Perhaps not all Alzheimer’s disease (AD) is created equal. In the September Archives of Neurology, neuropathologists make the case that there is a subtype in which people deteriorate twice as quickly as typically seen. Researchers led by Christian Schmidt and Inga Zerr at Georg-August University, Göttingen, Germany, combined observations from their institution with a literature review to suggest that up to a third of AD cases may be of the rapidly progressing variety. These data need to be confirmed in longitudinal studies, the authors emphasize. If it is, it would imply that AD may be more heterogeneous than has been thought, and it would have implications for personalizing treatment to the patient.

Some other pathologists agree. “I like this paper a lot. It points clearly to the importance of distinguishing different forms of AD,” Annemieke Rozemuller at VU University Medical Center, Amsterdam, The Netherlands, wrote to ARF (see full comment below).

Schmidt and colleagues became interested in this issue when they determined the underlying pathology of cases of fast-progressing dementia at their institution, which houses the German Prion Disease Surveillance Unit. Every year, using this national service, hospitals around Germany refer about 5,000 cases of rapidly progressive dementia to the unit. Although referring doctors suspected their patients had suffered from Creutzfeldt-Jakob disease (CJD), only 2 to 3 percent of these cases actually turned out to be CJD. Neuropathological examination revealed that the rest represented diverse neurodegenerative conditions including AD, Schmidt told ARF. The authors noticed that some of the AD cases advanced quickly, and clinically resembled CJD more than classic AD. Patients had numerous motor problems such as trouble walking, rigidity, and jerking muscles. They declined about twice as quickly as do most AD patients on the Mini-Mental Status Exam (MMSE), and died two to three years after diagnosis instead of the usual eight to 10 years (see Schmidt et al., 2010).

To see if this form of AD is a common phenomenon, Schmidt and colleagues combed the literature. They found a dozen or so prion studies that reported cases of rapidly progressive AD that mimicked CJD. In several cross-sectional, retrospective, and longitudinal AD studies, the percentage of Alzheimer’s cases identified as rapidly progressing varied from around 10 percent to 30 percent. Each paper used its own definition for what constituted “rapid” decline, which probably contributed to the wide variability, the authors suggest. As a starting point for comparing studies, Schmidt and colleagues propose adopting the definition put forth by a recent consensus paper, which suggested a drop of more than six points per year on the MMSE should be considered rapid (see Soto et al., 2008). “We encourage the scientific community to discuss what ‘rapid’ actually means and to agree on a firm definition that would make future studies more comparable,” Schmidt wrote to ARF.

The authors looked for a biomarker signature of rapid AD. Alzheimer’s disease is characterized by low levels of Aβ42 and high levels of tau and phosphorylated tau in the cerebrospinal fluid (CSF). Some papers suggest that rapidly progressive forms of the disease may be distinguished by particularly low levels of CSF Aβ42 and particularly high levels of tau and phosphorylated tau, although variations among labs make it hard to set absolute cutoff values (see Snider et al., 2009 and Wallin et al., 2010). The presence in CSF of protein 14-3-3, a marker of neuronal destruction, also serves to help discriminate rapid AD from the typical variety (see Van Everbroeck et al., 2004; Jayaratnam et al., 2008; Mahmoudi et al., 2010).

A genetic contribution to the rate of AD progression is unclear, the authors found, with some studies finding that ApoE4 carriers had an increased risk of rapid decline, and other studies showing the opposite (see Cosentino et al., 2008 and van der Vlies et al., 2009).

To better characterize rapid forms of AD, researchers will need to do large longitudinal studies, Schmidt said. His institution is starting such a study among their rapid dementia population. In particular, they will look for biomarkers or clinical markers that distinguish rapidly progressive AD from CJD, Schmidt told ARF. Currently, researchers can only separate these conditions at autopsy. Schmidt also noted the importance of investigating the pathophysiology that underlies the heterogeneity within AD, as this could have implications for treatment. For example, one study found that people whose dementia progressed quickly had the best response to cholinesterase inhibitors (see Wallin et al., 2009).—Madolyn Bowman Rogers


Make a Comment

To make a comment you must login or register.

Comments on News and Primary Papers

  1. I like this paper a lot. It points clearly to the difference in definitions and the importance of distinguishing different forms of AD. As neuropathologist of the Netherlands Brain Bank, and also as head of the prion centre in the Netherlands, I see a lot of different forms as well.

    We have to stress that rapidly progressive dementia can be caused by capillary cerebral amyloid angiopathy (CAA, see Richard et al., 2010), so this is a subgroup of rapidly progressive dementia/AD. This group frequently has one or two ApoE4 alleles and is older and sometimes grouped as vascular dementia. Often 14-3-3 protein is positive in CSF as well.

    The other rapidly progressive forms I see are younger and non-ApoE4 carriers. It has been suggested that microglia are more abundant in this group. Rapidly progressive forms can occur after surgery with delirium and more inflammatory factors. Small heat-shock proteins induce an inflammatory reaction in the brain. We need more research on that.

    I think it is time to join forces and form large groups to distinguish the different subgroups and look for inflammatory proteins.


    . Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2010 Nov;69(11):1158-67. PubMed.

    View all comments by Annemieke J.M. Rozemuller
  2. This review is very interesting and highlights the possibility that there is a subgroup of AD patients who progress more rapidly. Our group has also observed this in a number of papers (Wallin et al., 2006; Blom et al., 2009; Sämgård et al., 2010; Wallin et al., 2010) and concurs with the findings of Schmidt and colleagues. We have found no correlation between CSF levels of Aβ42 and progression in patients with AD. However, we have, exactly as Schmidt et al., observed that both AD and MCI patients in the group with the highest CSF level of T-tau progress faster than the groups with lower levels. The same is observed for P-tau in CSF. Also, we found a correlation between CSF levels of both T-tau and P-tau with change in MMSE and ADAS-cog.

    The question is whether to use annual change in MMSE as a marker for rapid progression or time to death. Furthermore, the exact cutoff in annual drop in MMSE to be classified as rapid progression will have to be examined in larger studies. For the classification to have a real prospective value, the use of a biomarker is important. Thus, the classification of rapid progression might actually benefit from using a cutoff level for T-tau instead annual drop in MMSE or time to death. It is important to know early on for relatives, doctors, and the pharmaceutical industry if the patient in question will be affected with the rapid progressive form, as it affects response to treatment as well as time to disability and death.


    . CSF biomarkers for Alzheimer's Disease: levels of beta-amyloid, tau, phosphorylated tau relate to clinical symptoms and survival. Dement Geriatr Cogn Disord. 2006;21(3):131-8. PubMed.

    . Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype. Dement Geriatr Cogn Disord. 2009;27(5):458-64. Epub 2009 May 7 PubMed.

    . Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity. Int J Geriatr Psychiatry. 2010 Apr;25(4):403-10. PubMed.

    . CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology. 2010 May 11;74(19):1531-7. PubMed.

    View all comments by Bob Olsson
  3. This is a very interesting paper. It raises important questions about the heterogeneity of Alzheimer’s disease and the possible role of biomarkers in understanding the disease process. The cohort studied here, derived from a national prion disease registry, is inherently unlike those seen in the community or in Alzheimer’s research centers, since, as the authors point out, research of diagnostic criteria exclude such patients because they exhibit focal symptoms, behavior changes, and extrapyramidal signs. This study provides a unique opportunity to explore a broader range of clinical presentations of dementias with Alzheimer’s type pathology and supports the idea of Alzheimer’s diseases rather than a single disease process.

    Some of the questions raised are semantic, but nonetheless critically important. First, what is rapid progression in AD? It is difficult at present to firmly establish an average disease duration even in typical AD, given the variability in when the diagnosis is made. Is onset of disease when first clinical symptoms are detected, defined at some centers as mild cognitive impairment (MCI) or even “pre-MCI,” or when symptoms become severe enough to interfere with daily function and frank dementia is present? The trend toward diagnosis at milder stages of disease will necessarily result in longer disease durations, while using alternative diagnoses (e.g., MCI) for milder stages of disease and using the onset of frank dementia as the start of disease will result in a shorter disease course, even more so since there is evidence that the rate of cognitive decline is more rapid later in the disease course (e.g., see Storandt et al., 2002).

    Using rate of change in MMSE and other standardized tests is also problematic. MMSE has the advantage of broad usage, but is heavily dependent on language function and can decline rapidly with the onset of aphasia, even when other cognitive symptoms may be unchanged.

    The study also raises interesting questions about the role of CSF biomarkers in diagnosis and in predicting rate of disease progression. The finding that levels of amyloid-β peptide 1-42 were lower in this cohort (266 pg/ml) than reported for most AD cohorts supports the idea that lower levels of Aβ42 may predict more rapid disease progression, particularly at the milder stages, as we and others have observed (Snider et al., 2009; Okonkwo et al., 2010; Wallin et al., 2010). The observation that these individuals have low Aβ42 but lack significant elevations in tau is particularly interesting. This could reflect timing of the lumbar puncture relative to disease progression, since most studies suggest that a reduction in Aβ42 levels precedes elevations in tau, or perhaps this cohort has a largely amyloid-driven disease.

    The other interesting finding here was the large proportion of cases (31 percent) where 14-3-3 was detectable in the CSF. This may reflect selection bias, as cases could have been referred to the prion surveillance unit based on the elevated 14-3-3. It also emphasizes the difficulty with interpreting the 14-3-3 CSF test, and adds more evidence to the argument that those who decline more rapidly clinically likely also have a more aggressive and destructive underlying AD pathology.

    There is clearly much more to do in understanding the variability in clinical presentations in Alzheimer’s disease and in learning how CSF and other biomarkers can reveal the disease mechanisms that underlie this disease heterogeneity.


    . Rates of progression in mild cognitive impairment and early Alzheimer's disease. Neurology. 2002 Oct 8;59(7):1034-41. PubMed.

    . Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol. 2009 May;66(5):638-45. PubMed.

    . Cerebrospinal fluid abnormalities and rate of decline in everyday function across the dementia spectrum: normal aging, mild cognitive impairment, and Alzheimer disease. Arch Neurol. 2010 Jun;67(6):688-96. PubMed.

    . CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology. 2010 May 11;74(19):1531-7. PubMed.

    View all comments by Joy Snider
  4. This paper is very helpful because it provides substantial data based upon neuropathological observations. It provides further evidence that it is always important to confirm clinical diagnoses at autopsy. Prion surveillance provides the opportunity in these cases, and more systematic neuropathological studies are needed to understand the full spectrum of AD.

    These cases are highly selected based upon rapid progression of dementia, so it isn't possible to see if they are one end of a normal distribution or if they truly represent a subset. Nevertheless, it is important to recognize that motor symptoms can occur in late-onset cases, as most of these are, not just with familial early-onset dementia (Moretti et al., 2004), and that they have dire prognostic significance.

    The Schmidt article suggests a criterion of more than six MMSE points per year progression. I think it is helpful to have some criterion, but this would mean a course of about five years (30 going to 0), and is too inclusive. It is a misunderstanding that AD is homogeneous in progression; that is clearly not the case in my experience.


    . Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology. 2004 May 25;62(10):1865-8. PubMed.

    View all comments by Norman Foster


Paper Citations

  1. . Clinical features of rapidly progressive Alzheimer's disease. Dement Geriatr Cogn Disord. 2010;29(4):371-8. PubMed.
  2. . Rapid cognitive decline in Alzheimer's disease. Consensus paper. J Nutr Health Aging. 2008 Dec;12(10):703-13. PubMed.
  3. . Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol. 2009 May;66(5):638-45. PubMed.
  4. . CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology. 2010 May 11;74(19):1531-7. PubMed.
  5. . Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients. J Neurol. 2004 Mar;251(3):298-304. PubMed.
  6. . Rapidly progressive Alzheimer's disease and elevated 14-3-3 proteins in cerebrospinal fluid. Age Ageing. 2008 Jul;37(4):467-9. PubMed.
  7. . Atypical case of Alzheimer's disease mimicking Creutzfeldt-Jakob disease: interest of cerebrospinal fluid biomarkers in the differential diagnosis. J Am Geriatr Soc. 2010 Sep;58(9):1821-3. PubMed.
  8. . APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology. 2008 May 6;70(19 Pt 2):1842-9. PubMed.
  9. . Most rapid cognitive decline in APOE epsilon4 negative Alzheimer's disease with early onset. Psychol Med. 2009 Nov;39(11):1907-11. PubMed.
  10. . Can CSF biomarkers or pre-treatment progression rate predict response to cholinesterase inhibitor treatment in Alzheimer's disease?. Int J Geriatr Psychiatry. 2009 Jun;24(6):638-47. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Rapidly progressive Alzheimer disease. Arch Neurol. 2011 Sep;68(9):1124-30. PubMed.