16 September 2011. 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.
Schmidt C, Wolff M, Weitz M, Bartlau T, Korth C, Zerr I. Rapidly progressive Alzheimer disease. Arch Neurol. 2011 Sep;68(9):1124-30. Abstract