Epidemiology : prevalence after age 65 : 5-10%. 15-18 million people worldwide

• age 65-74 : 3%
• age 75-84 : 3%
• age > 85 : 47%

• sporadic AD (90-95%) : amyloid-b (Ab) peptide that is associated with AD behave like an infectious agent when injected into the brain of a mouse model of AD, generating phenotypes that depend on both the host and the agent^ref, providing provide in vivo evidence of such a time- and concentration-dependent seeded aggregation of Ab previously shown in vitro^ref. Their experiments used brain extracts from deceased AD patients or from aged mice genetically predisposed to develop an AD-like disease (transgenic AD mice), or synthetic Ab. The extracts were injected into the brains of young, presymptomatic transgenic AD mice. In all instances, seeding activity was observed (although with reduced efficiency in the case of synthetic amyloid). Ab peptides seem to be responsible for the seeding activity because this activity was lost if injected extracts were used in which either the Ab conformation had been destroyed or Ab removed. These studies further strengthen observations of in vivo seeding of Ab in transgenic mice^ref and in non-human primates^ref, suggesting a mechanism reminiscent of prion infectivity. Furthermore, the pathology of Ab formation is governed by both the injected agent and the host, features typically observed for prion strains. Meyer-Luehmann et al.^ref used 2 distinct transgenic mouse models of Alzheimer's disease: APP23 mice and APPPS1 mice. APP23 mice overproduce mainly the 40-amino-acid Ab peptide, which results in the deposition of predominantly diffuse and filamentous Ab in aged animals. APPPS1 mice overproduce mainly the 42-amino-acid Ab, and show a compact (punctate) deposition of Ab with age. Injection of brain extracts from aged APPPS1 mice into young APP23 hosts consistently induced punctate Ab deposition that was mainly confined to one part of the brain (the subgranular layer of the hippocampus). In contrast, extracts from aged APP23 mice injected into APP23 hosts yielded primarily diffuse and filamentous lesions, with substantial diffuse Ab deposition. When the experiments were applied to the APPPS1 host, deposition induced by the APPPS1 extract was even more punctate, whereas that induced by the APP23 extract was a mixture of the filamentous and punctate Ab forms. What factors might make an amyloid infectious? According to a mathematical model^ref validated by experiments in 3 strains of yeast prion, the generation of a prion and its phenotype depends on several factors: the amount of amyloid; the conformation-dependent growth rate of the amyloid; the division rate of the amyloid into seeds; and the concentration of the soluble protein counterpart. On this account, manipulation of any of these variables can transform any amyloid into a prion. For example, an increase of soluble amyloid protein in the host might be sufficient to transform an amyloid into a prion. In contrast, the formation of long fibrils decreases the ratio of the number of seeds to amyloid protein, reducing the seeding capacity. The amyloid conformation determines its growth and division rates, thereby influencing the titre of infectivity and the prion phenotype. Indeed, Meyer-Luehmann et. al.^ref observed induction of Ab formation by Ab injection only in Ab-overproducing transgenic mice and not in normal mice. Injection of long, synthetic Ab fibrils resulted in a low seeding capacity, and the different amyloid phenotypes described might be attributed to the distinct properties and 3D structures of amyloids consisting of either the 40- or the 42-amino-acid A^{ref1, ref2}. It might sound shocking that AD, and possibly other amyloid diseases, can be infectious under certain circumstances (in this case^ref, intracerebral injection into Ab-overproducing mice). According to the nucleation–polymerization model of amyloids, however, it is to be expected. So where do we go from here? The experimental evidence^{ref1, ref2, ref3}, and widespread incidence of amyloid diseases highlight the need for basic, clinical and epidemiological studies into the possible transmission of amyloid diseases between humans. In the USA alone, 4.5 million people suffer from AD, and 20 million from type II diabetes; in particular, we need to find out whether seeds can be transmitted and can accelerate the onset of disease in humans. For those involved in basic research, there are plenty of other issues to tackle. Is the use of mice that overexpress prion protein still adequate to study TSEs, given that overexpression might mask the real properties of the agent^ref? How many strains of AD are there, and how well are they reflected in the established transgenic mouse strains? If there are several strains — and so several amyloid conformations — how relevant are the structural studies of amyloids that are generated in vitro?
• obesity
• acid-forming diet, such as one high in dietary fat, or to a lesser extent, total energy (caloric intake), can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage
• diabetes mellitus (vascular damage, oxidative stress, insulin replacement therapy),
• Ab interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Ab across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Ab-induced vasoconstriction
• mental activity : experts have previously suggested that keeping the mind active, through reading or crossword puzzles, can help to stave off dementia in old age. Those who develop the debilitating form of dementia are more likely to have had jobs that do not tax the brain, lending weight to the 'use it or lose it' theory. Perhaps AD has an early impact that prevents sufferers from entering mentally demanding professions such as writing, accountancy or law. But people who stimulate their minds might build up a reserve of nerve cells in the brain. Alternatively, those who exercise their grey matter might simply be better practised at thinking : this would make them more likely to perform well in the mental tests used to diagnose the disease. as people with intellectual careers tend to enjoy higher socioeconomic status, they may have better access to healthcare that may protect against AD (e.g. hormone-replacement therapy (HRT)^ref) (Smyth 498-505 )
• among the more potent Ab₄₂-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Ab₄₂, including multiple COX-2-selective derivatives of 2 Ab₄₂-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Ab₄₂. These compounds seem to target the -secretase complex, increasing g-secretase-catalyzed production of A42 in vitro. Short-term in vivo studies show that 2 Ab₄₂-raising compounds increase Ab₄₂ levels in the brains of mice. The elevations in Ab₄₂ by these compounds are comparable to the increases in Ab₄₂ induced by Alzheimer disease-causing mutations in the genes encoding amyloid  protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Ab₄₂ production in humans^ref
• stroke : the annual incidence for AD is 5.2% for patients, compared with 4% among those without stroke, with a RR = 1.6. The RR is significantly increased with the additional factors of systemic arterial hypertension (RR = 2.28), diabetes mellitus (RR = 4.59), or ischemic heart disease (RR = 1.95).
• a transmissible CJD-like agent is prevalent in the human population^ref. Buffy coat of the blood from 5 out of 11 relatives of AD patients, including 2 with suspicious or early signs of AD, produced histologically documented spongiform encephalopathy on primary intracerebral inoculation into recipient hamsters. Material from 3 of these positives was serially transmitted in a second passage. The histological alterations observed in the brains of positive hamsters were similar to those seen in experimental CJD. These transmission results raise the intriguing possibility that CJD-like agents may be involved in at least some forms of AD^{ref1, ref2}
• recycling of APP from the cell surface via the endocytic pathways plays a key role in the generation of Ab in AD. Inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset AD. These variants, which occur in at least 2 different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Ab-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing AD^ref
• b-methylamino L-alanine (BMAA)
• inherited forms (5-10% : usually earlier onset around age 55)
• dominantly inherited forms : missense mutations in
• b-amyloid precursor protein (APP) / protease nexin-II (V717F, V642I, L670A, M671L). In vitro, Arctic-mutant Ab forms (proto)fibrils more effectively than wild-type Ab. Amyloid plaques form faster and are more extensive in transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP) than in hAPP mice expressing wild-type A, even though Arctic mice have lower Ab_1-42/1-40 ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo^ref.
• the APP gene is located on chromosome 21 : this explains the early onset of AD in the Down's syndrome patient (100% after 45 years), who has an additional copy of chromosome 21.
• presenilin 1 (PS1)
• presenilin 2 (PS2)
=> increased Ab42 production throughout life.
• nondominant forms
• ApoE4 : individuals with apoE4e (25-33%) and CYP46*TT SNPs are more likely to develop AD. It has been shown that the efflux of cholesterol from neurons depends on the isoforms of ApoE, in the following order : ApoE2 > ApoE3 > ApoE4. As a result, the cholesterol concentration is increased in the exofacial leaflet of synaptic plasma membranes of human ApoE4 knock-in mice
• strong association between the presence of HHV-1 / HSV-1 in brain and carriage of an apoE-e4 allele in the case of AD patients (even patients with Down's syndrome) but not of controls : APP has a role in fast anterograde transport of HSV-1 from its site of synthesis in the neuronal cell body out the neuronal process to the mucosal membrane and is a major component of viral particles, at least as abundant as any viral encoded protein, and also conventional kinesin is also associated with viral particles. HHV-6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV-6, unlike HSV-1, is not directly associated in AD with apoE-e4. In 59% of the AD patients' brains harbouring HHV-6, type B is present while 38% harbour both type A and type B, and 3% type A. HHV-2 / HSV-2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and HHV-5 / CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV-6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV-1 and apoE-e4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals.
• decreased expression of BDNF.
=> faulty Ab degradation => gradually rising Ab levels with age

• higher levels of serum ACE due to insertion/deletion polymorphism in intron 16
• fish, whole grain cereals and vegetables consumption
• cigarette smoking : nornicotine is involved in Ab glycation
• people on statins are 70% less likely to be diagnosed with Alzheimer's than those who are not. In a study of 63 people with mild to moderate Alzheimer's disease, the performance of those who took atorvastatin declined less on tests of memory and brain function
• the variety of leisure and physical activity one engages in -- and not its intensity in terms of calories expended - may reduce dementia risk in older people : an association between variety of activity and dementia risk, however, did not hold up in those with apoE4e^ref

• Ab is generated from :
• b-amyloid precursor protein (APP) / protease nexin-II is a putative receptor for the microtubule motor kinesin, a cell surface protease inhibitor and reduces Cu : it can bind ...
• amyloid beta (A4) precursor protein-binding, family A, member 1 (X11)
• amyloid beta (A4) precursor protein-binding, family A, member 2 (X11-like)
• amyloid beta (A4) precursor protein-binding, family A, member 3 (X11-like 2)
• amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)
• amyloid beta precursor protein (cytoplasmic tail) binding protein 2
• FE65-like protein 2
... by sequential proteolytic cleavages of 2 enzymes :
• a-secretase : ADAM9 cleaves at residue 671
• b-secretase : b-site APP-cleaving enzyme 1 (BACE1) (whose deficiency rescues memory deficits and cholinergic dysfunction in AD-prone mouse model) and BACE2 cleaves at residue 687
• g-secretase^ref : presenilin 1 (PS1) and PS2 cleaves at residue 716. PS1 is expressed at higher level. Nicastrin (Nct) / APH2, APH-1A/APH-1B, and PSENEN / PEN-2, when combined with a heterodimer of endoproteolysed presenilin fragments, form a stable, catalytically active, high-molecular-mass protein complex. This unusual aspartyl protease is the founding member of a novel class of proteases that carry out intramembrane cleavage, resulting in peptide-bond hydrolysis within the hydrophobic environs of the lipid bilayer^{ref1, ref2, ref3, ref4}. These novel proteases share similar catalytic residues with hydrophilic proteases, yet have devised a creative means of introducing water within the membrane. Moreover, g-secretase's involvement in cleavage of Notch and type-I membrane receptors reveals an important role in signal transduction and developmental biology. Thus, therapeutics aimed at inhibiting g-secretase to stave off Alzheimer disease could have deleterious effects. Binding of Aph-1 and nicastrin to presenilin is an early event in gamma complex formation, providing the subcomplex with stability. Pen-2 finally activates g-secretase by an unknown mechanism. Together, these interactions prevented degradation of presenilin and facilitated its self-cleavage. We don't even know the stoichiometry of the complex, what it looks like, how active it is. There is still no structural information about this complex. Who are the immediate neighbors? How do they interact and talk to each other, and what do they do? Needless to say, an X-ray crystal structure of the complex is a long way off. What kind of abnormality in g-secretase leads to increased cleavage at the 42nd position, resulting in the amyloid b₄₂ species that more readily aggregate (cleavage at the 40th position is generally more common). Knowing this will pave the way for developing "selective" g-secretase inhibitors for treating Alzheimer disease that won't interfere with Notch function. g-secretase exhibits heterogeneous activity, with several complexes performing the same function : we're not sure if individual complexes are processing multiple substrates.


Amyloid precursor protein (APP) is first cleaved by g-secretase to generate C99, the substrate for g-secretase processing. C99 enters the active site of g-secretase residing in presenilin, which together with Nct, Aph-1, and Pen-2 forms the g-secretase complex. 2 critical aspartates in transmembrane domains 6 and 7 catalyze the endoproteolytic cleavage which occurs at 2 topologically distinct sites (double arrowhead). Amyloid b liberated into extracellular space can form aggregates^ref
The g-secretase lacks sequence specificity, therefore could generate Ab proteins with 39 to 43 amino acids. Its exact length is important for its toxicity : Ab_1-42 or Ab_1-43 is much more toxic than the normal Ab_1-40. APP can be degraded also by carboxypeptidase B2 (plasma, carboxypeptidase U), kallikrein 6 (neurosin, zyme) and cathepsin B1.
• Ab42 accumulates and oligomerizes
• long-lived Ab_1-42 oligomers and polymers have subtle effects on synaptic efficacy : temporal and frontal cortical biopsies performed within an average of 2 to 4 years of the onset of clinical AD revealed a 25 to 35% decrease in the numerical density of synapses (painstakingly counted in electron micrographs) and a 15 to 35% decrease in the number of synapses per cortical neuron. Even at the end of the disease, quantitative correlations of postmortem cytopathology with premortem cognitive deficits indicate that synapse loss is more robustly correlated than are numbers of plaques or tangles, degree of neuronal perikaryal loss, or extent of cortical gliosis. Synaptophysin- and MAP2-positive neurons are 30% less in the cortex. Decreases in presynaptic terminals are critically dependent on cortial Ab levels, not on plaque burden or APP levels.
• adult astrocytes (Alzheimer's cells) migrate in response to CCL-2 / MCP-1, a chemokine present in AD lesions, cease migration upon interaction with immobilized Ab_1-42 and degrade it, implicating deficits in astroglial clearance of Ab_1-42 in the pathogenesis of AD.
• an early event after exposure of postmitotic neurons to Ab is tyrosine phosphorylation of FISH adapter protein. FISH binds to and potentially regulates certain ADAM family members. FISH and ADAM12 mediate the neurotoxic effect of Ab. Expression of an ADAM12 protease-deficient mutant (ADAM12DMP) blocks Ab-induced neuronal death, and expression of an N-terminal fragment of FISH reduces A toxicity. The C-terminal fragment of FISH containing the ADAMs binding region is found to be sufficient for induction of neuronal death, which is prevented by coexpression of the ADAM12DMP. A treatment, as well as expression of the C-terminal toxic FISH fragment, induces accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease/sheddase activity. ADAM12 protein is reduced in AD brains, pointing to a possible increase in ADAM12 proteolytic activity^ref.
• Ab_1-42 oligomers gradually deposit extracellularly (amyloid plaques (AP) / argyrophil plaques / neuritic plaques (NP) / senile plaques)
• extracellular proteins may aggregate through hydrophobic and electrostatic interactions facilitated by metal ions, causing AB amyloidosis. b-amyloid formation starts, or can start, extracellularly and is toxic to the surrounding neurons. The intracellular hypothesis cannot be excluded; however, so far, nobody has provided evidence for the intracellular hypothesis in vivo. Unorganized aggregation of proteins is inherently cytotoxic. Ab aggregation may induce additional toxicity in the following 2 ways:
• activating microglia and astrocytes which are involved in the clearance of Ab aggregates, but also in generation of free radicals and inflammatory cytokines which could be cytotoxic
• altered neuronal ionic homeostasis
• accumulation of cholesterol or ceramide => oxidative injury
• down-regulation of protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1 (PIN1) and altered GSK3b/phosphatase activities => hyperphosphorylation of microtubule-associated protein (MAP) tau causes its dissociation from microtubules and aggregation into insoluble paired helical filaments (PHF) which are the constituent of neurofibrillary tangles (NFT) (Alzheimer's neurofibrillary degeneration)
• intracellular Ab₄₂, but not extracellular soluble Ab, can induce neuronal apoptosis by generating ROS, possibly via Met³⁵
• mitochondrial APP occurs in a transmembrane-arrested orientation, in contact with the mitochondrial translocation complexes required for the import of proteins. Accumulation of transmembrane-arrested APP blocks protein translocation, disrupts mitochondrial function, and impairs brain energy metabolism
• decrease in circulating B and CD8⁺CD28^- cells, as well as an increase in CD8⁺ cells expressing CD71⁺ and CD28⁺, was observed in AD patients. A significant decrease in IL-10 production was also found after stimulation of PMBC with Ab[1-40]. The decreased IL-10 production was not related to disease severity. The observed imbalance of immune peripheral cell subpopulations and decreased IL-10 production point to a reduction of suppressor cell function^ref

amyloid plaques (AP) / argyrophil plaques / neuritic plaques (NP) / senile plaques

neurofibrillary tangles (NFT)

Lewy bodies

• prodromic or reactive phase : minimal cognitive impairment (MCI) (diminishing vocabulary, causing a person to feel the desired word frustratingly 'on the tip of one's tongue', often precedes problems with sentence construction), depression, anxiety, generic memory impairment, discomforting sensation of change, social isolation, sleep disorders (> 70% : due to reduced sunlight exposure, drugs (aminophylline, antihypertensives), nycturia, depression, anxiety, pain, caffeine, ethanol, involvement of brainstem, epiphysis, and hypothalamus, and reduced responses to behavioural stimuli), maintained social and proffesional role, demential episodes (false recognitions, spatio-temporal disorientation, micturition in inappropriate places, mistakes with money, exhibitionism, ...); slowly progressive, lasting > 12 months; differential diagnosis with involutive melancholia and pseudodementia
• the vocabulary of Jackson's Dilemma, published shortly before the British novelist Iris Murdoch (died in 1999) was officially diagnosed with Alzheimer's in 1995, is less rich than that of an earlier work The Sea, The Sea, published at the height of her powers in 1978. A team of British researchers made the discovery by using text-analysis software to compare the variety of words used in 3 of her novels. What's more, the rate at which new words are introduced is greater in this work and in Murdoch's 1954 first novel, Under the Net, than in Jackson's Dilemma^ref
• people who will go on to develop AD display warning signs years before their official diagnosis. The signs include a worsened memory for past episodes in their own life. Unfortunately, most of these warning signs are also characteristic or normal aging. This could make it hard to diagnose the disease earlier, although the problems are worse in those who go on to be diagnosed with it. They reached the conclusions after combing through 47 AD studies from the past 20 years. The researchers crunched data from a decade’s worth of studies. This included records on 1,207 people who were later diagnosed with the disease, and 9,097 controls who stayed healthy. Scientists are investigating the disease’s pre-diagnosis stages in hopes that it might help them understand how the disease progresses, and help doctors improve treatment by catching at-risk patients earlier. The researchers said they found pre-diagnosis Alzheimer’s patients had marked deficits in overall cognitive ability, memory for episodes in their own life, speed of perceptions, and executive functioning, a set of processes that includes planning, inhibitory control and flexibility in attention. The pre-diagnosis patients showed somewhat smaller deficits in verbal ability, visuospatial skill, and attention. However, there was no deficit in their so-called primary memory, the information actively kept in mind for a task. The deficits seen in these patients mirror quite closely those seen in normal aging. Still, these problems are exacerbated in those who will go on to be diagnosed. There are no clear qualitative differences in patterns of cognitive impairment between the normal old 75-year old and the preclinical AD counterpart. Rather, we think of the normal elderly person, the preclinical AD person, and the early clinical AD patient as representing 3 instances on a continuum of cognitive capabilities. This presents an obvious challenge for accurate early diagnosis.”^ref
MCI is a transitional stage between normal aging and AD. A recent study suggests that the prevalence of MCI, characterized by a cognitive decline without impairment of the ability to carry out activities of daily living, is 19% among persons younger than 75 years of age and 29% among those 85 years of age or older”^ref. Among persons with mild cognitive impairment, about 30% have amnestic MCI, characterized by abnormal memory for age but normal general cognitive functioning”^{ref1, ref2}. Approximately 12% of patients with amnestic MCI have progression to AD each year, and up to 80% have progression to AD after 6 years^ref
• neuropsychiatric phase : progressively evolving dementia of the Alzheimer's type lasting 3-7 years => mental disruption; amnesia, Reich's alogic syndrome (central aphasia, agnosia and apraxia), gross mistakes and exitations in problem solving, demential logorrhea (automatic, repetitive, confabulatory language with agrammatism, paraphasias, echolalia, perseverations, use of passe-par-tout words, neologisms, ...; language may be exitating in demential mutism. Frontal impairment symptoms (attention deficit, abstract thinking deficit, alogic thought, apraxia, adynamia), Klüver-Bucy syndrome; accessory symptoms : mood disorders (dementia with depression => frontal alteration (impulsivity, irritability, fatue and incongrous euphoria, emotional lability, apathy), obsessive phenomena (collectionism), fragmented or reversed sleep-wake rhythm, fragmentary and variable delirium (latrocinium, persecution, misery, hypochondria, jealousy => dementia with delirium), hypnagogic or hypnopompic hallucinations, afinalistic and iterative movements
• neurological phase : onset of neurological signs (decline in movement and reflexes), 1 year; akinetic parkinsonian disorders (50-80%), ataxia, sphincterial disorders, onset of primitive reflexes, epilepsy, hyperkinesia, terminal adynamic syndrome
• internal phase : cachexia and immunodepression lasting < 6 months => death by inanition of intervening infectious diseases

• diagnosis (NINCD/ADRDA criteria)
• definitive (AD can be confirmed only after death)
• probable : clinical dementia and positive neuropsychological test, deficit > 2 cognitive areas, worsening of memory and other cognitive functions, no consciousness disturbance, age between 40 and 90, other diseases excluded< with about 85% accuracy >
• cognitive tests
• FreeCell, that heinously addictive and complicated version of Solitaire > performance in this computerized card game might reveal MCI.  Standard memory tests, brain imaging and biological markers are all currently being used. There are a lot of interesting data but no solid answers. The Oregon researchers wanted to develop an unobtrusive continuous monitoring system that might reveal more reliable information than intensive, yearly memory check-ups. FreeCell requires a lot of mental planning to play, and it's cheap, non-invasive and fun. 9 senior citizens were chosen for a preliminary 3-week study. They usually played 30-50 games a week and one subject played 660 games in 3 weeks. A computer algorithm judged the easiest way of completing each game, recalculating it after every card move, so the researchers could calculate the efficiency of each player. The 3 players who had already been diagnosed with MCI were less efficient than healthy players, and also showed less day-to-day consistency. However, three weeks was too short to spot any actual decline in game-playing efficiency. Amusing as it sounds, the basic idea is not so dissimilar from other kinds of tests that clinicians use to monitor cognitive decline. The only question is: does it work? No one, not even the researchers involved, knows yet. Any statistically justifiable conclusions will have to wait until a planned study with 300 volunteers has been completed. If the test works, it could be a more sensitive approach than current MCI tests. The standard tests are performed irregularly. The patients come in, they might be having a bad day, then might not be measured for another year. We look at continuous performance over time, and feel that we can tell the difference between, say, Alzheimer's and apathy. The next logical step is to see whether games such as FreeCell can improve brain function. The games company Nintendo already markets console games such as Brain Age and Dr Kawashima's Brain Training, which involve completing a daily series of quickfire puzzles, from arithmetic questions to spot-the-difference games. Each day, the player receives a 'brain age' assessment. Computer games probably do improve cognitive function, but this improvement is likely to be very specific to the type of game played. It's unclear whether it will have any impact on day-to-day brain function or risk of dementia. As for keeping your brain cells fit, "probably the best thing people can do is go out and get some exercise. But if you are stuck at your computer playing cards, it might be helpful to know that some FreeCell card layouts are in fact unsolvable. Trying to play those ones may be enough to drive anyone demented (Jimison H., et al. IEEE Trans. Inf. Technol. Biomed, 8 . 248 - 252 (2004))
• computer analysis of language could help experts spot the warning signs earlier
• brain scans
• ¹⁸F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies^ref
• cortical atrophy => ventriculomegaly (differential diagnosis with hydrocephalus)
• in vivo detection of amyloid plaques :
• after injection Pittsburgh Compound B (PIB) binds to amyloid plaques and can then be detected with
• PET brain scan^ref
• fluorescence microscopy (can only reveal 0.5 mm into the brain)
• PET scan after injection of ¹¹C
• PET scan after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), for use as an in vivo chemical marker of cerebral amyloid and tau proteins. Initial studies have shown that PET scans show significantly higher values for FDDNP binding in the temporal, parietal, and frontal regions of the brain in patients with AD than in older control subjects without cognitive impairment^ref. Both FDDNP and its parent molecule, 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile, are fluorescent and provide clear in vitro visualization of plaques and tangles in specimens of brain tissue obtained on autopsy from patients with AD and examined with a confocal fluorescence microscope^ref. FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with AD and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles^ref
• MRI : a brain scan developed in mice could herald a safe and affordable way to screen patients for AD before they show any symptoms. To turn up the contrast, one atom of a non-toxic compound that is known to bind to the plaques was substituted with a derivative of fluorine that is not naturally found in mice or humans. It produces a distinctive magnetic signal that is easy to detect using MRI. When the researchers injected the compound into mice that had a condition equivalent to AD, it bound successfully to the plaques in their brains. PET scanning is being tested in clinical studies, but its resolution is limited to millimetres, and individual plaques are at least 10 times smaller than that. The use of MRI could be a better option : in addition to its high resolution, it is cheaper, more widely available and safer than PET, which requires the patient to be injected with a radioactive substance. Having shown that the MRI method works in mice, the researchers hope to be able to test the technique in humans within a few years. Before moving to clinical trials the team will need to refine the technology and the design of the compound to be absolutely sure of the method's safety
• possible

• chemotherapy
• therapeutic vaccine
• gene therapy
• mice with memory loss have had their condition reversed, a discovery that should help refine the search for a cure for AD and other dementias. The study also helps clarify the actual cause of dementia, which should give more focus to drug studies. The brains of people with AD's and some 50 other forms of dementia are known to have certain characteristic features, including messy bundles of fibres in nerve cells called neurofibrillary tangles. But no one has been sure whether the tangles are a cause or symptom of dementia. Mice engineered to massively overproduce a protein called tau tend to grow more of the tangles and display the same problems with memory and learning as humans with dementia : it is a certain version of the tau protein, rather than a simple over-abundance, that leads to the tangles. It has been speculated that these tau proteins, rather than the tangles, kill nerve cells. They trained mice to navigate a maze partly submerged in water, and watched for signs of memory loss. By the age of 3 months, mice genetically engineered to express 13 times too much tau protein couldn't remember the route to dry land, and had developed tangles in their brains. But surprisingly, when the researchers turned off the switch promoting tau expression, the mice began to gain back some lost memory. The performance of the 'switched-off' engineered mice was roughly half as good as their normal counterparts, and twice as good as those that continued to overproduce tau. And their performance improved even through the tangles in their brains remained. Some variety of tau proteins, and not the tangles it promotes, is responsible for dementia-related memory loss^ref. The next step is to figure out the molecular form of tau that is poisoning the neurons : that should give drug developers a better understanding of the molecules they should target. But in the context of dementia, this is just half the story. AD's patients also have plaques in their brains made of b-amyloid. Most think that this also plays a role in causing memory loss. This is a 2-protein disease

• higher adherence to the Mediterranean diet is associated with a reduced risk for AD^ref. Higher folate intake may decrease the risk of AD independent of other risk factors and levels of vitamins B6 and B12. These results require confirmation with clinical trials^ref.
• exercise helps to flush a toxic molecule from the brain and causes a beneficial one to move in and protect nerve cells, research on mice shows. The discovery might help to explain why staying fit and keeping mentally active seem to fend off AD in humans. Experiments support the idea that exercise is a good approach to all types of problems in the brain and that a sedentary lifestyle is a risk factor. Exercise slows mental decline in mice engineered to mimic AD : exercise doubled the levels of megalin / LDL-related protein 2 (LRP2) / gp330, a protein that helps to flush molecules thought to underlie AD out of the mice's brains and into their blood. In AD patients, amyloid-b accumulates in clumps throughout the brain. Megalin also binds to IGF in the blood and transports it to the brain : IGF is perhaps best known for bulking up muscles after exercise, but it also helps to keep nerve cells healthy. To reveal the tricks of megalin, the researchers manipulated levels of the protein in the brain of mice with AD-like disease. Artificially boosting megalin partly improved mental performance, as measured in a maze test. Levels of megalin decline with age in normal mice. The researchers suggest that this hints at a molecular link between ageing and neurodegenerative disease. But whether they will hold true remains to be seen. For brains of mice in a different model of AD, exercise does not boost levels of the protective IGF. The findings open the door to developing drugs that could boost levels of the megalin shuttle and help keep the brain healthy. The link between exercise and brain health is still not certain in humans, although the evidence is mounting up. Other research has found that staying mentally agile or even maintaining a slim physique may help to protect against AD and other brain disorders^ref.

• synthetic Ab peptides have generally been applied at mM concentrations (in contrast to the low nM levels of natural Ab found in the brain and CSF) and they can aggregate into an array of assembly forms, some of which may have biophysical properties unlike those found in vivo. Moreover, assessing the effects of such synthetic aggregates is tricky, because they occur as complex mictures and may undergo rapid transitions to more or less neurotoxic forms in cell culture models or after injection into the brain
• mouse that coexpress trangenes encoding mutant human tau and APP can be used to perform in vivo electrophysiological analyses and correlate the results with both behavioral and biochemical measures, but do not yet p rovide a model of full-blown AD, because they largely lack tangle formation and neuronal loss
• a transgenic mouse model that genetically mimics the arrest of Ab production expected from treatment with secretase inhibitors has been generated. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. Doxycycline administration inhibits transgenic APP expression by > 95% and reduces Ab production to levels found in nontransgenic mice. Suppression of transgenic Ab synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Ab deposits retain a considerable amyloid load, with little sign of active clearance^ref.
• loss of autophagy : protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin–proteasome system, emerging evidence points to the importance of autophagy—the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover—in the protein quality-control proces. However, little is known about the precise roles of autophagy in neurons. Loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. Mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies^ref. Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5^-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration^ref.

• Alzheimer's Association
• Alzheimer's Disease Education & Referral Center
• Alzheimer’s Society
• Alzheimer Research Foundation
• Alzheimer Research Forum
• Usenet sci.med.diseases.alzheimer



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