Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neuropathol Exp Neurol. Author manuscript; available in PMC 2009 October 19.
Published in final edited form as:
PMCID: PMC2763411


Rudy J. Castellani, M.D.,1 Hyoung-gon Lee, Ph.D.,2 Xiongwei Zhu, Ph.D.,2 George Perry, Ph.D.,2,3 and Mark A. Smith, Ph.D.2


Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized clinically by dementia and neuropathologically by accumulation of senile plaques and neurofibrillary tangles. Identification of their constituents in the mid 1980s led to an exponential expansion of knowledge pertaining to metabolic pathways of amyloid-β (Aβ) and tau, in terms of normal human physiology and pathophysiology of neurodegeneration. Forgotten is the fact that our experience with AD pathology is based on end-stage lesions that have an imperfect correlation with clinical dementia in terms of lesion burden and affected brain region, and that the an AD is based on lesions that also occur in cognitively intact elderly. Attempts at addressing this fundamental defect now focus on toxic intermediates, namely Aβ oligomers, and their potential direct involvement of the synapse. Current thinking on AD pathology includes the concept that hallmark lesions may be non-toxic- something we have long been suggesting. We favor the interpretation that AD pathology represents a host response to an upstream pathophysiological process, and targeting lesions, including toxic intermediates, will not likely be beneficial so long as the host response is directly deleterious. Therefore, renewed efforts directed at basic age-related processes, such as oxidative stress and/or inflammatory mediators, are warranted.

Keywords: Alzheimer’s disease, amyloid, tau


The discipline of neuropathology is principally concerned with structural alterations in neurologic disease and, in particular, structural alterations that can be visualized microscopically (Figure 1). This being the case, the pathological interpretation of neurodegenerative diseases necessarily focuses on inclusions and that which can otherwise be visualized. The question at issue here is whether such lesions, in addition to being convenient for study by the simple fact of their detectability, contain components or molecules that drive the disease, or whether those lesions are better viewed as by-products of the basic pathobiology that preceded the accumulation. Neuroscientists, since the time of Alois Alzheimer and up to about 20 years ago, entertained a variety of mechanistic hypotheses to explain the neurodegeneration (1). Inclusions tended to be viewed as “hallmark” lesions, rather than indicators of etiology. However, in more recent years, genetic analysis has led to the linkage of lesions to specific proteins, and led the field to pathogenic cascades that are presumed to be etiological (2).

Figure 1
The microscopic lesions of AD have shaped our views on the etiology and pathogenesis of the disease. The neurofibrillary tangle (A), composed of hyperphosphorylated tau protein accumulated in paired helical filaments, and senile plaques containing amyloid-β ...

Of concern, such expanded knowledge of inclusion constituents has led to an increased and undue enthusiasm among many neuroscientists to presume etiology, and has diverted attention toward processes that are, in essence, a host response to the underlying pathophysiology. Indeed, despite considerable time, expenditures, and repeated modifications, lesion-based therapies continue to be disappointing (3, 4), such that the standby of simple enhancement of neurotransmission remains the only modestly useful therapy (5). In our opinion, a fundamental re-organization of the thought processes, reflecting the basic premise that proteinaceous accumulations are consequence of the disease rather than cause, maybe in order and is, in fact, somewhat overdue (6).


Historical Notes

While plaques were a known accompaniment of senile dementia in the late 1800’s, the first description of the neurofibrillary tangle (NFT) in 1907 can be attributed to Alzheimer (7). The lengthy description of “neurofibrils” by Fuller several months prior to Alzheimer’s description of Auguste D. has been suggested as evidence that the NFT was also known prior to Alzheimer’s description (8); however, a careful review of Fuller’s paper indicates that he was most likely describing normal cytoskeletal elements and not genuine NFTs. It is also interesting to note that Alzheimer devoted ten sentences and two paragraphs to his initial description of the NFT, compared to only two sentences to the senile plaque (7, 9); this, and the fact that plaques were a known component of senile dementia at that time (10), suggests that the NFT was the more intriguing lesion. So much so that Alzheimer was compelled to spend considerable time and effort illustrating NFTs and their variations (11). Nevertheless, in spite of copious literature written by Alzheimer and his contemporaries, it is difficult to find firm allusions to the cause of the basic disease process (913). Rather, the importance and controversy rested for the most part in whether this condition affecting a relatively young patient represented a new disease or, instead, was a form of senile dementia with early onset (13).

The fact that NFTs stained intensely with the Bielschowsky silver technique, while unaffected neurons failed to stain, highlighted the utility of the silver impregnation for diagnostic purposes. Moreover, Bielschowsky silver made visible extracellular NFTs, which were sometimes numerous, and raised theories that date to Alzheimer’s description of Auguste D. about altered cytoskeletal elements that conferred their insolubility (11).

“Because these fibrils were stained differently from normal neurofibrils, a chemical conversion of the neurofibrils must have occurred. This may well explain why the fibrils survived the decay of cells…”

The structure of the NFT was further elucidated by Terry in 1963 (14), and Kidd in the same year who described paired helical filaments (15). Some ultrastructural details were subsequently added to literature (16), but it was not until 1986 that NFTs were purified and the microtubule associated protein tau determined as the major protein component (17). Since purification of tangles and the identification of tau occurred about two years after the identification of amyloid -β, and since Down’s syndrome and familial Alzheimer’s disease (AD) linked to amyloid-β protein precursor gene mutations provided compelling genetic evidence of a link between amyloid-β (Aβ) and disease, it is not surprising that Aβ assumed primacy over tau as the important pathogenic, if not etiologic, factor in AD (2, 18, 19).

Tau Protein

Since the identification of tau as the major component of neurofibrillary pathology, knowledge of tau has expanded considerably. We now know that the tau gene is comprised of over 100 kb and contains 16 exons (20). Upstream of the first exon are consensus binding sites for transcription factors such as AP2 and SP1. Alternative splicing of tau nuclear RNA transcribed in the adult brain on exons two, three, and ten, results in six tau isoforms. The isoforms differ in the presence of either three of four peptide repeats of 31 or 32 residues in the C termimal region encoded on exon 10. This peptide repeat region comprises the microtubule binding domain. Tau isoforms also differ in the expression of zero, one, or two inserts encoded on exons two and three. The relative amounts of these tau isoforms as well as their phosphorylation status changes during development; 3 repeat tau with no inserts is expressed in the fetus and early post natal infant, while heterogeneous isoforms are expressed in the adult brain. This switch in RNA splicing also corresponds to a reduction in tau phosphorylation. Tau is relatively abundant in neurons but is present in all nucleated cells and functions physiologically to bind microtubules and stabilize microtubule assembly for polymerization.

In disease, tau is abnormally hyperphosphorylated at proline directed serine/threonine phosphorylation sites (2022), including Ser-202/Thr-205 (AT8 site), Ser-214 and/or Ser-212 (AT100 site), Thr-231 and/or Ser-235 (TG3 site), and Ser-396/Ser-404 (PHF-1 site). In addition, alternative tau splicing as noted above has a tendency to differ depending on pathological phenotype, such that tau accumulation in AD is a mixture of 3R and 4R tau, Pick disease tends to be 3R tau, corticobasal degeneration and progressive supranuclear palsy tends to be 4R tau, and so-called argyrophilic grain disease accumulates small inclusions comprised of 3R tau. The general term “tauopathy” is thus used as a means of broad classification of neurodegenerative diseases.


Historical Notes

Historical accounts indicate that senile plaques were described in 1892 by Blocq and Marnesco in the brain of an epileptic patient (10). Redlich also described plaques in two elderly epileptics in 1898 and termed them “milar sclerosis.” Beljahow described plaques in association with senile dementia in 1887 (23), as did Redlich and Leri shortly thereafter (24). Alzheimer himself acknowledged previous descriptions of plaques in the setting of senile dementia (13, 25):

“The patches in the cortex had in the meantime been observed in Presbyophrena by Fischer who described them in detail in a number of papers and considered them as characteristic of that disorder. Redlich had also demonstrated them by different methods. I had myself already observed and described them in Dementia senilis using Nissl and Weigert staining…”

Nevertheless, like NFTs, senile plaques had not been previously described in association with early onset or presenile dementia. It is also noteworthy that the second described case of AD, Johann F., was ostensibly a case of “plaque only” AD, while pedigree analysis indicated a case of familial AD (13).

Emil Kraepelin was the first to use Alzheimer’s name in association with dementia in the 8th edition of his textbook of Psychiatry (12), not because of the association of specific lesions with disease, but because the disease affected a relatively young individual. Alzheimer was reticent to accept the new eponym but nevertheless acknowledged:

“Even if the anatomical findings might suggest severe mental impairment, the early onset (one would have to assume a ‘senium praecox’), the profound language disturbance, spasticity, and seizures are very different from those of presbyophrenia which is usually associated with purely cortical senile changes…” (13, 25)

If terminology were applied today as it was in the early 1900’s, “Alzheimer’s disease” would be reserved for early onset disease, while late onset disease would be referred to as “senile dementia,” a condition known to be associated with advanced age and accumulation of senile plaques prior to Alzheimer’s description. Given the association between early onset disease and germline mutations (26, 27), one might also suggest that “Alzheimer’s disease,” or presenile dementia, is essentially familial early onset AD, while an arguably different process, “senile dementia,” refers essentially to sporadic disease.

Similar to NFTs, senile plaques showed an affinity for silver with the Bielschowsky silver technique, and were recognized as largely extracellular lesions since Marinesco’s suggestion that plaques were derived from condensation of intercellular ground substance (28), foreshadowing the work of Divry who reported in 1927 that plaques, like amyloid, were birefringent following Congo red staining (29). Little progress had been made into plaque pathogenesis aside from some ultrastructural details (30), until modern molecular techniques were applied to purified vascular amyloid and amyloid plaque cores (31, 32), and demonstrated a small protein, designated amyloid-β, later discovered to be a metabolic product of amyloid-β protein precursor, transcribed on chromosome 21. Review of the literature around this time period demonstrates a conspicuous shift in the notion that plaques are an accompaniment of disease, to the assignment of plaques being directly tied to etiology and pathogenesis (3336). Identification of kindreds of familial AD linked to point mutations within and around the Aβ coding region, and the neuropathology of Down’s syndrome (early plaque pathology), reinforced this notion.


Like the expansion of knowledge related to tau, the discovery of Aβ was followed by an encyclopedic accumulation of data regarding the protein, its processing, and alterations in disease. It is now known that Aβ is the normal metabolic product of the amyloid-β protein precursor (AβPP) via the action of two aspartyl proteases, β-and γ-secretase (2). β-secretase first cleaves AβPP which sheds a large C terminal fragment. The remaining membrane bound C terminal stub is then cleaved by γ-secretase producing an Aβ peptide of 38, 40, or 42 amino acids. The Aβ42 fragment is said to be more pathogenic with a greater tendency to form fibrils and deposit in neural parenchyma (37). Indeed, the increased Aβ42/Aβ40 ratio is considered a basic pathophysiological process that drives the disease, per the Amyloid Cascade Hypothesis (38).


Evidence that Aβ causes AD is largely genetic, based on key findings with respect to Down’s syndrome (AβPP overexpression) and familial AD (inherited mutations that alter AβPP processing resulting in Aβ) (2, 6). Data with respect to apolipoprotein E (ApoE) are sometimes cited in support of a causative role of Aβ, as ApoE variously facilitates Aβ fibrillogenesis experimentally as a function of polymorphic alleles that are associated with various risks for late onset AD, although ApoE studies lack the precision of the AβPP data, as well as a clear biochemical link to disease. The host of transgenic constructs and their experimental manipulations are also touted as critical evidence that substantiates the hypothesis, although models suffer with respect to relevance (e.g., the necessity for multiple mutations, absence of neuronal loss, relevance of cognitive dysfunction in mutated mice, presence of cognitive dysfunction in some animals with minimal pathology) (39). All things considered, the presence of AβPP-linked familial AD and changes in Down’s syndrome brains are still the most compelling pieces of evidence in favor of the Amyloid Cascade Hypothesis, without which the hypothesis would not be credible.

The Amyloid Cascade Hypothesis thus relies on the following pieces of data: 1) Aβ accumulates in senile plaques in the AD brain; 2) specific point mutations in the gene for AβPP cause familial, early onset AD; and 3) increased copy numbers of AβPP in some cases of Down’s syndrome lead to relatively early Aβ deposits and pathology generally associated with AD later in disease, including neuritic plaques and neurofibrillary pathology. Also noteworthy is an anecdotal report of a rare case of a Down’s syndrome, in whom the distal location of the 21q breakpoint left the patient diploid, rather than triploid, for the AβPP gene (40). This patient showed no signs of dementia and very little amyloid deposition at autopsy. The identification of kindreds carrying mutations in the presenilins are also suggested as evidence of the primacy of Aβ, as presenilins comprise a component of the γ-secretase complex (4143) that generates Aβ from AβPP.

While the evidence of a genetic lesion involving a specific protein (AβPP mutation, trisomy 21) and a resulting, protein-driven phenotype resembling AD is well established, it is important to point out that the total identified familial early onset AD kindreds, with known mutations number only about 450; of these, AβPP kindreds number less than 100 and PS2 mutation kindreds less than 20 (Alzheimer’s Disease and Frontotemporal Dementia Mutation Database, This is in contrast to the denominator of dementia subjects who number at least 20 million across the globe. Moreover, in sporadic disease, specific risk factors come into play (e.g., head trauma, diet, sex hormones, educational background, aluminum exposure) (6), many of which are either unaccounted for by the Amyloid Cascade Hypothesis, or accounted for only on an ad hoc basis. Clinical presentation in familial disease is also heterogeneous and often unrecognized as AD. Presentations such as cerebral hemorrhage without dementia, spastic paraparesis with delayed dementia, subcortical dementia with Parkinsonism, and seizures (6, 44, 45) clearly differ from sporadic AD. Also, pathologically, the extensive Aβ burden including extensive white matter, deep gray matter, and cerebellar amyloid, and “cotton wool” plaques that lack fibrillar Aβ (e.g., PS1 mutation cases) differ from classical sporadic AD. These clinicopathological data suggest overall that early onset familial AD imperfectly mimics the far more common sporadic condition.

Finally, while the Aβ1–42 species is commonly accepted as “pathogenic,” and the increased ratio of Aβ1–42: Aβ1–40 in familial AD is posited as a central piece of evidence (37, 46, 47), more recent studies show that the increased ratio is not due to an increase in Aβ1–42 but rather a marked decrease in Aβ1–40 (48, 49). As such, mutations that cause AD do so by producing less Aβ (50). Why this would be the case is a matter of investigation, but it raises the point that the primary role of Aβ in AD pathogenesis should be open to question; the question of whether or not the Aβ cascade is a primary process should be a research priority, rather than the copious search for supporting evidence.


A Diagnosis of Exclusion

The wealth of knowledge now available about the molecular biology of tau and Aβ tends to distract from the basic human neuropathology. Several problems are nevertheless important to keep in mind. Shortly after the initial description of AD, it was recognized that senile plaques and NFTs both occur with advanced age in non-demented individuals (13). The diagnosis of AD at autopsy therefore was, and still is, a quantitative exercise (6). In reality, the presence or absence of senile plaques and NFTs is diagnostically meaningless; clinical dementia is required to establish the diagnosis, as are numerous plaques and tangles. Diagnosis of AD is therefore a clinicopathological correlation that requires lesion quantitation, rather than a pathological diagnosis per se.

It is further interesting to note that among the various neurodegenerative diseases, AD is the only condition that overlaps substantially with “normal aging.” Cortical Lewy bodies and Lewy neurites, the various pathological changes associated with frontotemporal dementia, and the various inclusions associated with subtypes of tauopathy, for example, are generally not encountered in the cognitively intact elderly. One exception may be Argyrophilic Grain Disease (AGD), although the frequent co-existence of other conditions in AGD (51), and the general poor relationship with frank dementia, suggests that AGD is (arguably) better classified as an age-related change rather than a specific neurodegenerative disease. AGD aside, it may be stated that AD is the only neurodegenerative disease that is essentially a diagnosis of exclusion. Most neuropathologists who have had the opportunity to examine elderly brains at autopsy, and compelled to provide a prospective diagnosisin the absence of detailed neurological data and in the presence confounding factors such as polypharmacy, hydrocephalus, and a host of metabolic derangements, understand the limitations of histopathology, and the often mythical concept of “autopsy-proven” AD. Indeed, in one study, the diagnosis of “dementia of unknown etiology” approached 50% in nonagenarians (52).

Moreover, AD is a chronic, non-neoplastic disease, usually examined pathologically at the end-point, i.e., at autopsy. In other chronic, non-neoplastic disease processes in which biopsy experience is available (e.g., chronic renal failure, chronic liver disease, interstitial lung disease, neuromuscular disease), pathology invariably loses specificity with increased disease duration (6). Yet, in interpreting neurodegenerative disease, the task of the neuropathologist is to distinguish among clinicopathological entities and to provide specificity. This being the case, it is not surprising that such terms as “possible,“ “probable,” and “intermediate likelihood” are part of diagnostic terminology, even after rigorous semiquantitation and correlation with age.

Specific Diagnostic Criteria

The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) convened a Neuropathology Task Force with the expressed long term goal “to produce more accurate and reliable neuropathologic criteria for AD, to determine the neuropathologic spectrum of AD, and to establish the types and frequencies of other disorders coexisting with AD or occurring alone.” (53) The criteria included sampling of three neocortical areas among other regions, impregnation with Bielschowsky silver, semiquantitation of senile plaques into categories (sparse, moderate, frequent), and then comparing senile plaque frequency with age (younger than 50 years, 50–75 years, and older than 75 years), with the concept being that the older the patient, the more plaques are required for the diagnosis of AD. The precursor Khachaturian criteria employed a similar concept (54). The Braak method for neuropathological “staging” of AD (described around the same time as CERAD criteria) (55), on the other hand, presumes that everyone with a lesion has some degree of AD regardless of clinical signs, with the stage depending on the brain regions affected. Moreover, Braak staging relies on neurofibrillary pathology rather than senile plaques, because of the stepwise progression from transentorhinal to limbic to neocortical of the former, and wide intra- and inter-interindividual variation of the latter. The NIA -Reagan consensus criteria, published six years after CERAD and Braak, is a combination of the two methods (56).

The disconnect between lesion and pathogenesis is perhaps nowhere better illustrated than in these standard neuropathological criteria for AD. The fact that the competing standardized methods for assessing AD, CERAD and Braak, quantitate different lesions comprised of different proteins belonging to different metabolic pathways is prima facie evidence of the poor correlation between lesion and cause. Also problematic is that according to CERAD, Khachaturian, and NIA-Reagan, the older the patient, the more plaques are “forgiven,” and the more senile plaques are required to make the diagnosis of AD. It is a mathematical fact that instances exist in which the same number of senile plaques results in different diagnoses with application of standard criteria. A 49 year old patient with a sparse number of senile plaques and dementia would have histologic findings that “indicate” the diagnosis of AD by CERAD criteria (definite AD), while a 76 year old patient with the same number of senile plaques would have histological findings that are “uncertain” of the diagnosis of AD (possible AD). By extension, if pathology presumes toxicity, it becomes axiomatic that older patients tolerate senile plaques better than younger patients. Few, of course, would accept this conclusion, yet most believe in the toxicity of accumulating substances.

Regardless, a careful look at standard criteria, the capricious relationship between AD pathology and clinical disease, and the extensive overlap between AD and advanced age, should suggest that the pathology is a variable host response to the underlying etiology, and one that, due to the insolubility of the response, accumulates with age.

The following thought experiment might be considered, albeit imperfect. Chronic renal failure, like Alzheimer’s disease, is a common medical illness, a form of which is associated with advanced age, vascular disease, and diabetes mellitus. For the sake of argument, consider chronic renal failure the analog to senile dementia. If such cases were examined at autopsy (i.e., end-stage), there would be extensive glomerulosclerosis, deposits of which include collagen and other extracellular matrix proteins. If we quantitated the extent of glomerulosclerosis, into sparse, moderate, and frequent for example, we might find increased diagnostic certainty with higher numbers of sclerotic glomeruli. We might also find that higher numbers are required in older age groups since sclerotic glomeruli (analogous to the senile plaque or NFT) increase with advanced age normally, so the criteria would have to take this into account (analogous to CERAD or Khachaturian). On the other hand, we could look at the kidney irrespective of clinical disease and “stage” the changes (analogous to Braak), with the idea that fewer numbers of lesions is simply preclinical disease. Further, we might isolate and purify glomeruli and find specific cellular proteins that are products of dysfunctional cellular metabolism, one of which is type IV collagen, which is deposited as a poorly soluble aggregate. We might then, in turn, note that rare cases of early onset familial glomerulosclerosis exist, some of which have mutations in type IV collagen (57), and therefore produce transgenic models with type IV collagen mutations, subject the models to therapeutic intervention, and then treat patients with age-related sporadic chronic renal failure based on those data.


All present knowledge with respect to the amyloid cascade and tau protein metabolism exists because lesions, senile plaques and NFTs, are detectable by light microscopy. Amyloid -β was first purified and identified from visible microscopic lesions, namely amyloid-laden blood vessels in Down’s syndrome brains and amyloid plaque cores of AD, while tau was first purified and identified from bulk isolation of NFTs. Had the respective lesions not been visible, neither Aβ nor tau would have been linked to them, and our copious knowledge of the amyloid cascade and tau metabolism delayed or left uninvestigated. Therefore, the microscopic pathology of Alzheimer’s disease is the foundation for the amyloid cascade and tau hypotheses (6).

The models early on favored the straightforward notion that insoluble proteins, either Aβ or phosphorylated tau, were toxic to brain. It was shown, for example, that toxicity of Aβ was linked to fibril formation (58). Aβ has been shown to be toxic in vitro by a variety of mechanisms, including induction of apoptosis (59), promotion of inflammatory mediators (60), and an accelerant of oxidative stress (61). Toxicity of phosphorylated tau is also said to be linked to its aggregated state with similar properties in vitro (62).

On the other hand, a widely recognized defect, particularly with the Amyloid Cascade Hypothesis, is the weak correlation between Aβ deposits and cognitive status (55, 6367), and lack of correlation between neural function subserved by a given brain region (e.g., medial temporal lobe and memory) and extent of Aβ deposits in that brain region (6366). Similarly, large amounts of amyloid, and varying plaque types, may be encountered in the brains of cognitively intact elderly (66, 68), while there is a consistently better correlation between neurofibrillary pathology and the above indices.

The Amyloid Cascade therefore has been amended to accommodate this defect. The revised version suggests that synaptic damage mediated by low-n oligomeric, soluble (supernatant fraction following high speed centrifugation), non-fibrillar Aβ is the fundamental pathogenic event (69, 70). Evidence for such a mechanism is supported by correlations between soluble Aβ levels, synaptic loss, and cognitive deficits (2, 7173). Experimentally, impairment in spatial memory in Tg2576 transgenic mice coincides with the appearance nonameric and dodecameric Aβ, while decreased spine density of fascia dentate neurons and impairment in long term potentiation (LTP) at ages prior to the appearance of dodecamers indirectly implicated smaller n -oligomers (7476). Microinjection of low-n Aβ oligomers blocked LTP in another experimental study, while immunodepletion of the conditioned medium pre vented the block of LTP. Degradation of monomers, on the other hand, did not alter the LTP effect, again implicating low-n oligomers, rather than monomers, or longer n-Aβ species. Structural damage to dendritic spines in organotypical hippocampal sections on exposure to Aβ oligomers has also been demonstrated.

These data are interesting; nevertheless, a degree of circumspection may still be warranted. The study of LTP with various manipulations of tissue cultures, as means of analogy to synaptic damage in neurodegenerative disease that develops over decades, has obvious problems with respect to relevance. Testing spatial memory in genetically altered rodents via water mazes and sequential pressing of levers, and relating those findings directly to sporadic AD, may also be dubious. It should also be noted that synaptic degeneration is more a concept than an objective neuropathological finding. Synaptic damage simply cannot be assessed as a diagnostic criterion, while synaptophysin immunohistochemistry, a standard assay for synapses (which can only be seen directly by electron microscopy), is a measurement more of synaptic vesicle content than junctional synaptic complexes per se, or synaptic “activity.” The assumption of selective and specific structural damage to the synapse by an overall reduction in synaptophysin immunostaining is therefore of limited validity, especially since neuronal loss would cause synaptic loss as a secondary phenomenon. Moreover, immunohistochemistry and electron microscopy, as a general rule are more useful and more meaningful as qualitative tools than quantitative, as evidenced by the fact, again, that synaptophysin immunostaining and the counting of synapses by electron microscopy have no diagnostic value. Finally, and perhaps most damning to then -Aβ species hypothesis, is the fact that transgenic manipulation of Aβ mice to ablate production of Aβ (whether it be monomer, n-or fibril) fails to rescue the cognitive deficit (77). Equally, other manipulations, leaving Aβ levels stable, can completely rescue this phenotype (78). Therefore, much like in their human counterparts, Aβ bears little (in fact, no) relationship to cognition (79).

As noted above, the correlation between regional distribution of phosphorylated tau and clinical signs suggests a close relationship between tau and AD pathogenesis. The increased tau phosphorylation that accompanies AD is said to result in separation of tau from the microtubule, possibly aided by other factors (Aβ, oxidative stress, inflammatory mediators), and sequestration in NFT’s and neuropil threads. The loss of normal tau function (stabilization and maintenance of microtubules), combined with a toxic gain of function could compromise axonal transport and contribute to the synaptic degeneration that is now a central theme (22, 80). Interestingly, the concept of NFT toxicity, like senile plaque toxicity, is increasingly being challenged. In one transgenic model, mice expressing a repressible human tau developed NFTs, neuronal loss, and behavioral impairments which, after tau suppression, stabilized. Yet NFTs continued to accumulate, suggesting that they are not sufficient to cause cognitive decline or neuronal death (39). In another AD-like model, axonal pathology with accumulation of tau precede plaque deposition (81), while studies of a P301S tauopathy model demonstrated microglial activation and synapse loss prior to NFT formation (82). It is highly likely that, much like those studying Aβ, the tauist will chose to now assume that toxicity of hyperphosphorylated tau relates to the presence of toxic tau intermediates, analogous to Aβ oligomers. The fact that neurons with NFT (and presumably tau oligomers) survive for decades (83) and show intact microtubules (84) will presumably remain an overlooked inconvenience to the Tau idealists.


With a mindset that the pathological lesions and the complex biochemical cascades that accompany them in disease are a response to a more fundamental, age-associated upstream process, such as oxidative stress (85) or inflammation (86), several problematic aspects of AD pathology become less so (Figure 2). The difficulties in distinguishing AD from aging on the basis of neuropathology is no longer an issue since the pathology does not presume to address cause. Host responses across the spectrum of diseases differ from one disease to the next, and from one patient to the next, and generally bear an imperfect relationship with the severity of the primary insult. The presence of such pathologies as hippocampal sclerosis, α-synuclein pathology, achromatic neurons, variations in extent of cerebral amyloid angiopathy, differences among senile plaque types (cored, diffuse, neuritic, cotton wool, etc), differences among the various forms of tau pathology, would be reserved for clinicopathological correlation rather than insight into causality. Clinical and demographic risk factors such as diabetes mellitus, atherosclerotic cardiovascular disease, steroid hormones, education level and cognitive reserve, diet and exercise would be less relevant to lesion counts and more relevant to discovering upstream processes that lead to lesions, inherently variable, that occurred as a response. Modeling AD by genetically engineering rodents may also be more focused on dementia and less focused on production of lesions that require endless modification.

Figure 2
Host Response Hypothesis. Age-related etiological factors lead to a multitude of host responses among which are the lesions of AD.

Lesion-based therapies thus depend on the concept that the host response is deleterious. If true, ameloriation of pathology by binding of “toxic intermediates,” such as with Aβ vaccination, will make some progress toward treatment. If, on the other hand, this construct does not address an upstream cause, classic AD becomes tangle -only dementia, the Lewy body variant of AD becomes diffuse Lewy body disease, and plaque-only AD becomes dementia lacking distinctive histology.


AD pathology, and its irregular association with disease, has remained essentially unchanged since the original description of Auguste D. by Alois Alzheimer in 1907. In the last 20 plus years, however, knowledge of lesion constituents and pathophysiological cascades has expanded exponentially. Driving this expansion has been the genetics of AD and the resulting enthusiasm over identification and treatment of the underlying cause. Seemingly lost in this frenzied activity is the poor relationship between Aβ deposits, as detected neuropathologically, and neuronal dysfunction in brain regions affected by those deposits, this despite the fact that all knowledge of Aβ, and of tau, was derived directly from neuropathological lesions. Also remarkable is the shift in thought processes with respect to the both hallmark AD lesions from visible, insoluble and therefore toxic, lesions that causes neuronal loss, to visible, insoluble and therefore non-toxic epiphenomenon that distracts attention from real process that is, incidentally, invisible and impossible to verify by direct observation (e.g., synaptic damage mediated by soluble toxic intermediates).

Approaches that seek to ameliorate lesions will continue; however, a fundamental reorganization of the concept of AD pathology, that AD lesions represent effect, rather than cause, may serve a purpose if current efforts continue to fail. The advice of Max Bielschowsky in 1932 (87) may be nonetheless apropos:

“Such observations demonstrate to us that we may employ the conception of specificity in the histopathology of ganglion cells only with the greatest caution. It must be emphasized once again that pathological cell types give us no direct indications for a precise diagnosis, but only reveal that in the nervous system pathological processes have been taking place. They indicate whether these processes are progressing more or less rapidly and whether they tend to destroy the cell life or only exert a passing influence. Consequently cell pictures are of value as indicators of pathological reactions only in the general sense. Moreover, it must be remembered that they may be considered only partial manifestations of processes involving the whole tissue complex. The changes of neuroglia, of the circulatory apparatus and connective tissue are of equal importance in the formation of our judgments of the etiological relationship between occasional anatomical findings and the associated clinical picture. Moreover, that the most careful consideration of a fine layer and regional localization is indispensable must again be emphasized.”

Whether the microscope gives us insight into etiology, or merely a “passing influence,” awaits further study.


Sources of Support: NIH R01 AG026151 (MAS)


1. Tomlinson BE. Ageing and the dementias. In: Adams JH, Duchen LW, editors. Greenfield’s Neuropathology. London: Oxford University Press; 1992. pp. 1284–410.
2. Walsh DM, Selkoe DJ. A beta oligomers -a decade of discovery. J Neuro chem. 2007;101:1172–84. [PubMed]
3. Birmingham K, Frantz S. Set back to Alzheimer vaccine studies. Nat Med. 2002;8:199–200. [PubMed]
4. Golde TE. Disease modifying therapy for AD? J Neurochem. 2006;99:689–707. [PubMed]
5. Castellani RJ, Zhu X, Lee HG, et al. Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees? Expert Rev Neurother. 2007;7:473–85. [PubMed]
6. Castellani RJ, Lee HG, Zhu X, et al. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 2006;111:503–9. [PubMed]
7. Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allg Zeitschr Psychiatr. 1907;64:146–8.
8. Fuller SC. A study of neurfibrils in dementia paralytica, dementia senilis, chronic alcoholism, cerebral lues and microephalic idiocy. Am J Insanity. 1907;63:415–68.
9. Wilkins RH, Brody IA. Alzheimer’s disease. Arch Neurol. 1969;21:109–10. [PubMed]
10. Berrios G. Alzheimer’s disease: a conceptual history. Int J Geriatr Psychiatry. 1990;5:355–65.
11. Maurer K, Mauer U. Alzheimer’s disease: The life of a physician and the career of a disease. Chichester, West Sussex: Columbia University Press; 2003.
12. Kraepelin E. Ein Lehrbuch fur Studierende und Arzte. Leipzig: Verlag von Johann Ambrosius Barth; 1910. pp. 533–54.pp. 93–632.
13. Moller HJ, Graeber MB. The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections. Eur Arch Psychiatry Clin Neurosci. 1998;248:111–22. [PubMed]
14. Terry RD. The Fine Structure of Neurofibrillary Tangles in Alzheimer’s Disease. J Neuropathol Exp Neurol. 1963;22:629–42. [PubMed]
15. Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature. 1963;197:192–3. [PubMed]
16. Tellez-Nagel I, Wisniewski HM. Ultrastructure of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome. Arch Neurol. 1973;29:324–7. [PubMed]
17. Grundke-Iqbal I, Iqbal K, Quinlan M, et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986;261:6084–9. [PubMed]
18. Marx J. Mutation identified as a possible cause of Alzheimer’s disease. Science. 1991;251:876–7. [PubMed]
19. Nash JM. Alzheimer’s disease. New insights into its cause lead to new drug strategies. Time. 2001;157:80–1. 5. [PubMed]
20. Hernandez F, Avila J. Tauopathies. Cell Mol Life Sci. 2007;64:2219–33. [PubMed]
21. Plattner F, Angelo M, Giese KP. The roles of cyclin -dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem. 2006;281:25457–65. [PubMed]
22. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8:663–72. [PubMed]
23. Beljahow S. Pathological changed in the brain in dementia senilis. J Ment Sci. 1889;35:261–2.
24. Simchowicz T. Sur la signification des plaques seniles et sur la formule senile de l’ecorce cerebrale. Rev Neurol (Paris) 1924;31:221–7.
25. Alzheimer A. Uber eigenartige Krankheitsfalle des spateren Alters. Z Gesamte Neurol Psychiatr. 1911;4:356–85.
26. Janssen JC, Beck JA, Campbell TA, et al. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology. 2003;60:235–9. [PubMed]
27. Finckh U, Muller-Thomsen T, Mann U, et al. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000;66:110–7. [PubMed]
28. Marinesco G. Sur la structure des plaques dites seniles dans l’ecorce cerebrale des sujets ages et atteints d’affections mentales. C R Acad Sci III. 1911;70:606–8.
29. Divry P. Etude histo-chimique des plaques seniles. J Belg Neurol Psychiatr. 1927;27:643–57.
30. Luse SA, Smith KR., Jr The ultrastructure of senile plaques. Am J Pathol. 1964;44:553 –63. [PubMed]
31. Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122:1131–5. [PubMed]
32. Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985;82:4245–9. [PubMed]
33. Glenner GG. On causative theories in Alzheimer’s disease. Hum Pathol. 1985;16:433–5. [PubMed]
34. Yankner BA. Amyloid and Alzheimer’s disease--cause or effect? Neurobiol Aging. 1989;10:470–1. discussion 7–8. [PubMed]
35. Joachim CL, Selkoe DJ. The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease. Alzheimer Dis Assoc Disord. 1992;6:7–34. [PubMed]
36. Vines G. Alzheimer’s disease--from cause to cure? Trends Biotechnol. 1993;11:49–55. [PubMed]
37. Gravina SA, Ho L, Eckman CB, et al. Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43) J Biol Chem. 1995;270:7013–6. [PubMed]
38. Younkin SG. Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Ann Neurol. 1995;37:287–8. [PubMed]
39. Santacruz K, Lewis J, Spires T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309:476–81. [PMC free article] [PubMed]
40. Prasher VP, Farrer MJ, Kessling AM, et al. Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol. 1998;43:380–3. [PubMed]
41. Wolfe MS, De Los Angeles J, Miller DD, et al. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry. 1999;38:11223–30. [PubMed]
42. Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 1999;398:522–5. [PubMed]
43. Ye Y, Lukinova N, Fortini ME. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature. 1999;398:525–9. [PubMed]
44. Jimenez-Escrig A, Rabano A, Guerrero C, et al. New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004;11:663–9. [PubMed]
45. Shrimpton AE, Schelper RL, Linke RP, et al. A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology. 2007;27:228–32. [PubMed]
46. Citron M, Oltersdorf T, Haass C, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature. 1992;360:672–4. [PubMed]
47. Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993;259:514–6. [PubMed]
48. Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006;96:732–42. [PubMed]
49. Kumar-Singh S, Theuns J, Van Broeck B, et al. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006;27:686–95. [PubMed]
50. Lee HG, Zhu X, Castellani RJ, et al. Amyloid-{beta} in Alzheimer Disease: The Null Versus the Alternate Hypothesis. J Pharmacol Exp Ther. 2007 [PubMed]
51. Jicha GA, Petersen RC, Knopman DS, et al. Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol. 2006;65:602–9. [PubMed]
52. Crystal HA, Dickson D, Davies P, et al. The relative frequency of “dementia of unknown etiology” increases with age and is nearly 50% in nonagenarians. Arch Neurol. 2000;57:713–9. [PubMed]
53. Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 1991;41:479–86. [PubMed]
54. Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol. 1985;42:1097–105. [PubMed]
55. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59. [PubMed]
56. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging. 1997;18:S1–2. [PubMed]
57. Voskarides K, Damianou L, Neocleous V, et al. COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol. 2007;18:3004–16. [PubMed]
58. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A. 1994;91:12243–7. [PubMed]
59. Forloni G, Chiesa R, Smiroldo S, et al. Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35. Neuroreport. 1993;4:523–6. [PubMed]
60. Eikelenboom P, Veerhuis R, Scheper W, et al. The significance of neuroinflammation in understanding Alzheimer’s disease. J Neural Transm. 2006;113:1685–95. [PubMed]
61. Mark RJ, Blanc EM, Mattson MP. Amyloid beta-peptide and oxidative cellular injury in Alzheimer’s disease. Mol Neurobiol. 1996;12:211–24. [PubMed]
62. Bandyopadhyay B, Li G, Yin H, et al. Tau aggregation and toxicity in a cell culture model of tauopathy. J Biol Chem. 2007;282:16454–64. [PubMed]
63. Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–9. [PubMed]
64. Giannakopoulos P, Herrmann FR, Bussiere T, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–500. [PubMed]
65. Bierer LM, Hof PR, Purohit DP, et al. Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol. 1995;52:81–8. [PubMed]
66. Dickson DW, Crystal HA, Mattiace LA, et al. Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging. 1992;13:179–89. [PubMed]
67. Berg L, McKeel DW, Jr, Miller JP, et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol. 1998;55:326–35. [PubMed]
68. Knopman DS, Parisi JE, Salviati A, et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol. 2003;62:1087–95. [PubMed]
69. Snyder EM, Nong Y, Almeida CG, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005;8:1051–8. [PubMed]
70. Tanzi RE. The synaptic Abeta hypothesis of Alzheimer disease. Nat Neurosci. 2005;8:977–9. [PubMed]
71. Lue LF, Kuo YM, Roher AE, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 1999;155:853–62. [PubMed]
72. McLean CA, Cherny RA, Fraser FW, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol. 1999;46:860–6. [PubMed]
73. Wang J, Dickson DW, Trojanowski JQ, et al. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp Neurol. 1999;158:328–37. [PubMed]
74. Dineley KT, Xia X, Bui D, et al. Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem. 2002;277:22768–80. [PubMed]
75. Jacobsen JS, Wu CC, Redwine JM, et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:5161–6. [PubMed]
76. Lesne S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–7. [PubMed]
77. Smith MA, Hirai K, Hsiao K, et al. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998;70:2212–5. [PubMed]
78. Galvan V, Gorostiza OF, Banwait S, et al. Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006;103:7130–5. [PubMed]
79. Lee HG, Zhu X, Nunomura A, et al. Amyloid-beta vaccination: testing the amyloid hypothesis?: heads we win, tails you lose! Am J Pathol. 2006;169:738–9. [PubMed]
80. Trojanowski JQ, Lee VM. Pathological tau: a loss of normal function or a gain in toxicity? Nat Neurosci. 2005;8:1136–7. [PubMed]
81. Stokin GB, Lillo C, Falzone TL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science. 2005;307:1282–8. [PubMed]
82. Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–51. [PubMed]
83. Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol. 1999;58:188–97. [PubMed]
84. Cash AD, Aliev G, Siedlak SL, et al. Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol. 2003;162:1623–7. [PubMed]
85. Nunomura A, Castellani RJ, Zhu X, et al. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol. 2006;65:631–41. [PubMed]
86. Mrak RE, Griffin WS. Common inflammatory mechanisms in Lewy body disease and Alzheimer disease. J Neuropathol Exp Neurol. 2007;66:683–6. [PubMed]
87. Bielschowsky M. Histopathology of Nerve Cells. In: Penfield Wilder., editor. Cytology and Cellular Pathology of the Nervous System. Montreal: Paul B. Hoeber, Inc; 1932.