Can Tau Formation be Independent of Amyloid-β in Alzheimer’s Disease?

3 February 2019

I read the article on the possibility of sparing Alzheimer’s disease (AD) by nonsteroidal anti-inflammatory drugs [1] with great interest. It is stated that AD is characterized by the start of amyloid-β (Aβ) deposition in brain with consequent decreases in the cerebrospinal fluid (CSF), and therapeutic opportunities at this initial stage are at their highest. It is also stressed that biomarker studies suggest that phase 2 (Braak staging) sets in about 5 years later. Aβ deposits in the brain have built up to the level where they can be easily detected by PET scanning with Pittsburgh compound B. Aβ decreases in the CSF continue. They are now joined by tau levels [1].

Can APOE affect tau pathology independent of Aβ?
APOE4 is a major genetic risk factor for late-onset AD and has been shown to influence the harmful accumulation of the protein tau and exacerbate tau-mediated neurodegeneration and neuroinflammation [2]. Using a mouse model of tauopathy (where tau aggregates harmfully in tangles in the brain), David Holtzman and colleagues [3] showed that the apolipoprotein E4 (ApoE4) protein influenced tau pathogenesis, and increased neuroinflammation and tau-mediated neurodegeneration independent of Aβ pathology in the brain. ApoE4 increased brain Aβ pathology relative to other ApoE isoforms. However, whether ApoE independently influenced tau pathology or tau-mediated neurodegeneration was not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, they showed that P301S/E4 mice had significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice [3].

This recent study suggests that ApoE protein isoforms, particularly ApoE4, appear to accelerate brain-wide tau propagation that eventually leads to neuronal injury and death in a manner independent from Aβ, according to findings from transgenic mouse model studies [3]. The researchers utilized mice that lacked their own version of the mouse ApoE gene or replaced it with one of the three variants of the human ApoE gene: ApoE2, ApoE3, or ApoE4. By the time the mice were 9 months old, the ones carrying human ApoE variants had distinct phosphorylated tau protein staining patterns with widespread brain damage. The hippocampus and entorhinal cortex, important for memory, were shrunken and markedly more brain atrophy and neuroinflammation had developed. ApoE4 mice exhibited the most severe neurodegeneration, and ApoE2 the least. The mice that lacked ApoE entirely showed virtually no brain damage. Compared with the majority of people who have the more common ApoE3 variant, people with ApoE4 are at elevated risk of developing AD, and those with ApoE2 are protected from the disease. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect [3].

To find out whether ApoE in people similarly exacerbates neuronal damage triggered by tau, the researchers collaborated with Bill Seeley, MD, from the University of California, San Francisco. Seeley identified autopsy samples from 79 people who had died from tauopathies other than AD in the past 10 years. The researchers examined each brain for signs of injury and noted the decreased ApoE variants. They found that, at the time of death, people with ApoE4 had more damage than those that lacked ApoE4. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele was associated with more severe regional neurodegeneration [3]. These findings suggest that decreasing ApoE specifically in the brain could slow or block neurodegeneration, even in people who already have accumulated tau tangles. Most investigational therapies for AD have focused on Aβ or tau, and none has been successful yet in changing the course of the disease. Targeting ApoE has not yet been tried [3].

Their results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of Aβ pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective [3].

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in AD
Findings of other recent studies claim that tau pathology correlates better than Aβ pathology with clinical features of dementia. Recently, it has been shown that increased amyloid-β protein precursor (AβPP) with or without familial AD mutations, not Aβ, may work as a receptor of abnormal tau fibrils and promote intracellular tau aggregation, suggesting that AβPP rather than Aβ may accelerate tau accumulation and propagation [4].

It is well-known that Aβ amyloidosis due to AβPP metabolic impairment leads to neuroinflammation, which may further affect the progression of tau pathology [5]. So far, there is no evidence that Aβ itself directly affects tau pathology. It may be quite possible that AβPP metabolic impairment and tau pathology might be initiated independently in sporadic AD. In any event, there is now convincing evidence that the main factor causing progression of AD is tau, not Aβ, and that Aβ amyloidosis and tau pathology should be regarded as independent pathological events. Indeed, it was recently shown that the AD risk factors ApoE4 and TREM2 are linked to tau pathology [6].

Besides, the brains of patients with primary age-related tauopathy contain NFTs that are indistinguishable from those of AD, in the absence of Aβ amyloid plaques [7].

Reconsideration of AβPP and presenilin mutations in familial AD indicate that the trigger of AD is closely linked to impairments of AβPP metabolism and accumulation of AβPP C-terminal fragments, rather than Aβ production and Aβ formation. The results described propose that AD is a disorder that is triggered by impairment of AβPP metabolism, and that progresses through tau pathology [4].

There is evidence showing that AD is a disorder that progresses through tau pathology, not Aβ. Plus, patients with the ApoE4 allele show more severe neurodegeneration and a greater interaction of tau pathology and neurodegeneration. Amyloid deposition is associated with less severe neurodegeneration [2]. Investigators conclude that the high-risk ApoE4 allele is the linchpin that links neuroinflammation to neuronal death in the setting of tau pathology. ApoE itself may directly be involved in inducing neurotoxicity in tau-expressing susceptible neurons.

In the case phosphorylated tau can be produced without Aβ formation, then nonsteroidal anti-inflammatory drugs may not be as effective as described since their therapeutic functions are at the maximum when Aβ deposition has started.

Umur Kayabasi, MD
Asst. Prof.- Neuroophthalmology
Bahcesehir University, Istanbul
E- mail:

[1] McGeer PL, Guo JP, Lee M, Kennedy K, McGeer EG (2018) Alzheimer's disease can be spared by nonsteroidal anti-inflammatory drugs. J Alzheimers Dis 62, 1219-1222.
[2] Maestre G1, Ottman R, Stern Y, Gurland B, Chun M, Tang MX, Shelanski M, Tycko B, Mayeux R (1995) Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol 37, 254–259.
[3] Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C; Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523-527.
[4] Kametani F, Hasegawa M (2018) Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer's disease. Front Neurosci 12, 25.
[5] Leyns CEG, Holtzman DM (2017) Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener 12, 50.
[6] Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, Kokiko-Cochran ON, Crish SD, Lasagna-Reeves CA, Ransohoff RM, Landreth GE, Lamb BT (2017) TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 12, 74.
[7] Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128, 755–766.



The letter from Dr. Umur Kayabasi is an excellent example of the age-old adage “mice are not men”. He claims, based upon mouse models, that there is “evidence showing that Alzheimer disease (AD) is a disorder that progresses through tau pathology, not amyloid beta protein (Abeta) pathology. However, the histological evidence from post mortem AD tissue is that it is Abeta deposits, and not tau deposits that specifically characterize AD pathology.  Although tau deposits do occur in AD, they also occur in a variety of other diseases known as tauopathies. The evidence of Dr. Kayabasi’s mouse models is therefore not an exclusive characteristic of AD itself. Consequently, it fails to represent evidence that AD is a tauopathy.


 I am sorry that Dr. McGeer has not read my Letter carefully. I have not given information just on mouse studies, but also on human beings with AD.  To tell the truth, I was not expecting such a simple response. A detailed answer sophisticater than ' mice are not men ' would have been appreciated.