Possible Evolutionary Origin of Alzheimer’s Disease: Comparison
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The enormous, 2–3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer’s disease (AD) in today’s long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aβ1–42 monomers into the interstitial fluid, where they seed the formation of toxic amyloid-β oligomers (AβOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AβOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AβOs from ground zero is supported by Aβ’s own production mediated by target cells’ Ca2+-sensing receptors (CaSRs).

  • Alzheimer’s disease
  • evolution
  • hippocampal memory
  • entorhinal cortex
  • neocortex

1. Where Does Alzheimer’s Disease Start?

Our memory system began with the ancient medial pallium (Latin for covering) linked to olfactory lateral and proto-cortex dorsal pallia. In the various vertebrates, it has evolved over millions of years into a remarkably conserved ‘hippocampus wrapped in a unique neocortex’ [1][2]. The job of hippocampi extending from their pallial beginnings to now, is to rapidly record information from the neocortex into neuronal ensembles [3]. Small mammals such as mice can directly transmit primary neocortical information to the hippocampal system, but, as we shall see below, humans cannot directly transmit primary information to the hippocampal system from our massive neocortices [4]. Instead, we must transmit abstracted neocortical information to the hippocampal system.
The key feature of the evolution of primate brains has been the low growth of the limbic components (amygdala, entorhinal cortex, hippocampus, olfactory system, and septum) and the enormous growth of the human neocortex and that even includes it’s invading the brain stem and cord [5]. The current focus is on the likely pathological consequence of the enormously disproportionate expansion of the hominin neocortex, which began ~2.5 mya and ended ~3000 years ago [6]. This evolutionary neocortical ‘Big Bang’ happened without an equivalent expansion of the EC-hippocampus in the medial temporal cortex. This required the development of ways to manage the increased flow of messages converging on the memory system [7][8][9][10][11][12][13][14][15]. This challenge was met with an internet-like [16] increase in the routing of messages through the perirhinal and parahippocampal cortices via the EC to the hippocampus, which rapidly induces the cortical rubbing of the abstracted original event-inducing networks into interacting ensembles for on-cue replay [3][12][17][18][19].
These two cortical message collectors or abstracting routers are well described by Reagh and Ranganath [14], Michon et al. [8], Sekeres et al. [20], and Rudy [12]. Messages in the ventral stream carrying the gist of messages about objects from the perirhinal cortical neurons and in the dorsal stream carrying the gist of messages about spatial actions from the parahippocampal cortical neurons are delivered to the entorhinal cortical (EC). EC then constructs a hexagonal neuronal grid to contain the hippocampal message-processing place cells and identify where the animal or human was when the messages were thus ‘GPSed’ by the EC-hippocampus system [2]. Cueing the combined activation of the originally induced group of cortical ensembles after they have been hubbed (wired) together in the neocortex by the integrating hippocampus gives a replay of the events—the what and where and when [2][21][22][23].
As we shall see below, a powerful device was invented about 2/3 of the way through the neocortical expansion, likely by Homo erectus, which channeled the enormous flow of information about the individual’s external and internal worlds from the neocortex to the temporal hippocampus memory recording system. This became the deeply embedded temporal library of relatively small neuronal ensembles, which evolved into the words of our current human languages. These words can be accessed, variously combined, and recorded by the hippocampus system to produce and store throughout the neocortex as sets of words, each of which, when expressed, activate the original huge ensembles of neurons that produce the images that make up the flow of consciousness.
Alzheimer’s disease (AD)-like pathology emerges at low levels in the ECs of primates, such as aging macaque monkeys and very old chimpanzees, but it emerges far sooner and at a much greater level in the human lateral entorhinal cortex (LEC). AD is likely the product of the lifelong overloading of our memory-recording system, with immense amounts of data continuously streaming on it from the enormous neocortex that now occupies ~ 80% of the brain [24][25]. As pointed out above by Khan et al. [26] and Small and Swanson [27], AD starts in the tiny (only 1.3 × 105/~1.6 × 1010 neocortical neurons; 0.3/1843 cm2 neocortical area) entorhinal-perirhinal border-zone (BAs 28b and 35). This region is uniquely structured to guzzle ATP and receive non-spatial messages from the ventral stream. The message is further routed through the perirhinal collector, along with the parahippocampal spatial messages from the dorsal stream, into the dentate gyrus-hippocampus and the vmPFC/ACC (medial prefrontal cortex/anterior cingulate cortex) system for ‘engramming’ [1][3][27][28][29][30][31][32][33][34].
Unlike any other part of the neocortex, the human LEC (Lateral Entorhinal Cortex) has bumps called verrucae (Latin for warts), which are visible to the naked eye. They contain dense clusters of large neurons with dendrites reaching up into the layer 1 bundle of axons carrying message packets from the perirhinal collector/router to the LEC gateway and from there to the dentate gyrus-hippocampus [27][35][36].
As pointed out above, the basic core of AD is the selective targeting and pruning of PrPCs-bearing synapses by amyloid-β oligomers (AβOs). Therefore, this electrostatic attack by AβOs is probably most effectively carried out on neurons assembled, for example, to map exterior objects and events with their PrPCs-rich clusters of spines and synapses maintained in an LTP configuration, thus poised to replay the episode upon cue [12][37][38]. Each poised synapse’s post-synaptic component is loaded with increased numbers of actin filaments, clumps of PSD-95 associated with GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that, when activated by a Glu pulse, trigger a spike of Ca2+ by activated NMDARs The early reptilian proto-hippocampal medial pallium probably directly received and recorded the small amounts of minimally associated and edited primary sensory data projected into it from the tiny dorsal and the larger olfactory lateral pallia. As the evolving EC-hippocampal regions were induced to process ever-escalating amounts of diverse data from the expanding neocortex, they developed the two-collector system. The modern images in the modern conscious brain are produced by large interconnected ensembles of neocortical neurons. This probably did not challenge the ancestral, hippocampus-destined reptilian medial cortical pallium, which was as large or larger than the connected tiny dorsal cortical pallium and the then larger olfactory lateral cortical pallium [39][40][41][42][43][44][45]. The brains of our reptilian ancestors had no mammalian-strength neocortex. Their survival depended on such things as the OT (optical tegmentum) visual ‘Where’ system to locate and appropriately respond to predators, potential mates, and food sources. While on the other hand, the simple recognition of familiar salient objects depended on the olfactory and thalamic ‘What’ systems [46]. These things came together with the invention of the massive 6-layer, functionally diverse modules of the human neocortex wired together with long, invasive axons, which took control of the brain-stem OT and complexified the visual system. This created the four modern neocortical visual pathways, which included the OT ‘What’ pathway in the occiptotemporal pathway [46][47]. The medial pallium eventually became the hippocampal conformation, and its archaic lateral and dorsal pallial connections became, in part, the small LEC super-hub [41][44].
As mentioned in the Introduction, the AD’s AβOs are basically synapse-pruners and, therefore, network-disconnecting connectopathies. They are a kind of connectional diaschisis that spread along what appears to be a prescribed trajectory stretching from an EC nidus or ‘Ground Zero’ via parahippocampal gyrus to the retrosplenial cortex, posterior cingulate cortex, precuneus connector hubs, and the hub-rich default-mode network (DMN) [26][27][48][49][50][51][52]. Indeed, looking at the left medial hemisphere of the end-stage AD brain (Van Hoesen and Solodkin, Ref. [53]) and the striking overlap of the Aβx–42s deposition with cortical hub sites described by Buckner et al. [51], one can trace the destructive trajectory of the pathology from its EC nidus in the medial temporal lobe to the synapse-loaded neocortical hub-way. According to the electrostatic model discussed above, the toxic AβOs spreading out of the EC are likely to follow hub-ways with synapses loaded with PrPC targets in their PSDs.
So, after starting within the LEC nidus, AβOs likely spread upwards into the cerebral cortex leaving behind them a trail of highly visible amyloid plaques and pyramidal neurons stripped of their synapses [26][53][54][55][56][57][58][59][60][61][62][63][64][65][66]. However, AβOs seem to avoid the deeply anchored canonical sensory-motor regions (i.e., A1, MT, S1, and V1) and, at least initially, spare the basal ganglia-cerebellum non-declarative memory circuits [67].

2. Origins

The human brain, with its strikingly enormous neocortex dominating the relatively small limbic system, is the product of a disproportionate expansion of the neocortical prefrontal and the parietal association regions, with the vital memory-recoding machinery (including entorhinal cortices and the hippocampus) lagging behind [5][68][69][70]. This disproportional expansion of the neocortical/limbic region induced by the evolutionary neocortical ‘Big Bang’ might be a contributing factor in the development of AD in the longer-living, aging brain.
The current enormous 6-layer cortex is the product of a 3-layer reptilian-like brain consisting of periventricular sheets known as medial, dorsal, lateral, and ventral pallia, each with only one layer of pyramidal neurons [40][41][42][43][44][68][71][72]. Between the medial and lateral pallia was a narrow wedge of dorsal neuropil with an immense World-changing future—the enormous human neocortex. Something momentous happened in the third-layered (allocortical) brains of the mammal-like cynodontian reptiles that had survived the massive Permian Period extinction (~250 mya) and were on their way to full mamahood while coping with the emerging diurnal dinosaurs. These dinosaurs, with their special oxygen-conserving respiratory system, could thrive and grow in very low oxygen levels (~5–10%) during the ensuing Triassic and Jurassic Periods [73]. However, the evolving mammals, with their far less efficient respiratory system, had to stay small to cope with the oxygen lack and avoid the growing, evolving, and increasingly fierce dinosaurs. This forced them to shelter in burrows and function as much as possible in the cold at night with eye-supplementing-whiskers to scan and ‘feel-see’ things in dark places, advanced ear structures, and high-frequency communications to escape the attention of the ferocious diurnal dinosaurs [9][71][73][74].
One major brain-altering consequence of avoiding dinosaurs and coping with the lack of oxygen was a large expansion of the olfactory bulbs and the pre-piriform lateral pallium [5][44][68][75][76]. Consequently, the expanding lateral pallium slid over the dorsal pallial wedge to produce a potent double allocortical ‘sandwich’ with multiple layers of wide-ranging pyramidal neurons. This consisted of the overlapping part of the lateral cortex contributing layers II (2), III (3), and IV (4) and the underlying dorsal allocortex contributing the future layers V (5) and VI (6) of the unique mammalian neocortex. The non-overlapping, still three-layered part of the ancient lateral pallium stayed attached to the new neocortex as the allocortical piriform cortex [72].
Eventually, the mammals coming out of their nocturnal refuges took the first step on the road to the evolutionary ‘Big Bang’ and AD. With the extinction of the still-dominant and thriving non-avian dinosaurs as a consequence of the collision of a massive meteorite-asteroid with the earth, the early small mammals, with their novel neocortices, could spread out into the daylight and occupy terrestrial niches. The nocturnal limbic olfactory era then gave way to the diurnal audio/visual era. According to Paredes et al. [77], the increasing brain size and, with it, a lengthening RMS (rostral migratory stream) increasingly impeded and reduced the flow of progenitor neurons into the olfactory bulb. The lagging allocortical medial pallium stayed tightly connected to both the antique limbic olfactory region and the new elaborate neocortex and eventually became the hippocampus. Thus, was born the dangerously overstrained EC.
Thanks to the deadly diurnal dinosaurs, our ancestors developed the 6-layer neocortex, consisting of a two-dimensional, ~2–3 mm-thick, ~2600 cm2 layer consisting of Mountcastle cortical columns (modules packed side-by-side and functioning according to the regions to which they are linked) [78][79][80][81]. Thus, was produced the strikingly gyrified (wrinkled) powerful human neocortex because this was the only way a neocortical sheet could enormously expand without avoiding conduction delays and supporting high synaptic connectivity.
The dentate gyrus•hippocampal memory-recording machinery in the brains of the rat-sized early mammals was nearly half the size of the overlying neocortex (which, as in the rat, is itself less than 15% of the entire brain). They were likely flattened banana-shaped allocortical tubes attached by their stems to the septal complex of thalamically and hypothalamically connected nuclei in the evolving temporal lobe [41][42][44][45][81][82][83][84][85]. Alongside the hippocampal slab was the amygdala, which was also attached by a short extension to another hypothalamus-connected septal nucleus, the bed nucleus of the stria terminalis [44][85]. With the growing temporal cortex pulling on septal connections, the hippocampal and the amygdalar short medial septal connections were circularly pulled down into the dentate gyrus’s indusium griseum, the hippocampus’s fornix and the amygdala’s stria terminalis [45][85][86][87]. Thus, was formed, the group of ‘cables’ stretching down over the striatum and thalamus to the amygdala, the dentate gyrus-hippocampus attached to what became the subiculum, parasubiculum, and, the temporal EC gateway along with the pyriform, perirhinal and parahippocampal collectors and routers of the LEC and MEC hubs from the diverse neocortical regions [41][44].
Between ~6 and ~2 mya, while a succession of African hominins (Sahalanthropus, Ardipithecus, and Austalopithecus) was progressively distancing themselves from the panin ancestor but holding the sizes of their brains at ~320–450 mL, they were drastically modifying their skeletons to become uniquely bipedal [88]. While the hominins (with 46 chromosomes) originally had chimpanzee-sized brains, their brain size ‘suddenly’ began growing as if destined for a 1000-pound super-gorilla. However, the mutating genes in bipedal chimpanzee-like hominins generated a neocortical ‘Big Bang’. The surge began with Homo habilis, who emerged ~2.5–3 mya with ~612 mL brains. Then, ~21 mya, on the way through the Big Bang came early Homo erectus, who had the first modern body form and a ~870-mL brain. Then, ~ 1 million-50,000 years ago came late Homo erectus with a ~ 950 mL brain. These growing brains were encased in extremely thick skulls with thick occipital tori and very thick supraorbital ridges [89][90]. The H. erectus brain was followed ~200,000 years ago by the massive ~1500 mL H. neanderthalensis brain and the ~1350 mL (~8.6 × 1010 neurons) 46 (23 pairs)-chromosome H.sapiens brain, both of which had disproportionately massive neocortices loaded with ~200 functional regions [43][69][71][90][91][92][93][94][95].
As mentioned above, the evolutionary expansion of our enormous neocortex and, with it, today’s AD began when the mammal-like cynodonts with their reptilian-type allocortical brains were forced to shift over to olfaction by the emerging diurnal dinosaurs. It now appears that another event leading to the enormous neocortical expansion happened ~14 mya when an ancestral primate’s cortical NOTCH2 gene duplicated into a functional and a pseudogene [96]. During this time, both the hominin and non-hominin primates’ neocortices were growing because of the expansion of the gestational cortical VZs (ventricular zones) and the formation and subdivision of the SVZs (subventricular zones) into inner and outer regions (iSVZs and oSVZs) with NOTCH2-promoted accumulation of the progenitor cells in the oSVZs [97][98][99][100].
The next event leading to the massive growth of the human and Neanderthal neocortices may have happened ~3–4 mya only in a hominin ancestor with PDE4DIP-NOTCH2NL by interacting with the NOTCH2 gene. The enormous growth of the hominin neocortex over the subsequent millennia triggered by these Notch-involved events was due to the truncated NOTCH2NL-Bs somehow increasing the level of NOTCH2 activity, particularly in the oSVZ of the developing hominin neocortex [101][102]. This NOTCH2NLs-induced NOTCH2 activity increased neocortical growth via the increased NOTCH2′s NICD-induced Hes1 gene activity that prolonged transit amplifying (TA) cell accumulation in the oSVZ [97][98][101][103].
Another contribution to the hominin neocortical expansion was made by the ARHGAP11A gene when its partial duplication included a single base substitution [104][105], which shifted the original ARHGAP 11A localization from nuclear importation into neural progenitor cells’ mitochondria [105]. This stimulated glutaminolysis which, like Hes 1 gene stimulation by NOTCH2, increased oSVC and upper neuron production by stimulating TA proliferation and increasing the number of cells to differentiate into neurons and, with this, an enlarged number of neocortical columns.
This massive expansion of the neocortical mantle with its huge cognitive leap forward from Australopiths’ chimpanzee-sized brains to the expanding Homo brains was due mainly to increasing numbers and widths of the mini Mountcastle columns, enhanced prefrontal cortex’s executive functioning with increased axonal connections to the pre-motor and the parietal and temporal association regions [27][69][78][106]. The enormously increased cognitive power of the human neocortex also benefitted from cheaper, shorter, and denser interconnecting wiring by hemispherically lateralizing, cognitively advanced multimodal networks [107].
When the caudally increasing neocortex began pushing against the occipital cranial wall, it shifted its expansion downward and rostrally to produce a special primate protrusion, the temporal lobe of the memory machinery [44][80]. The pushing against the ventricular wall caused the allocortical plate to be forced into a sea horse (e.g Hippocampus leria)-like structure [44]. Although it was also growing, this ancient hub was only ~1.0–1.5% of the size of the massive neocortex. Though small, these relatively old complexes continued sending increasing amounts of data through the collector cortices into the EC-hippocampus for cortical hubbing of the event-participating networks [3][27][35][36][44][108]. This disproportionately expanding neocortex, now with more neurons than the other primate neocortices and an increased modal diversity of radial neuronal columnar units, resulted in the projection of enlarged streams of messenger packets to the LEC ‘hot spot’ gateway and through there to the hippocampus [27][44][71][108][109][110]. Thus evolved our powerful brain but with an age-hidden deadly glitch in the early short-lived humans.
Despite its undersized LEC data nexus, the big brain served the short-lived (~20 years) populations extremely well because the common life-long youthful brains were protected by the anti-stress array of protective mechanisms. Then, the only AD in the small tribes of big-brained Homo. neanderthalensis and Homo. sapiens would have been very rare EOD/FAD mutants locally spreading the connectopathy. This could have been caused by inbreeding or, maybe, by funerary cannibalism as was practiced not very long ago by the Fore tribe of Papua New Guinea, as suggested by the death of a tribe member from the PrPsc- induced Creutzfeldt-Jakob prion encephalopathy they called Kuru [111]. However, now, in our long-living (~75 years) populations, there are increasing numbers of super-old people with brains having only declining PQCs and failing glymphatic disposal systems that cannot prevent late onset or sporadic Alzheimer’s disease (LOAD/SAD).
Finally, relatively short lives and lack of sufficiently disproportionately large neocortices could explain the very late emergence of an AD-like connectopathy in aging monkey and chimpanzee brains. Thus, for example, the human neocortex is ~3 times larger than the chimpanzee cortex, but it is without a correspondingly enlarged entorhinal cortex [91]. This human combination accelerates and magnifies AD emergence. However, when artificially infused into the lateral ventricles of the much smaller brains of aged female rhesus monkeys, human AβOs accumulate in layer 3 of their dorsolateral prefrontal cortices and in the hippocampi where, just as in human AD, they target PSD95 and destroy spines and synapses [112]. In other words, all that is required to start and accelerate the connectopathy in the primates is to provide an endogenous or exogenous source of AβOs, i.e., create an artificial, human-like overworking entorhinal gateway.

3. How Might Alzheimer’s Disease Start?

Why are human LEC cells the AD starters? As mentioned above, the human LEC is structurally unique. Khan et al. [26] have found that the superficial layers of the AD-vulnerable LEC are extremely active; that is, they are a metabolic white-hot spot. The layer 2 cells are packed into striking bumps or verrucae, enmeshed in dense networks of blood vessels. Its neurons are loaded with mitochondria, and with the glucose and oxygen from the dense blood vessels, they generate ATP [113][114][115][116][117]. Obviously, this temporal region has evolved from overloading it with immense volumes of data to process from, for example, the conscious, awake neocortex. This is expensive; it requires lots of glucose and ATP. However, the production of toxic mitochondrial ROS byproducts (e.g., O●− → H2O2) in the LEC verrucae [118] becomes especially dangerous for aging LEC neurons with their declining protective tool kits.
The EC FC and SC gateway cells’ function is to appropriately process and then project the abstracted cortical data from the perirhinal and parahippocampal collectors into the dentate gyrus and the hippocampus proper for hubbing cortical networks into a cueable engram to replay the cortical event. The ‘ground zero’ AD initiators are the hyperactive LEC fan cells. Because the LEC II (2) verrucal cells are so active, they have more AβPP and are thus prone to produce more Aβx–42s than other neurons in normal brains. Thus, when their PQC systems start declining, they promptly start over- accumulating Aβx–42s, and secreting them into the surrounding pulsing perivascular shearing ISFs, which energize them into AβOs-seeding Aβ*s [27][119][120][121][122]. In other words, the LEC data nexus is a medial temporal ‘hot spot’ that releases large amounts of Aβx–42s into the pulsing ISF for making AβOs-seeding Aβ*s. As expected from this, Welikovitch et al. [54] have seen Aβx–42s ominously increasing with age in EC neurons before the appearance of any AD hallmarks, even in post-mortem brains from still cognitively normal individuals. Also, there is a large decline of connectivity in the medial temporal lobe, probably because of the early onset of synapse pruning by AβOs before a significant decline in cognition [52][123].
Another feature of these dentate gyrally-projecting layer 2 cells is their reelin, homodimers of which are needed to produce hippocampal dendritic spines and synapses in the adult brain [124][125]. In aging brains, as the Aβx–42s-clearing PQC systems are declining, layer II neurons start accumulating prion protein (PrPCs), which bind to reelin and cause the assembly of non-functional reelin multimers [124][126]. Normally the reelin dimers activate the ApoER2 receptors that stimulate fyn to tyrosine (Y)-phosphorylate Dab1 adaptors and inhibit GSK3β [127]. However, unlike the reelin dimers, the AβOs-induced reelin multimers do not cause ApoER2-Dab1-mediated activation of the fyn pathway. Thus, this process activates GSK3β, which, in turn, phosphorylates tau and produces toxic HPTOs [126]. Thus, AβOs and HPT start their long connnectopathogenic process from the limbic region.
Because the layer II (2) verrucae of the small LEC → hippocampal gateway are incessantly bombarded by multimodal messages from the huge neocortex, it becomes the most heavily damaged of all cortical regions by the AD connectopathy [115]. It costs a lot of ATP to process this data flow, but the EC astrocyte•neuron teams (ANTs) must contend with toxic ROS-byproducts from their overworking synapses’ mitochondria [118][128][129][130][131]. This could be the reason why these neurons are so vulnerable to destruction. Indeed, the continual ROS-generating data processing in the hot spot is equivalent to focusing a destructive beam of ionizing radiation on it [132].
Neurons in the nidal EC layer 2 verrucae, like other active neurons, can make a lot of Aβx–42s during SVC (synaptic vesicle cycling) and release it, through, for example, exosomes, along with the glutamate transmitter, into the synaptic cleft [27][120][121][122][124][133][134][135][136]. In the reelin-expressing EC ‘hot spot’ nexus of a young brain, these activity-generated Aβx–42s are kept at a safe level by the cells’ diverse protection systems [120][121][133][134][135][136][137]. At this stage, the tau protein in the busy neurons is compartmentalized in the neuronal axons forming microtubule trackways in association with tubulin, along which the kinesin and dynein transporters carry cargos to and from the presynapses [138]. Tau is normally prevented from dangerously escaping into the somatodendritic compartment (SDC) by the AIS (axonal initial segment) filter [139]. As the brain ages, with the weakening PQC systems, neurons will start hyper-accumulating Aβx–42s which seed AβOs that stimulate tau-hyperphosphorylating kinases such as GSK 3β. The hyper-phosphorylated tau detaches from axonal tubulin and can pass through the AβOs-impaired AIS into the SDC [140]. In addition, activation of fyn kinase signaling by the accumulating AβOs stimulates tau synthesis via MAPK (ERK), S6, and the loading of the SDC with hyperphosphorylated tau. Thus, the AβOs have set the stage for the massive multipronged network-destroying attack on the PrPC-displaying synapses [124][126][133][141][142][143][144][145].
Besides this, AβOs in the ISF also start the core synapse-pruning by selectively and avidly binding to PrPC -displaying PSD to form a transmembrane signaling receptor complex with the mGluR5 (the metabotropic GluR5 receptor). This activates the SDC fyn kinase in PSD and contributes to synapse destruction along with the complement system-activated microglial cells, as described above. The activated fyn kinase can also hyper-activate neighboring ionotropic NMDAR, which destroys the synapse by triggering an excitotoxic Ca2+ surge through the receptor [62][133][146][147][148][149][150].
This is not all. As we outlined in more detail above, the AβOs also induce the ANTs astrocytes to induce the neurons to tag their synapses with complements of C1q and C3 to form C1q•C3 complexes that stimulate microglia hovering nearby in the ISF to phagocytose the synapse by activating their C3 receptors [151][152][153][154]. The AβOs also inhibit NKA-α3 (Na/K ATPase-α3), and with it, the ability to generate action potential and eventually open another way for toxic Ca2+ build-up [155][156].
As discussed above, the vulnerability of these energy-guzzling cells in LEC verrucae is also partly attributable to their synapses’ large loads of mitochondria that are also the targets of AβOs [157][158][159]. The AβO•PrPC•mGluR5•Fyn signaling complex converts the mitochondria from ATP producers to ROS producers and releasers of apoptogenic cytochrome c by disabling various mitochondrial targets, including the Complexes V and IV, and ATPsynthase [143][145][158][160][161][162][163]. Thus, these cascades of events stimulate the production of superoxide and its toxic products instead of driving ATP production, leading to the killing of cells and thus, destruction of the EC gateway [158][164]. The accompanying mislocalization of hyper-phosphorylated tau prevents any mitochondrial replacements from reaching the moribund neuronal synapses from the neuronal soma. [165][166]. Thus, the EC gates are closing, and the data/information-collecting olfactory, perirhinal and parahippocampal regions are disconnected from the dentate-hippocampus and, with this, episodic memory recording.
Until very recently, another likely participant in AD connectopathy has been ignored. Neurons, like most other mammalian cells, have immobile primary cilia bristling with various receptors and are key parts of the cognitive machinery [167][168]. They are most likely involved in AD because it has recently been shown that AβOs target the p75NTR in the primary cilia of murine hippocampal neurons, the resulting signals from which impair recognition memory [169]. It is known that the AβOs in the ISF somehow collect at the ciliary base where they prevent such things as ciliary growth and p75NTR and SHH [Sonic Hedgehog]signal transductions in the dentate-gyrus and thus contribute to spreading the connectopathy [168][169][170][171]. It is not clear how AβOs reach the ciliogenic machinery in the centrosomal hub. One possibility is that the AβOs in the pulsing ISF simply bind to the waving cilium and are carried down to the cilial base [119]. Another possibility might involve the PCM-1 protein. This is a 228.5 kDa protein that is believed to be involved in ciliary structure and function [172][173][174]. PCM-1 has a highly basic, K+-rich patch in its 1276–1314 region, which selectively binds AβOs [175]. Thus, we speculate that PCM-1 may pick up negatively charged AβOs with its polybasic patch and deliver them to the ciliary base and affect their function.

4. The Spreading of Late- Onset or Sporadic Alzheimer’s Disease (LOAD/SAD) Connectopathy

At the heart of the slowly spreading LOAD/SAD in the aging brain is the heavy intercellular traffic of EVs (extracellular vesicles, exosomes) along the main cerebral pathways [176][177]. The EV cargos are normally lipids, proteins, and mRNAs. The cargo might also include products such as the AβOs that are delivered by the attachment of the donor’s loaded vesicles to the recipients’ membranes, followed by the endocytic release of the AβOs [178][179]. The connectopathy is also locally spread from the nidus by the release of AβOs-seeding Aβx–42s into the ISF by neuronal SVC and AβOs from periplaque halos [119]. As mentioned earlier, this happens at first asymptomatically and spreads from the nidus, with AβOs pruning synapses and disrupting the dense connections of the allocortical olfactory, amygdala complex, and the transitional entorhinal–allocortical hippocampal complex [26][52][53][127][141][144][165][180][181][182][183][184][185]. The spread of the connectopathy is likely maintained by at least two things: the selective attraction and binding of ISF AβOs to postsynaptic PrPCs, and the resulting Ca2+ surge-induced stimulation of CaSRs that induces the cell to make more AβOs [186][187][188]. When the ANTs in parts of aging brains, such as the hippocampus, start seeding toxic AβOs, they try to destroy them with their fading autophagic machinery. They inflate MVBs (multivesicular bodies) with the degradation-resistant AβOs that are eventually released as EVs into the ISF, with their toxic contents being delivered to nearby cells [127][133][176][177][178][179][189][190][191][192][193][194]. Moreover, instead of being released from neurons or astrocytes in EVs, some AβOs may enter the ANT cells’ nuclei and bind to the AβID (Aβ-interacting domain) regions of the AβPP and BACE1 gene promoters to increase endogenous Aβ production and enhance the spreading intra-brain infection [195][196]. In contrast, AD trajectory in an EOAD/FAD brain can spontaneously hyper-accumulate AβOs-seeding Aβx–42s either because they have 3 chromosome 21s (Down’s syndrome), each carrying an AβPP gene or one of the two autosomal dominant secretase genes (e.g., presenilin 1). However, here too, the LEC is likely to be the nidus because these “mutant” neurons are also equipped to hyper-produce Aβx–42 in their structurally unique EC nidal ‘hot spots’ although we would expect them to be maintained much closer to the picomolar ‘red line’ than pre-LOAD/SAD cells and likely to be pushed over it by earlier and therefore smaller declines in a younger brain’s Aβx–42s clearance mechanisms [165][197][198][199].

5. Ca2+-Sensing Receptors Participation in Driving the Connectopathy

Neuronal activity promotes the production and release of Aβx–42s along with neurotransmitters from the ANT neurons, and thus the amount released into the pulsing ISF is a function of neuronal activity. Indeed, SVC is necessary for amyloidogenic AβPP processing [121][136][200]. In a normal plasma membrane, AβPP is compartmentalized into one set of small lipid rafts, and the individual secretases that cleave the Aβx–42s out of it reside in separate rafts. This separation in the normal membrane is maintained by the MARCKS (myristolylated alanine-rich protein kinase C substrate) protein with its myristoylated N-terminus inserted into the membrane and its highly basic (K-rich) 152–172 patch bound to membrane PIP2s (phosphatidyl inositol bisphosphates). Under these conditions, AβPP is directly targeted by the non-amyloidogenic membrane α-secretase, ADAM 10, and produces a neurotrophic and neuroprotective sAβPPα fragment [136][201][202][203][204]. Besides synaptic stimulation, another early event in AD development appears to be increased PKC activity [205]. PKC phosphorylates several sites on MARCKS protein (S159, S163, S167, S170), which causes the strongly positive K-rich 152–172 patch to become less positive and thus separate it from PIP2. This permits the fusion of lipid rafts, which allows the interaction of AβPP with secretases resulting in the production of Aβx–42s [136][186][201][202][203][204][205][206]. When the neuron empties these loaded synaptic vesicles, the Aβx–42s are released into the synaptic cleft along with the neurotransmitter [54]. The released Aβx–42s in the pulsing ISF then seeds AβOs that can infect more distant cells as described earlier [119][136][176][177][189][207]. A consequence of the Aβx–42s accumulation in the aging EC cells appears to be the stimulation of CaSR expression [208]. Small locally produced AβOs-‘barrels’ lined with their negatively charged N-‘tails’ are inserted into the cell membranes and enable a Ca2+influx, which would activate the CaSRs [119][136][155][186][209][210][211][212][213]. The AβOs can also stimulate CaSR via the AβOs → PrPCs → mGluR5 → NMDA triggered Ca2+ surge described above. Most importantly, activated CaSRs are also AβOs replenishers that maintain the ‘contagion’. Thus, there are two ways the anionic AβOs can selectively induce connectopathy-driving reactions, one via Ca2+•CaSR-mediated production and release of AβOs seeding Aβx–42s, and another by reducing ADAM10 and increasing AβPP [186][210]. Moreover, the AβOs → Ca2+ → Ca2+•CaSR signaling induces various harmful cytokines [181][186][187][210].

6. Why Is Late OAD/SADnset or Sporadic Alzheimer’s Disease a Disease of Aging?

As pointed out above, the densely crowded and intricately structured cellular inner nanoworld, be it neuronal or astrocytic, is constantly battered by the aqueous Brownian maelstrom [214][215]. Thus, the complex interacting nano-devices in such a place must constantly be repaired or replaced. As these systems decline over the years in the wild-type brain, the damage mounts, and LOAD/SAD is one of its many consequences. An example of one such important decline in the aging brain is that of BDNF, likely because of the reduced physical exercise of older people [216]. The high activity forced on the neurons in the EC gateway-hippocampus complex in a young brain produces relatively large amounts of Aβx–42s which normally promote synaptic plasticity and episodic memory recording provided they are kept at or below picomolar levels [120][122][124][133][134][135]. As the PQCs decline with age, some of the increasingly uncleared Aβx–42s seed mixed ‘cocktails’ of toxic AβOs in the ISF and on the surfaces of large plaques [119][156][166][186][217][218][219][220][221]. In the healthy young brain, PQCs prevent Aβx–42s surging above the physiologically safe picomolar level. For example, Aβx–42s/AβOs can be cleared by zinc-metalloproteinases such as insulysin and neprilysin and/or by transportation across the blood–brain barrier (BBB) into the blood circulation by lipoprotein receptor-related protein-1 (LRP1) [218][222][223][224]. Then, there is also the glymphatic system in which networking astrocytes take up waste from the brain with their neurovascular endfeet and drain it into the peripheral lymphatic circulation [119][225][226][227][228][229]. Glymphatic processing starts in CSF from the four ventricular choroid plexuses flowing out of the fourth ventricle into the SAS (subarachnoid space) through the foramina of Magendie and Luschka [230]. As the CSF flows through the SAS, portions are pulled down into the perivascular Virchow–Robin spaces by the pulsing arteries and arterioles. Stationed along these pulsing vessels are phalanxes of astrocytes attached to them by end-feet containing AQP4 (Aquaporin 4) water channels [229][230][231][232]. This astrocyte system, functioning optimally in a young sleeping brain, sends a bulk flow of waste-bearing ISF through the large veins, into the arachnoid granulations, the superior sagittal sinus, and finally into the peripheral circulation. With advancing age, the penetrating arterial and arteriolar walls stiffen, and thus, the glymphatic system’s principal pumps weaken, the phalanxes of periarterial astrocytes disperse, and the Aβx–42s/AβOs-bearing ISF flow slows [228][229][233]. Along with this, the system is likely being progressively dismantled with the perivascular AQP4-bearing astrocytes being dispersed by the accumulating AβOs. Various cytokines, as well as NO and its toxic derivatives and MMP9 (Matrix MetalloProteinase 9), produced by astrocytes in response to AβOs, disrupt the claudin-attached BBB lining of the blood vessels [229][232][234]. The destructive impact of the declining sewage system on the cognitive machinery is increased by the build-up of high molecular weight AβOs not being clearable from the interstitial fluid [155][235].

7. The Clinical Emergence of Late LOAD/SADOnset or Sporadic Alzheimer’s Disease after Its Long Stealthy Prelude

As the connectopathy spreads outwards and upwards from its shrinking nidus, it leaves a trail of harmless Aβx–42s monomers and toxic ‘cocktails’ of ‘infectious’ AβOs that will destroy, for example, the hippocampus, the posterior cingulate gyrus, and parietal cortical rich-club networks, but not primary motor, or somatosensory areas [53][223][236][237][238][239][240][241]. However, the Aβx–42s and AβOs from the cells are locked into the dense cores of large senile plaques that prevent them from spreading the contagion beyond their immediate neighborhoods [217]. However, Aβx–42s being squeezed and stretched by flowing over the surfaces of large plaques can seed AβOs that can attack and prune nearby synapses [217]. Most importantly, the plaques can mark the trajectory of the connectopathy from the EC to its neocortical targets [242][243][244]. The changes in the levels of the Aβs in the blood and CSF also reflect the kinetics of formation and clearance of Aβx–42s/AβOs and have enabled the detection of the spreading pathology much before the onset of clinical symptoms [217][245][246][247]. Along with synaptic pruning and cell cycle initiation, there is a surprising pre-plaque fMRI-detected surge of false hyperactivity in the hippocampus despite the degenerating fornix and the EC layer II2 [26][153][219][248][249][250][251][252][253][254][255][256][257]. Despite this spurious hyperactivity, there is a significantly impaired functioning of the dentate gyral/CA3 regions in MCI brains, along with their shrinking hippocampi [258][259]. One cause of this early hippocampal hyperactivity could be the accumulating AβOs that activate CaSRs that can hyperactivate hippocampal pyramidal cells by downregulating their GABA-B-R1 receptors [187][260][261][262]. A related reason could be the increased MMP-9 levels that damage the pyramidal neuron-restraining hippocampal GABA-ergic PV+ (parvalbumin) interneurons by destroying their protective PNNs (perineuronal nets) [263][264]. Since fMRI gives a signal based on blood oxygen and volume levels [265], another possible contributor is the AβOs-stimulated release of VEGF (vascular endothelial growth factor) and proinflammatory cytokines (i.e., Il-1β, IFN-γ, TNFα) from astrocytes’ end feet attached to hippocampal blood vessels during the prolonged presymptomatic period. Such a sustained VEGF bombardment should drive angiogenesis and increase the EC gyral/hippocampal microvasculature density and, with it, the BOLD fMRI signaling responses [260][266][267][268][269][270][271][272][273][274]. An enhanced surge of blood through such an expanded vasculature would flood the shrinking hippocampus with oxygen and glucose, thus instead of a fading BOLD fMRI signaling, there is supernormal BOLD signaling peaking in mid-MCI [248][259][274][275][276][277]. This means that a hypersurging blood flow along with damage to the GABAergic PV+ neurons will make DG/CA3 cells hyperoxic, hyperglycemic, hyperactive, and, consequently, hypofunctional [270]. Moreover, and most importantly, the hyperactive neurons will produce and release into the ISF increasing amounts of AβOs-seeding Aβx–42s [121][248][250][278][279]. The post-MCI collapse of the BOLD fMRI signal when the brain converts to full-blown AD is likely, at least in part, due to the sustained spreading of perforation and severing of blood vessels, particularly in the hippocampus induced by Aβ (Aβ1-40) deposits and the production of NO and its toxic derivatives [260][268][272][280][281]. There will be spreading regions of hypoxia from the vascular damage leading to a buildup of HIF-1 (hypoxia-inducible factor-1), which in turn would stimulate Aβx–42s/AβOs production by activating BACE1 and γ-secretases [266][282][283][284][285][286]. Along with this spreading BBB breakdown are the local leakages of toxic serum components into the brain, which can activate astrocytes and microglia to produce inflammatory cytokines. This is accompanied by a spreading shortage of glucose and thus ATP [229][287][288][289][290][291]. Thus forms the basis of the hypo-metabolism indicated by declining 18FDG-PET signaling in regions along the AβOs’ trajectory, such as the PCC and precuneus [245]. As conversion to full-blown AD nears, not enough damage has so far been done to disrupt daily activities, but the roiling intra-brain pathological activity could be seen in disappearing EC layer 2 verrucae, shrinking hippocampi, and cerebral ventricles swelling [115][116][129][245][288][292][293][294][295]. However, the spreading of AD connectopathy becomes increasingly entangled with other pathologies-of-age, especially neurodegeneration-promoting cardiovascular diseases. Eventually, the spreading damage reaches the threshold of irreversibility.

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