Ayurvedic medicinal plants for Alzheimer's disease: a review

Alzheimer's disease is an age-associated, irreversible, progressive neurodegenerative disease that is characterized by severe memory loss, unusual behavior, personality changes, and a decline in cognitive function. No cure for Alzheimer's exists, and the drugs currently available to treat the disease have limited effectiveness. It is believed that therapeutic intervention that could postpone the onset or progression of Alzheimer's disease would dramatically reduce the number of cases in the next 50 years. Ayurvedic medicinal plants have been the single most productive source of leads for the development of drugs, and over a hundred new products are already in clinical development. Indeed, several scientific studies have described the use of various Ayurvedic medicinal plants and their constituents for treatment of Alzheimer's disease. Although the exact mechanism of their action is still not clear, phytochemical studies of the different parts of the plants have shown the presence of many valuable compounds, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects. This review gathers research on various medicinal plants that have shown promise in reversing the Alzheimer's disease pathology. The report summarizes information concerning the phytochemistry, biological, and cellular activities and clinical applications of these various plants in order to provide sufficient baseline information that could be used in drug discovery campaigns and development process, thereby providing new functional leads for Alzheimer's disease.

surgical procedures for the treatment of various ailments. An entire body of literature in the Ayurvedic texts deals with the nervous system and disorders associated with it. Nervous system disorders, called 'VataVyadhi' in Sanskrit, were thought to be brought on by imbalances of Vata, the biological air humor, the energy that moves through the brain and the nerves (the ancients considered nerve impulses to be a kind of wind or air traveling through the body) controlling both voluntary and involuntary functions. Hence, Vata derangements always involve some weakness, disturbance, or hypersensitivity of the nervous system. Included in these texts are direct references to age-associated memory loss, preventive care, and therapeutic interventions. Th ese texts explain the use of several herbs and their qualities and energetics for nervous system disorders, including memory loss typically seen in older adults, but only recently have there been mechanistic studies on the role of these herbs in nervous system disorders and dementias, including dementia associated with AD [8]. Indeed, several scientifi c studies have described the use of various Ayurvedic medicinal plants termed 'nervines' and their constituents to strengthen the functional activity of the nervous system and restoration of memory [8,9]. Phytochemical studies have shown the presence of many valuable compounds, such as lignans, fl avonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-infl ammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant eff ects [5][6][7][8]10].
Th e present review puts together research on various Ayurvedic medicinal plants that have shown promise in reversing the AD pathology. Th e report summarizes information concerning the phytochemical, biological, and cellular activities and clinical applications of these various plants in order to provide suffi cient baseline information that could be used in drug discovery campaigns and development processes, thereby provid ing new functional leads for AD. Below we describe the various Ayurvedic medicinal nervine herbs that are recom mended for AD and their actions on the brain.

Ashwagandha (Withania somnifera)
Ashwagandha is used extensively in Ayurveda as a nervine tonic, aphrodisiac, and 'adaptogen' and helps the body adapt to stress [9,11]. Ashwagandha is a member of the nightshade (Solanaceae) family, and the root is the part that is widely used. It is categorized as a rasayana (rejuvenative) and is believed to possess antioxidant activity, free radical scavenging activity, and an ability to support a healthy immune system [12]. Unlike other adaptogens, which tend to be stimulating, Ashwagandha has a calming eff ect and thus may be particularly indicated in people with AD [13]. A total alkaloid extract of Ashwagandha root exhibited a calming eff ect on the central nervous system (CNS) in several mammalian species, suggesting the use of this herb to produce relaxation. A recent double-blind, randomized, placebocontrolled study of the eff ects of Ashwagandha on stress found that it reduced symptoms of stress and inability to concentrate and reversed forgetfulness in a dose-dependent manner, and 500 mg/day was more eff ective [14]. No additional adverse eff ects were found.
Ashwagandha contains steroidal compounds of great interest to researchers, such as the ergostane-type steroidal lactones, including withanolides A to Y, dehydro withanolide R, withasomniferin A, withasomidienone, withasomniferols A to C, withaferin A, and withanone. Other constituents include the phytosterols sitoindosides VII to X and beta-sitosterol as well as alkaloids (for example, ashwagandhine, cuscohygrine, tropine, pseudotropine, isopelletierine, and anaferine), a variety of amino acids (including tryptophan), and high amounts of iron [9,15]. A subset of these components (withanamides) has been shown to scavenge free radicals generated during the initiation and progression of AD. Neuronal cell death triggered by amyloid plaques was also blocked by withanamides [13,[16][17][18]. Molecular modeling studies showed that withanamides A and C uniquely bind to the active motif of beta-amyloid (Aβ 25-35) and prevent fi bril formation [17,19]. In the CNS, Ashwagandha has been reported to increase memory and learning [20]. Aqueous extracts of this herb have been found to increase cholinergic activity, including increases in the acetylcholine content and cholineacetyl transferase activity in rats and this might partly explain the cognition-enhancing and memory-improving eff ects [21,22]. In addition, recent reports have provided exciting information on the ability of this herb to stimulate neurite outgrowth [23]. Treatment with the methanol extract of Ashwagandha caused neurite outgrowth in a dose-and time-dependent manner in human neuroblastoma cells [21,24]. Th e levels of two dendritic markers, MAP2 and PSD-95, were found to be markedly increased in cells treated with Ashwagandha, suggesting that it stimulates dendrite formation [21,24]. In an extension of the above study, the same research group treated cultured rat cortical neurons with amyloid peptide that induced axonal and dendritic atrophy and loss of pre-and postsynaptic stimuli. Subsequent treatment with a methanol extract of Ashwagandha induced signifi cant regeneration of both axons and dendrites. In addition to the reconstruction of pre-and postsynapses in the neurons, methanol extracts of Ashwagandha reversed amyloid peptide-induced memory defi cit in mice [24]. Th ese in vivo eff ects of Ashwagandha were maintained even after the discontinuance of the drug administration. Similarly, preliminary studies from this laboratory revealed signifi cant neurogenesis in the dentate gyrus region only in J20 mice -mice that express the mutant form of human amyloid precursor protein (APP) bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations -that were fed a diet containing the whole herb (Ashwagandha root powder, 2.5 g/kg body weight) in comparison with J20 mice that received only normal chow (unpublished data). Although the data mentioned above are quite promising for the use of Ashwagandha as an anti-AD agent, additional clinical trials need to be conducted to support its therapeutic use. While the herb has been used successfully in Ayurvedic medicine for centuries, a systematic study of the acute or chronic toxicity of this herb or its various components is still lacking and additional studies are warranted to confi rm the therapeutic signifi cance of this herb [9].

Note added in proof
While the manuscript of this review was in the review process, Sehgal et al. (Proc Natl Acad Sci U S A 2012, 109:3510-3515) reported that oral administration of a semipurifi ed extract of the Ashwag andha (W. somnifera) root reversed behavioral defi cits, plaque load, and accumulation of beta-amyloid peptides in mouse models of AD. Th is therapeutic eff ect of W. somnifera was mediated through upregulation of liver low-density lipoprotein (LDL) receptor-related protein (LRP).

Turmeric (Curcuma longa)
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. Derived from the rhizome and root, turmeric is used as a spice and coloring agent and in traditional medicine in Asia. Th e active constituents are thought to be turmerone oil and watersoluble curcuminoids, including curcumin [25]. Curcumin is the principal curcuminoid and is responsible for the yellow color of the turmeric root [25-27]. Turmeric is anti-infl ammatory, antiseptic, and antibacterial and has long been used in the Indian system of medicine to treat a variety of conditions. Th is versatile spice helps detoxify the liver, balance cholesterol levels, fi ght allergies, stimulate digestion, and boost immunity [28]. Epidemiologic studies show a 4.4-fold lower incidence of AD in Southeast Asian countries where turmeric is commonly used as a dietary spice [29]. Other studies indicate that the non-steroidal anti-infl ammatory property of turmeric is associated with a reduced risk of AD [30]. Indeed, when fed to aged mice with advanced plaque deposits similar to those of AD, curcumin reduced the amount of plaque deposition [27, [31][32][33]. It reduced oxidative damage and reversed the amyloid pathology in an AD transgenic mouse [32,33]. Direct injection of curcumin into the brains of the mice with AD not only hampered further development of plaque but also reduced the plaque levels [33]. AD symptoms charac terized by infl ammation and oxidation were also eased by curcumin's powerful antioxidant and anti-infl ammatory properties [33]. In addition, a low dose of turmeric (160 parts per million, or ppm) reduced proinfl ammatory cytokine levels that are linked to the neuroinfl ammatory cascades involved in neuritic plaque pathogenesis [32]. Curcumin's in vitro ability to inhibit lipid peroxidation and neutralize reactive oxygen species may be several times more potent than that of vitamin E [34]. Toxicity studies were conducted by the National Cancer Institute by administering turmeric oleoresin (organic extract of turmeric) in feed to groups of male and female rats and mice for 13 weeks and 2 years. Th ere were no acute or chronic clinical fi ndings related to toxicity in either rats or mice receiving 2,000, 10,000, or 50,000 ppm of turmeric oleoresin [35].
Owing to the promising fi ndings in animal models, clinical trials of oral curcumin supplementation in patients with early AD are already under way [10,36]. In addition, the results of a six-month randomized, placebocontrolled, double-blind, clinical trial of curcumin in 27 patients with AD found that oral supplementation with up to 4 g/day of curcumin was safe [37]. Larger controlled trials are needed to determine whether oral curcumin supplementation is effi cacious in AD [38].

Brahmi (Bacopa monnieri)
Brahmi (also known as Bacopa) is a bitter-tasting creeper plant found in damp and marshy areas and is commonly used in Ayurvedic medicine as a nerve tonic, diuretic, and cardiotonic and as a therapeutic agent against epilepsy, insomnia, asthma, and rheumatism [7,39]. Th e principal constituents of Bacopa monnieri (BM) are saponins and triterpenoid bacosapo nins that include bacopasides III to V, bacosides A and B, and bacosaponins A, B, and C. Other saponin glycosides include the jujubogenin bisdesmosides bacopasaponins D, E, and F. Other constituents include alkaloids, plant sterols, betulic acid, polyphenols, and sulfhydryl com pounds that confer antioxidant activity [7, 39,40]. Th us, BM could act by reducing divalent metals, scavenging reactive oxygen species, decreasing the formation of lipid peroxides, and inhibiting lipoxygenase activity [41]. Traditionally, BM was used to improve memory and cognitive function [42]. Th e BM extracts have been investigated extensively for their neuropharmacological eff ects and their nootropic actions [39,[42][43][44]. In the hippocampus, BM enhances protein kinase activity that may contribute to its nootropic action [45]. BM also inhibited cholinergic degenera tion and displayed a cognition-enhancing eff ect in a rat model of AD [46]. A team of researchers also reported that a standardized extract of BM reversed the cognitive defi cits induced by intracerebroventricularly adminis tered colchicines and ibotenic acid into the nucleus basalis magnocellularis [47]. In the same study, BM also reversed the (a) depletion of acetylcholine, (b) reduction in choline acetyltransferase activity, and (c) decrease in muscarinic cholinergic receptor binding in the frontal cortex and hippocampus [47]. BM extracts protected neurons from beta-amyloid-induced cell death by sup pres sing cellular acetylcholinesterase activity. In addition, BM extract-treated neurons expressed a lower level of reactive oxygen species, suggesting that Brahmi restrained intracellular oxidative stress [48].
An enriched phytochemical composition of BM was evaluated for short-term safety and tolerance in healthy adult volunteers. A detailed examination of clinical, hematological, biochemical, and electrocardiographic parameters did not reveal any untoward eff ects in any of the volunteers who received oral administration of a single capsule containing the enriched herb for 30 days (300 mg for the fi rst 15 days and 450 mg for the next 15 days) [49]. On the basis of the above-mentioned study and other clinical studies carried out to establish the effi cacy of BM in memory and attention disorders, BM has now been introduced in the Indian market for treatment of memory and attention defi cit disorders [50][51][52][53]. Th ese clinical studies with Bacopa serve as a model for the way forward for other herbs to ascertain their eff ective dosage range, the time required to attain therapeutic levels, and their eff ects over a longer term of administration.

Shankhpushpi (Convolvulus pluricaulis)
Various species for Shankapushpi, including Convolvulus pluricaulis (CP), Convolvulus microphyllus, Evolvulus alsinoides, and Clitoria ternatea (CT), have been described. Shankhpushpi is a common plant in India, where the whole plant is used in various formulae as a nervine tonic for improvement of memory and cognitive function [18, 54,55]. A wide range of secondary metabolites, including tri terpenoids, fl avonol glycosides, antho cyanins, and steroids, has been isolated and may be responsible for Shankhpushpi's nootropic and memory-enhancing properties in addition to other pharmacological activities [55][56][57][58]. It is believed that Shankhpushpi calms the nerves by regulating the body's production of the stress hormones, adrenaline, and cortisol [58]. It is also recom mended for nervous disorders such as stress, anxiety, mental fatigue, and insomnia [7, 43,55]. Th e ethanolic extract of CP and its ethyl acetate and aqueous fractions signifi cantly improved learning and memory in rats [59]. Th e ethanolic extract of CP also possesses signifi cant antioxidant activity when tested in vitro [18,54,59,60]. An ethanolic extract of the whole plant, when administered to cholesterol-fed gerbils, reduced serum cholesterol, LDL cholesterol, triglycerides, and phospholipids signifi cantly [55]. A dose-dependent enhancement of memory was observed in mice that were administered extracts of CP. Similarly, administration of CP extracts for 7 days enhanced memory in aged mice. Hippocampal regions associated with the learning and memory functions showed a dose-dependent increase in acetylcholine esterase activity in the CA1 and CA3 area with CP treatment [61]. Specifi cally, administration of aqueous root extract of CT to neonatal rat pups resulted in improved retention and spatial learning performance, indicating the memory-enhancing property of CT. In addition, a signifi cant increase in acetylcholine content was observed in the hippocampi of CT-treated rats in comparison with age-matched controls. Increase in acetylcholine content in the hippocampus may be the neurochemical basis for their improved learning and memory [62][63][64]. Young adult rats intubated with aqueous root extract of CT showed a signifi cant increase in passive avoidance learning and retention. A signifi cant increase in dendritic intersections, branching points, and dendritic processes arising from the soma of neurons in the amygdale region in CT-treated rats was observed in comparison with age-matched saline controls, suggesting that CT enhances memory by increasing the functional growth of neurons [65].

Gotu kola (Centella asiatica)
In the Ayurvedic system of medicine, gotu kola is one of the important rejuvenating herbs for nerve and brain cells and is believed to be capable of increasing intelligence, longevity, and memory [44,66]. Asiaticoside derivatives, including asiatic acid and asiaticoside, were shown to reduce hydrogen peroxide-induced cell death, decrease free radical concentrations, and inhibit betaamyloid cell death in vitro, suggesting a possible role for gotu kola in the treatment and prevention of AD and beta-amyloid toxicity [67]. Gotu kola extracts reversed the beta-amyloid pathology in the brains of PSAPP (APP/ Sw x PS1M 146L ) mice and modulated the components of the oxidative stress response [66][67][68][69][70].

Jyotishmati (Celastrus paniculatus)
Jyotishmati is a treasured medicinal herb that is revered for its eff ects on the brain and has been used for centuries in Ayurveda for sharpening the memory and improving concentration and cognitive function [71]. Aqueous extracts of CP seeds have cognition-enhancing properties and antioxidant properties. CP extracts protected neuronal cells against H 2 O 2 -induced toxicity in part by virtue of their antioxidant properties and their ability to induce antioxidant enzymes. CP extracts also protected neuronal cells against glutamate-induced toxicity by modulating glutamate receptor function. In addition, the CP extracts protected neuronal cells by virtue of their free radical scavenging properties, reducing lipid peroxidation, and also by their ability to induce the antioxidant enzyme catalase [68,[72][73][74][75]. In addition, aqueous extracts of CP seed have dose-dependent cholinergic activity, thereby improving memory performance [68].

Jatamansi (Nardostachys jatamansi)
Similar to its Western relative valerian, Jatamamsi is safe and balancing in its eff ects. Th e plant has a rich history of medicinal use and is highly regarded in the Ayurvedic system of medicine. Th e rhizomes and roots of the plant have medicinal value and, therefore, have been the focus of chemical studies. Th ey contain a variety of sesquiterpenes and coumarins. Th e sedative sesquiterpene valeranone, which is also found in valerian, is a major component of the root essential oil. Other terpenoids include spirojatamol, nardostachysin, jatamols A and B, and calarenol. Jatamansi is the predominant coumarin [76][77][78].
Studies on its role in the CNS revealed that extracts of Nardostachys jatamansi (NJ) alleviated all of the symptoms of chronic fatigue syndrome (CFS) in rats. CFS triggered increases in lipid peroxidation, nitrite, and superoxide dismutase levels, and low catalase levels were all reversed by NJ extracts. Th e data indicate the powerful antioxidant property of NJ [79]. Similarly, an alcoholic extract of this plant administered to both young and aged mice signifi cantly improved learning and memory and also reversed the amnesia induced by diazepam and scopolamine. Furthermore, it reversed aging-induced amnesia due to the natural aging of mice, suggesting that the compounds in this plant may prove to be useful in restoring memory in older individuals as well as in patients with age-associated dementia [80].

Guggulu
Guggulu is an oleogum resin exuding from the cracks and fi ssures in the bark or from incisions from several diff erent plant species, including Commiphora mukul, C. molmol, C. abyssinica, C. Burseraceae, and C. whighitii. Th e oleogum resin of guggulu is a mixture of 30% to 60% water-soluble gum, 20% to 40% alcohol-soluble resins, and about 8% volatile oils. Water-soluble constituents include mucilage, sugars, and proteins. Alcohol-soluble constituents include the commiphoric acids, commiphorinic acid, and the heerabomyrrhols. Among the volatile constituents are terpenes, sesquiterpenoids, cuminic aldehyde, eugenol, and the ketone steroids Zand E-guggulsterone, and guggulsterols I, II, and III [81][82][83]. Guggulu also contains ferulic acids, phenols, and other non-phenolic aromatic acids that are potent scavengers of superoxide radicals and could potentially be of importance for the treatment of AD and other oxidative stress-related disease [84][85][86]. Th e gum resin has been used for thousands of years in the treatment of arthritis, infl ammation, obesity, and disorders of lipid metabolism.
In animal models and in humans, administration of guggulipid is reported to signifi cantly lower both serum LDL cholesterol and triglyceride levels [87][88][89]. Insight into the mechanism of action for the hypolipidemic activity was provided by the demonstration that guggulu is an eff ective antagonist of the bile acid receptor farnesoid X receptor [87,90]. Epidemiologic and biochemical data suggest a link between cholesterol, APP processing, and AD [91][92][93][94][95][96]. Th ese studies indicate that there is a decreased prevalence of AD associated with the use of cholesterol-lowering drugs [93][94][95][96]. Decreased neuronal cholesterol levels, in turn, inhibit the betaamyloid-forming amyloidogenic pathway, possibly by removing APP from cholesterol and sphingolipid-enriched membrane microdomains. Th ese intriguing relationships raise the hopes that cholesterol-lowering strategies may infl uence the progression of AD [91][92][93][94][95][96]. A recent study demonstrated that gugulipid has a significant protective eff ect against the streptozotocin-induced memory defi cit model of dementia; the eff ect can be attributed to its cholesterol-lowering, antioxidant, and anti-acetylcholine esterase activity. Th ese observa tions suggest gugulipid as a potential anti-dementia drug [88].

Administration of Ayurvedic herbs
Th e biggest challenge to drug delivery into the CNS is bypassing the blood-brain barrier (BBB) as it limits access to the CNS. For decades, the BBB has prevented the use of many therapeutic agents for treating brain-related diseases and injuries, including AD, stroke, brain tumor, head injury, and other CNS disorders. Ayurveda relies on some novel methods of administering herbs or their preparations (or both) to treat CNS disorders. However, proper studies are lacking to demonstrate whether these herbs or their components given orally or by some other means cross the BBB and reach the CNS. One novel method of herbal delivery, called 'NASYA' , involves intranasal delivery of dry herbal powders or medicated oils and is a practical, non-invasive, rapid, and simple method to deliver the therapeutic agents into the CNS. Th e use of medicated oils, which require that the herbs be cooked in four parts oil and 16 parts water over a low fl ame until all of the water evaporates, ensures the transport of lipophilic and lipid-soluble molecules across the BBB membrane, where hydrophilic compounds demon strate minimal permeation [97]. Intranasal administration off ers numerous benefi ts for drug delivery into the CNS, and interest in this non-invasive route of administration has increased. Th e delivery is rapid, bypasses the BBB, and directly targets the CNS, thereby reducing systemic exposure and side eff ects [98][99][100][101][102].
A second, simple method of administration involves application of the medicated oil on the body and massaging the areas with gentle or deep hand strokes. It is not clear whether this technique facilitates the transport and movement of the herbal components through the BBB. Indirect evidence from recent studies points to such an exciting possibility. Signifi cant brain functional activation changes together with increased cerebral blood fl ow were observed in participants who received a massage. Massage reduced the levels of stress-related serum cortisol, arginine vasopressin, and salivary stress protein chromogranin A with concomitant increases in circulating lymphocytes and regional cerebral blood fl ow [103][104][105][106]. It is tempting to speculate that, in addition to the above-mentioned hormonal changes, application of medicated oil followed by a gentle massage could relax the tight junctions between endothelial cells in the CNS vessels and facilitate the entry of solutes and other components into the CNS.
Ayurveda also relies on several transcranial oleation therapies for nervous system disorders that are nonsystemic and non-invasive. Procedures like Shirodhara (gentle dripping of the medicated oil on the forehead), Shirobasti (a special leather cap is placed over the shaved head of a patient and medicated oil is poured and retained over the head for 30 to 45 minutes), ShiroAbhyanga (medicated oil is smeared on the head followed by a gentle massage), and ShiroSeka (medicated oil is poured over the head in a continuous stream) may also infl uence hormonal and cerebral blood fl ow levels to a degree similar to that of Ayurvedic massage as mentioned above [107][108][109][110]. While scientifi c studies regarding the permeation of the herbal components into the CNS through transcranial oleation therapies are lacking, recent work again points to the possibility that the endothelial cells facilitate the entry of the solutes through the frontal lobe and prefrontal cortex [109,110].
Aromatherapy, another popular method in the Ayurvedic system, involves the use of volatile plant materials known as essential oils for healing purposes for altering a person's mood and cognitive function. Th e essential oils are incorporated through steam inhalation or are topically applied to the face and arms. Aromatherapy used with massage may help to calm agitated people with dementia. Th ere is some preliminary evidence that aromatherapy using various essential oils may have some potential for improving cognitive function, especially in patients with AD [111][112][113].

Conclusions
Th e pharmaceutical industry is facing serious challenges as the drug discovery process for neurodegenerative diseases is becoming extremely expensive, riskier, and critically ineffi cient. A signifi cant shift from a single-target to a multi-target drug approach, especially for chronic and complex disease syndromes, is being wit nessed. Approaches based on reverse pharmacology (from the clinic to the bedside) also off er effi cient development platforms for herbal formulations. Th e Ayurvedic system of medicine has garnered increasing recognition in recent years with regard to diet and treatment options. Early development of Ayurvedic herbal supplements required only anecdotal or epidemiologic information (or both) without an understanding of the mode of action. Th e Ayurvedic medicine industry has come a long way from when it was considered unnecessary to test Ayurvedic formulations prior to use, to several randomized, double-blind, controlled studies and to the introduction of good manufacturing practice guidelines for the industry. It has taken a more rigorous scientifi c and quality-enhanced approach to provide 'proof of concept' and a 'mode of action' . It might be worth pointing out that, while Ayurvedic therapeutics has been prescribed for centuries for neurodegenerative diseases (including dementias), only recently have there been Western, mechanistic studies on AD; however, these mechanistic studies point to the same mechanisms addressed by the Ayurvedic therapeutics (for example, increase in nerve growth factors and neurotrophic factors and reduction in infl ammation and oxidative damage), providing strong support for herbal therapy for AD [11]. It is hoped that the strong knowledge base of Ayurveda coupled with combinatorial sciences and high-throughput screening techniques will improve the ease with which Ayurvedic products and formulations can be used in drug discovery campaigns and development process, thereby providing new functional leads for AD and other age-associated neurodegenerative diseases.

Competing interests
The authors declare that they have no competing interests.