N Y Acad Sci. Author manuscript; available in PMC Jun 2, 2011.
Published in final edited form as:
PMCID: PMC3107251
NIHMSID: NIHMS294530
Therapeutics for cognitive aging
Diana W. Shineman,1 Timothy A. Salthouse,2 Lenore J. Launer,3 Patrick R. Hof,4 George Bartzokis,5 Robin Kleiman,6 Victoria Luine,7 Jerry J. Buccafusco,8 Gary W. Small,5 Paul S. Aisen,9 David A. Lowe,10 and Howard M. Fillit1
1The Alzheimer’s Drug Discovery Foundation, New York, New York
2Department of Psychology, University of Virginia, Charlottesville, Virginia
3Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland
4Department of Neurology, Mount Sinai School of Medicine, New York, New York
5Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California
6Pfizer Global Research and Development, Groton, Connecticut
7Department of Psychology, Hunter College, New York, New York
8Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia
9Department of Neurosciences, University of California San Diego, La Jolla, California
10Memory Pharmaceutical Corporation, Montvale, New Jersey
Address for correspondence: Howard M. Fillit, Alzheimer’s Drug Discovery Foundation, 1414 Avenue of the Americas, Suite 1502, New York, NY 10019. hfillit/at/alzdiscovery.org
Abstract
This review summarizes the scientific talks presented at the conference “Therapeutics for Cognitive Aging,” hosted by the New York Academy of Sciences and the Alzheimer’s Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people—approximately 200 in all—the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.
One of the difficulties in developing therapies for cognitive aging is that the syndrome is not well defined clinically, pathologically, or mechanistically. While some consider cognitive aging to be a prodromal phase to dementia or Alzheimer’s disease (AD), others consider it a separate clinical syndrome. Cognitive aging can significantly affect productivity and quality of life, and while effective symptomatic or preventative treatments could provide many benefits to individuals and society, defining and differentiating the syndrome of cognitive aging from “normal” and “diseased” is a crucial first step.
It is becoming clear that many of the same neural network abnormalities found in AD (as discussed below) may be functionally impaired in cognitive aging; this fact supports the hypothesis that cognitive aging may be a prodromal phase to AD. On the other hand, many individuals exhibit symptoms of cognitive aging and never go on to develop AD. It is clear that individual differences in many factors (e.g., diet, lifestyle, stress, genetic factors) can play a major role in the aging process, adding to the complexity of distinguishing between normal cognitive aging and cognitive decline as a prodromal phase to AD.1 Understanding this complexity better may allow researchers to develop drugs that both boost cognitive performance and influence the underlying mechanisms that lead to cognitive dysfunction. In this report, cognitive aging will be defined, mechanisms explored, and potential therapeutic avenues investigated to begin to develop a consensus on this complicated disorder.
There are some common assumptions about cognitive aging: that it only begins in late life; that it is primarily confined to memory abilities; that the effects are very small; and that only some people are affected. But a great deal of data suggests that these assumptions may be false, or at least only partially correct.2,3 For example, there are several reasons why studies have not reported greater consequences of age-related cognitive decline. Among these are large differences among individuals at every age; people seldom need to perform at their maximum in activities outside the laboratory; cognitive functioning is only one factor affecting ability in most activities; and experience and knowledge are also important in most situations. In fact, the influence of these (and other such) factors is largely minimized in most laboratory assessments of cognitive abilities.
Another important issue here is that the differences between normal cognitive aging and pathological conditions, such as dementia, are not well known. But because the changes associated with normal aging begin relatively early in life, are gradual, and tend to allow for continuing high levels of functioning compared to the steep declines in functioning characteristic of dementia, it is often assumed that normal cognitive aging is clinically and qualitatively distinct from the cognitive impairment associated with dementia.
When considering interventions for age-related cognitive decline, it is important to consider an individual’s age at which detectable decline begins and therefore when preventative interventions should begin. Because the negative cognitive consequences of dementing pathologic changes are generally only detectable at late age, it has often been accepted that late age is the time to begin intervention. However, many studies, including those discussed at the “Therapeutics for Cognitive Aging” conference (see Appendix below), suggest that some cognitive functions begin to decline in middle age or even earlier. Thus one could conclude that middle age is in fact the right time for intervention, and that specific focus should be made on areas dealing with lifestyle choice and chronic disease prevention.4 Such intervention encompasses the field of preventive gerontology.
There is now increasing evidence that high numbers of early- and mid-life risk factors may initiate or promote cognitive decline. Such decline may take a long time to present clinically, but it is important to recognize that subclinical changes like metabolic alterations, chronic inflammation, and oxidative stress may also lead to behavioral changes, which can include reduced physical activity, dietary changes, and more social isolation later in life. The implications of this are that while the risk factors identified when cognitive decline is detectable may reflect causation (i.e., a given risk factor actually is the cause of the decline), cognitive decline may in fact be a response to subclinical alterations—a phenomenon known as reverse causality.
Several risk factors measured in mid-life have been studied in relation to late-age cognitive impairment. It has been reported, for example, that mid-life smoking and high body mass index (BMI) increases the risk for late-life cognitive problems; physical activity may decrease risk, but data on diet are conflicting. In addition, data from the Honolulu-Asia Aging Study, and others, suggest chronic cardiovascular disease, including peripheral artery disease, stroke, diabetes, and hypertension may also increase the risk for cognitive decline. These data suggest that intervention in mid-life may help prevent cognitive problems in late-life.5 They also suggest the possibility of developing effective interventions even earlier than mid-life.
The contributions of sex, hormones, and life experiences bring diversity to the aging process. The hormones discussed in particular at the “Therapeutics for Cognitive Aging” conference included gonadal hormones (estradiol in females and testosterone in males) and those released from the adrenal gland during stress (e.g., glucocorticoids). Studies on learning and memory in rats have shown that age-related memory losses are not identical in males and females,6 and some mechanisms by which hormones alter cognition, and even the aging process itself, may differ in the sexes.7
Chronic stress is also known to differentially affect cognitive function; for example, stress regimens that impair male rat cognitive function are associated with enhancements in some cognitive tasks in female rats;8 and responses to stress change in a sex-dependent fashion during aging.9 In addition, it is becoming increasingly evident that life history can alter hormone and drug responsiveness, as well as the aging process; for example, female rats that have had multiple pregnancies and bouts of rearing have a greater resilience to stress, decreased anxiety, and better memory abilities than female rats that have never experienced motherhood.10 Thus, the sensitivity to both hormones and drugs may differ depending on age and sex.
To summarize the issues presented in this part of the conference: neuroendocrinological factors—including sex, age, and life history—may be critical for drug discovery in aging and neurodegenerative disease. Aging research should thus be conducted in both sexes; responses should be documented in both young and aged subjects; and the life history of subjects, such as incidence of stress and reproductive activity, should be taken into account in testing.
Brain aging is becoming a critically important issue to consider as human longevity increases, because aging is a key risk factor for several neurodegenerative diseases, particularly AD. To understand the underlying pathogenesis of cognitive decline with aging and distinguish those changes associated with aging from those associated with dementia, it is important to identify the morphologic, age-related changes that occur in the brain. Age-related neuronal dysfunction involves many subtle changes within various brain regions. These changes include alterations in receptors, loss of dendrites and spines, and myelin dystrophy, as well as alterations in synaptic transmission. Pathological processes such as the abnormal aggregation of specific proteins are seen in many neurodegenerative diseases. Together, these multiple factors likely constitute the substrate for age-related loss of cognitive function.1113
To assess these age-related changes in cortical cellular integrity, stereological analyses were performed on a subset of pyramidal neurons known to be vulnerable in AD and characterized by high somatodendritic levels of unphosphorylated neurofilament protein.14,15 In the neocortex these large pyramidal neurons reside in layers III and V and form long corticocortical association pathways. A comparison of prefrontal cortex area 9 in elderly individuals (controls) and individuals with different degrees of cognitive dysfunction demonstrated that large pyramidal neurons decrease dramatically in cases of definite dementia, correlating strongly with the severity of cognitive dysfunction, to a nearly complete loss (> 90%) in the end stages of AD. Furthermore, these neurons are far more likely to develop neurofibrillary tangles (NFT) and do so at a faster rate than other pyramidal cells; they also shrink considerably during NFT formation, and the largest among them are preferentially affected. Thus, these unphosphorylated neurofilament, protein-enriched neurons (the large pyramidal neurons) emerge as a strikingly vulnerable subpopulation of neurons that provide specific corticocortical connections between association areas.16,17
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in AD. For example, assessed by immunoreactivity for the spine marker spinophilin, numbers of spines in the CA1 and CA3 fields of the hippocampus and area 9 are decreased in elderly individuals with various degrees of cognitive decline; reduced immunoreactivity was significantly related to both NFT staging and clinical severity. In addition, the total number of spines in the CA1 field and area 9 were predictive of variability in cognitive scores, and those in area 9 in particular significantly related to the cognitive outcome of the cases. These data suggest that neocortical dendritic spine loss is an independent parameter to consider in clinicopathologic correlations.18
Importantly, whereas neuronal loss in normal aging has not been demonstrated, alterations in the perforant path—which projects from the layer II neurons of the entorhinal cortex to the outer molecular layer of the dentate gyrus and is critically involved in learning and memory formation—was observed in a macaque monkey model. Expression of N-methyl-d-aspartate receptor subunit 1 (NR1) was significantly decreased in the outer molecular layer of aged macaque monkeys, while no differences in the number of layer II neurons were found.13,19 These results suggest that the circuit-specific decrease in NR1 expression occurs in the absence of structural deficits of the perforant path and is due to age-dependent changes in the functional properties of this circuit.
There were also age-related morphologic alterations in pyramidal neurons that contribute to working memory circuits in the macaque monkey superior temporal cortex and that form “long” projections to the prefrontal cortex. Global dendritic mass homeostasis, assessed by three-dimensional scaling analysis, was conserved with aging in these neurons. Spine densities, dendrite diameters, dendritic lengths, and branching complexity were all significantly reduced in their apical dendrites.20,21 The passive electrotonic structure in apical dendrites of the projection neurons was significantly reduced in aged monkeys and simulated, passive back-propagating action potential efficacy was significantly higher in the apical dendrites of old neurons. These effects, in turn, increase the excitability of pyramidal neurons in aging, thus compromising the precisely tuned activity required for working memory, and ultimately result in age-related cognitive dysfunction.
In summary, while a modest disruption of memory occurs frequently in normal aging in humans and in animal models, significant neuron death does not appear to be the cause of such age-related memory deficits. Evidence from rodent and nonhuman primate models reveals that the same hippocampal and cortical circuits affected in AD exhibit subtle age-related changes in neurochemical phenotype, dendritic and spine morphology, and synaptic integrity that correlate with impaired function. Molecular alterations of synapses, such as shifts in expression of excitatory receptors, also contribute to these deficits. As such, integrity of spines and synapses may reflect age-related memory decline, whereas the loss of select cortical circuits seems to be a crucial event for functional decline in AD. Likewise, these cortical components provide important targets for the development of preventive and protective therapeutic strategies.
Brain aging and the aging-related processes of myelin production, as well as subsequent maintenance, breakdown, and repair, are relevant to understanding the relationships between human brain development and age-related brain disorders like AD. The myelin model of the human brain incorporates the known physiological roles of gene products involved in familial AD (FAD) and late onset AD (LOAD) into a unifying pathophysiology of human brain aging and the various trajectories of decline of its circuitry into highly prevalent dementing disorders.22 This model proposes that at its earliest stages, highly prevalent diseases such as AD are rooted in an age-related increase in myelotoxicity that is, in part, driven by the extensive human brain myelination process itself, which, among other changes, results in increased cholesterol and iron levels.
The model proposes that the recently evolved extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as AD. The model focuses on the roles of oligodendrocytes and the myelin they produce as critical for brain function and uniquely vulnerable to damage; it posits that brain aging is an increasingly ineffective attempt by the body to “keep up” with the metabolically demanding repair of the vast new expanses of myelin on which human brain function depends. Within this framework, the genetic risks for FAD and LOAD influence myelin repair ability and therefore the age at onset of clinical symptoms, while pathologic markers of AD (Aβ and tau deposits, as well as synapse, axonal, and neuronal loss) are viewed as byproducts of the continual homeostaticmyelin repair process rather than direct causes of AD (reviewed in Ref. 22).
More than twenty years can elapse between the onset of brain changes suggestive of Alzheimer’s disease as manifested by the appearance of the first amyloid and tau deposits (reviewed in Ref. 23), appreciable neuronal loss, and clinical cognitive changes.24 The myelin model helps develop hypothesis-driven “roadmaps” of novel myelin-centered approaches to treatment interventions. Imaging biomarker technology has emerged that is safe, repeatable, widely available, and capable of tracking the dynamic changes in brain myelin, as well as associated changes in iron levels, over age span.25,26 This technology makes it possible to test the model in human beings25,27,28 and may accelerate medication development by identifying high-risk individuals26 and tracking treatment effects; 27 this provides the opportunity to begin treatments earlier, possibly even before differentiation from the healthiest brain aging of apolipoprotein E2 allele carriers.29,30 Myelin-centered interventions with relatively benign side-effect profiles may already be available. With early initiation, such interventions could, potentially, substantially reduce the increasingly catastrophic burden of dementia.22
Technological advances have led to several strategies for measuring the biological manifestations of cognitive aging.31,32 Structural imaging, particularly magnetic resonance imaging of regional atrophy, can identity people with mild symptoms that are likely to progress. Such functional methods as positron emission tomography (PET) scanning of glucose metabolism can also demonstrate regional declines that predict subsequent neurodegeneration. New neuroimaging methods under development can measure specific neurotransmitter systems, amyloid plaque and tau tangle concentrations, and neuronal integrity and connectivity. Measures of amyloid-β, tau, and other markers in cerebrospinal fluid and serum have been useful in identifying and tracking patients with varying degrees of cognitive aging.
New biomarker development has focused on small molecule probes that image amyloid plaques and tau tangles. For example, 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl} ethylidene) malononitrile ([18F]FDDNP) has been used to study symptomatic and asymptomatic carriers of PRNP gene mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology.33 In vivo accumulation of [18F]FDDNP in subcortical structures, neocortices, and cerebellum was found that is closely related to the distribution of prion protein pathology. The cortical pattern profile of regional FDDNP binding to β-amyloid and neurofibrillary tangles has also been quantitatively assessed on MR-derived cortical maps.34 These studies have shown that correcting for head movement and partial volume effects, as well as optimizing kernel size, provides sensitive statistical analysis of FDDNP distributions that confirm in the living brain known pathological patterns observed in cognitive decline postmortem.
Such brain imaging biomarkers also demonstrate associations with biomarkers from other tissue, such as cerebral spinal fluid (CSF). Tolboom and associates studied [18F]FDDNP, [11C]Pittsburgh compound B ([11C]PiB), and CSF measurements of β-amyloid-1–42 (Aβ1–42) and total tau.35 For both global [11C]PiB and [18F]FDDNP binding, significant correlations with CSF levels of Aβ1–42 (r = −0.72 and −0.37, respectively) and tau (r = 0.58 and 0.56, respectively) were found. There also was a positive association between global [18F]FDDNP binding and tau CSF levels (standardized β = 0.62, P < 0.01).
The utility of these approaches, however, depends upon the relevant biomarker not only tracking disease progression but also indicating responses to treatment. Successful co-development of such biomarkers and prevention treatments may eventually lead to a combination of tests or “biosignatures” that determine the risk for rapid cognitive aging, and which might be used to monitor disease-modifying medications, vaccines, or other interventions designed to reduce the risk of future cognitive losses and delay onset of disease. While these biomarkers have demonstrated utility for AD, it is yet to be determined if they will be relevant and, if so, sensitive enough to detect cognitive aging changes.
Cognitive function declines from middle age onwards to the extent that certain aspects of cognition are measurably impaired relative to function in young adults. While a large number of potential drug targets exist in the field of cognition pharmacology, there presently is no consensus as to what constitutes the most important or relevant one. The neurotransmitter acetylcholine has featured importantly in AD and in the associated cognitive impairment; three of the four drugs currently approved for the treatment of AD (donepezil, rivastigmine, and galantamine) inhibit acetylcholinesterase as their primary mechanism of action. However, many other neurotransmitter substances and their receptors are involved in cognition, reflecting the complexity of cognitive processes.
Positive allosteric modulators—compounds that facilitate endogenous neurotransmission without directly stimulating the target receptors—have been known for several years. Other than the benzodiazepine class of drugs, very few such compounds have been characterized in vivo. Though still in late-stage preclinical evaluation, the choline analogue JWB1-84-1 is showing promise as a cognition-enhancing drug in monkeys.36,37 This compound improved delayed matching accuracies in animals and reversed attention deficits induced by the introduction of distracter trials; JWB1-84-1 also was shown to be neuroprotective in several in vitro assays.38 Originally designed in a series for activation of the α-7 subtype of nicotinic receptors, JWB1-84-1, rather than activating nicotinic receptors, was shown to potently desensitize the receptor in subsequent studies,36 and its capacity to do so correlated with cognitive performance improvement in monkeys. If nicotinic receptor desensitization proves to be a valid drug mechanism to ameliorate cognitive disorders, further subtype selectivity could be achieved as more knowledge is gained regarding the sites of receptor interaction for these compounds.
Age-related changes in the primate prefrontal cortex (PFC) include the documented loss of synapses,20,39,40 changes in the brain transcriptional profile,41,42 and the cognitive disruption of top– down modulation deficits in inhibitory control.43 Transcriptional profiling of the aging frontal cortex from control humans has demonstrated significant alterations in gene expression after the age of 73.41 Among the changes observed are profound down-regulation of genes associated with synaptic transmission, vesicular transport, and signaling cascades implicated in plasticity, and increases in genes related to repair and inflammation, suggesting a setting that is not conducive to activity-dependent plasticity.42 Some of the most profound changes in gene expression are down-regulation of genes related to GABA neurotransmission, in both human and nonhuman primate samples of PFC.42 Additional analysis of transcriptional profiles collected from the aging brain across six different brain regions (Brodmann areas 10 and 46, hippocampus, temporal neocortex, caudate, and putamen) within the Gene Logic commercial data, using gene set enrichment analysis (GSEA) and GO categories, identified significant down-regulation of genes belonging to cyclic nucleotide signaling and phosphodiesterase categories (unpublished data, Pfizer). Similar analysis of the data set using Ingenuity® pathway analysis tools yielded significant effects on canonical pathways associated with synaptic long-term potentiation across multiple brain regions. Thus, in both analyses there is evidence of dysfunction within pathways associated with plasticity and cyclic nucleotide regulation across multiple brain regions.
Expressed by a family of 21 genes, the phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic nucleotides; they are distinguished from each other by specific expression patterns, subcellular compartmentalization, enzymatic regulation, and substrate affinities, providing the cells in which they are expressed (namely neurons) with precise ways to “sculpt” the spatial and temporal dynamics required for cyclic nucleotide signaling. Therapeutic inhibition of specific members of this gene family may provide a mechanism to restore dysfunctional cyclic nucleotide signaling in disease and aging and to bring cognitive benefit.
Pfizer’s neuroscience research unit has developed potent, selective, and brain penetrant inhibitors of the PDE9 enzyme to treat cognitive dysfunction associated with Alzheimer’s disease. PDE9 is a high-affinity cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase with widespread expression throughout the rodent and primate brain. Inhibitors of PDE9 produce large increases in cGMP in the brain and enhance activity-dependent forms of synaptic plasticity and episodic memory tasks. Evaluation of PDE9 inhibitors in appropriate primate models of age-related cognitive deficits will be an important future direction to determine the potential therapeutic utility in treating cognitive aging.
The symptoms of cognitive aging are problematic for most individuals beyond middle age: if such symptoms could be treated effectively and safely, many individuals might avail themselves of therapeutic intervention. Unfortunately, at present, there is no clear regulatory pathway for developing drugs that specifically target brain aging symptoms and disease (reviewed in Ref. 44). In general, the FDA requires that drugs demonstrate a sufficient beneficial effect on the primary symptoms of a disease to be considered clinically important. Even if cognitive aging were considered to be a treatable disorder, it would be challenging to meet this requirement. There is no consensus regarding the measurement of manifestations of cognitive aging, and it remains uncertain whether such measurement can achieve adequate precision. Since many experts consider the cognitive symptoms of aging to be at worst bothersome but not disabling, it is unclear how the requirement for clinically important benefit might be established. To change this view, the societal and personal consequences of cognitive aging need to be better quantified and openly discussed. These issues are particularly critical since the entire aging population might be targeted for treatment.
Much attention is being given by the pharmaceutical industry to AD, its prodromal phase often referred to as “mild cognitive impairment”, as well as to other forms of dementia, such as vascular dementia and tauopathies. This heightened attention is the result of increasing social and economic impact of these conditions; it also partly stems from the expectation of a reasonable return on the large research investments required to develop therapies. The age-related nature of these conditions, together with the general increase in human longevity,45,46 means that the attention of the pharmaceutical industry will likely be maintained, with the search not only for drugs that bring symptomatic relief but for more fundamental disease-modifying agents that offer real cures. Advances in basic science, particularly in the molecular mechanisms underlying these conditions, should lead to better treatments, more early diagnosis, and “personalized” medicine. The discovery of new drugs often starts with the identification of molecular targets, and then screening and optimization of active compounds that are tested for efficacy and acceptable safety profiles in animal models. Fortunately, powerful modern technologies are available at all stages of this process; as are other important advances such as the use of translational medicine protocols like electroencephalography (EEG), functional imaging, and cognition batteries (i.e., a group of specialized cognitive tests), all of which can be mobilized to prioritize and potentially accelerate the drug development process.
By contrast, industry has paid relatively little attention to other forms of cognitive decline that occur in “natural” aging, despite the documentation of this phenomenon by experimental psychology. This is partly due to the difficulty of dealing with potentially complex subgroups based on clinical diagnoses; the diverse nomenclature, such as age-related memory impairment (ARMI) and age-related cognitive decline (ARCD); the lack of certainty of common molecular etiologies, with the associated uncertainty that drugs addressing a specific mechanism of action will be applicable to a sufficiently broad population; the potential for off-label “cosmetic neurology” with cognition-enhancing drugs;47 and, finally, the perception that clinical trials will be difficult in this area. The lack of clearly defined regulatory paths for drug approval and label registration is also regarded as a major impediment to making the large research and development investments needed.
Despite these concerns, treatments for cognitive decline associated with natural aging are, and should remain, an attainable goal. Numerous molecular targets already exist, building on both the synaptic and intracellular pathways found to be involved in long-term potentiation (e.g., cAMP and CREB phosphorylation). A plethora of relevant new “systems” areas are emerging from studies of brain aging, including mitochondrial dysfunction, brain energetics, dendritic tree complexity, epigenetics, neurogenesis, neurotrophins, neurosteroids, and choroid plexus function. Parallel exciting developments at the molecular level include the role of prion-like cytoplasmic poly(A) element-binding protein (CPEB) in translating proteins involved in long-term potentiation;48 and the role of KIBRA,49 a WW domain–containing protein that is a substrate for protein kinase Cζ and which interacts with the postsynaptic protein dendrin and other proteins involved in synaptic plasticity.50 As illustrated at the “Therapeutics for Cognitive Aging” meeting, animal models of cognitive aging also exist for testing drug action, and interesting cognition targets such as nicotinic receptor agonists, phoshodiesterase inhibitors, and 5HT6 receptors are in preclinical and clinical trials. In addition, such translational tools as quantitative EEG and cognition batteries are available for longitudinal study in rodents, nonhuman primates, and humans, and all are being used to study normal cognitive aging. Many of the molecular targets discussed at the meeting may have relevance for drugs addressing cognitive deficits associated with other central nervous system disorders, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia, for which a regulatory pathway exists. Following marketing approval, off-label use of such “multi-optionality” drugs in ARMI/ARCD, perhaps through internet-based supply chains, may become a trend, depending on market appetite.
The Alzheimer’s Drug Discovery Foundation is dedicated to the mission of accelerating drug discovery, not only for AD and related dementias but also for cognitive aging. Better quantification of the societal and individual impact of cognitive aging, along with a consensus of terminology in the field, will help drive interest and the regulatory changes needed to develop therapeutics. Further research into the relationship of cognitive aging to Alzheimer’s disease and other dementias will also help determine whether intervention at early stages can prevent the onset of these devastating diseases.
While there are many hurdles to overcome in defining and differentiating cognitive aging as an independent clinical and pathological entity from Alzheimer’s and related dementias, progress has been made. As summarized in this conference review, the neuroanatomical and mechanistic alterations that underlie cognitive changes with aging, in some instances related to the pathology seen in neurodegenerative diseases, are definitely distinct. We currently do not know whether the changes that occur in the brain with cognitive aging are the beginnings of a continuum that sometimes ends in dementia or whether additional insults are needed to trigger the disease process. A better understanding of this relationship will hopefully open up new avenues for therapy.
Acknowledgments
The Alzheimer’s Drug Discovery Foundation and the New York Academy of Sciences would like to acknowledge the corporate sponsor of the “Therapeutics for Cognitive Aging” conference, Accera, as well as the conference media partners: the Alzheimer’s Research Forum, NψSPA, the Academy of Cognitive Therapy, and the Cognitive Neuroscience Society.
Appendix
“Therapeutics for Cognitive Aging”
  • Friday, May 15, 2009
    8:30 am–5:30 pm
    The New York Academy of Sciences
    7 World Trade Center (40th Floor)
    250 Greenwich Street
    New York, New York
    Organizer: Howard M. Fillit, MD, Executive Director, Alzheimer’s Drug Discovery Foundation
FRIDAY, MAY 15, 2009
7:45–8:30 amRegistration and Continental Breakfast
8:30–8:45Welcome and Opening Remarks
Howard M. Fillit, MD, Symposium Moderator
Executive Director, Alzheimer’s Drug Discovery Foundation
I. Defining Cognitive Aging
8:45–9:10What is Cognitive Aging?
Timothy A. Salthouse, PhD, University of Virginia
9:10–9:35Syndromal View: Day-to-Day Functional and Practical Implications of Cognitive Aging
Steven H. Ferris, PhD, New York University School of Medicine
9:35–10:00Medical Co-morbidities and Lifestyle Risks for Cognitive Decline with Aging
Lenore J. Launer, PhD, National Institute on Aging
10:00–10:30Panel Discussion
10:30–11:00Refreshment Break
II. Neurobiology of Cognitive Aging
11:00–11:25Anatomy and Pathology of the Aging Brain
Patrick R. Hof, MD, Mount Sinai School of Medicine
11:25–11:50Myelin and Processing Speed with Aging
George Bartzokis, MD, University of California, Los Angeles
11:50–12:15 pmPhosphodiesterase Inhibitors as a Mechanism for Enhancing Synaptic Plasticity
Robin J. Kleiman, PhD, Pfizer, Inc, Pfizer Global
Research and Development
12:15–12:40Neurochemical and Neuroendocrine Changes with Aging
Victoria N. Luine, PhD, Hunter College
12:40–1:10Panel Discussion
1:10–2:15Lunch
III. Therapeutics
2:15–2:40Novel Therapeutics for Cognitive Aging
Jerry J. Buccafusco, PhD, Medical College of Georgia
2:40–3:05Biomarkers of Cognitive Aging
Gary W. Small, MD, University of California, Los Angeles
3:05–3:30Clinical Trial Design for Cognitive Aging Therapeutics
Paul S. Aisen, MD, University of California, San Diego
3:30–4:00Refreshment Break
4:00–4:25Industry Perspective on Cognitive Aging Therapeutics
David Lowe, PhD, Memory Pharmaceuticals Corp.
4:25–4:50Cognition Enhancing Drugs: A Regulatory Perspective
Allan M. Green, MD, PhD, JD, Allan M. Green Esq., LLC
4:50–5:20Panel Discussion
5:20–5:30Closing Remarks
Howard M. Fillit, MD, Executive Director,
Alzheimer’s Drug Discovery Foundation
Footnotes
Conflicts of interest
The authors declare no conflicts of interest.
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