08 Dec 2012

With growing recognition that Alzheimer’s disease kicks off years before cognitive symptoms appear, scientists have ramped up efforts to understand early biomarker changes associated with preclinical AD. Testing asymptomatic adults at varying risk for the disease, researchers led by Eric Reiman at the Banner Alzheimer’s Institute, Phoenix, Arizona, report reduced activity in the posterior cingulate cortex that correlated with the number of apolipoprotein E4 alleles. ApoE4 is the major genetic risk factor for sporadic AD. The findings—reported in the December 3 Archives of Neurology online—suggest that hypometabolism in cortical subregions precede biomarker changes in other brain areas in cognitively normal ApoE4 carriers.

Scientists have extensively characterized brain biomarkers in ApoE4 carriers. Glucose metabolism, measured by fluorodeoxyglucose positron emission tomography (FDG-PET), falls in an ApoE gene-dose-dependent manner in people with mild to moderate AD (Mosconi et al., 2004), and in asymptomatic individuals (Rimajova et al., 2008). When Reiman and colleagues analyzed late middle-aged ApoE4 homozygotes with normal cognition, they found FDG-PET hypometabolism in posterior cingulate, parietal, temporal, and prefrontal regions—brain areas typically ravaged by AD—relative to age-matched controls (Reiman et al., 1996). The cortical hypometabolism showed up in advance of memory problems, whereas hippocampal volume, measured by magnetic resonance imaging (MRI), did not decrease until cognitive decline was underway (Reiman et al., 1998).

In the current analysis, first author Hillary Protas and colleagues confirm and extend these findings in a larger cohort. Whereas the prior research analyzed hippocampal volume and cortical metabolism in 11 ApoE4 homozygotes and 22 controls, the current study examined 149 people at three levels of genetic risk—42 ApoE4 heterozygotes, 31 ApoE4 homozygotes, and 76 non-carriers, all cognitively normal. The researchers also included a third measure—hippocampal metabolism. The Arizona team focused on the cortical FDG-PET results, while collaborators Michael Weiner and colleagues at the University of California, San Francisco, and Mony de Leon and Lisa Mosconi of New York University, analyzed hippocampal volumetric MRI and FDG-PET, respectively.

Of the three measurements, only cortical hypometabolism associated with ApoE4 gene dose. These findings provide “additional data to suggest that posterior cingulate hypometabolism may precede the other biomarkers in the preclinical stage of AD,” Reiman told Alzforum. “The [hippocampal] changes come later," he said. In a separate study, Reiman and colleagues found cortical metabolic decline in ApoE4 carriers as young as their twenties and thirties (Reiman et al., 2004), again suggesting these FDG-PET changes occur very early.

Is cortical hypometabolism in cognitively sound ApoE4 carriers evidence of preclinical AD? “The answer is not clear,” suggests William Jagust of the University of California, Berkeley, in an accompanying editorial. While “amyloid PET imaging has verified the association between ApoE4 and Aβ, and PET metabolic imaging demonstrates an association between ApoE4 and cortical hypometabolism, the association between Aβ and hypometabolism in ApoE4 carriers has not been shown,” he writes.

One shortcoming of the current study is that it does not use state-of-the-art methods for MRI data acquisition. Data collection began in 1994, and could not switch midway to the more powerful tools now used for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Hence, though the study includes three measurements—cortical metabolism (FDG-PET), hippocampal metabolism (FDG-PET), and hippocampal volume (MRI)—the use of suboptimal MRI methods makes it hard to directly compare MRI measures with PET measures, suggested James Brewer of the University of California, San Diego. The strength of the study lies in its power to reveal early FDG-PET hypometabolism in the cortex, he said. “Subregions of the cortex, particularly the precuneus, are an Alzheimer’s hotspot that should not be ignored.”

The present findings jibe with a recent study looking at brain amyloid and atrophy in seniors with mild AD or no cognitive impairment. Keith Johnson and colleagues at Massachusetts General Hospital, Boston, reported that Aβ deposition correlated more strongly with posterior cingulate/precuneus cortical thinning than with hippocampal volume loss (Becker et al., 2011).—Esther Landhuis

Comments

1. • Keith Johnson
     MGH, BWH, HMS
   • Posted: 08 Dec 2012

   This paper is very interesting. Longitudinal data will be the key to proving an anatomic pattern of progression, and the data here suggest a leading candidate hypothesis. These results are consistent with some findings we reported last year (Becker et al., 2011) relating amyloid more strongly to posterior cingulate/precuneus thinning of cortex than to hippocampal volume loss. The confound that many (including myself) are hoping to probe for this issue is the contribution of tau deposition in the medial temporal lobe versus other cortices. Ligands for that are coming.

   References:

   Becker JA, Maye J, Gidicsin C, Rentz DR, Hedden T, Marshall G, Olson L, Buckner RL, Sperling RA, Johnson KA. FDG metabolism, amyloid deposition and APOE status in cognitively normal elderly subjects. Human Amyloid Imaging 2011 Meeting Abstracts. 2011 Jan 15;

   View all comments by Keith Johnson

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References

Paper Citations

1. Mosconi L, Nacmias B, Sorbi S, De Cristofaro MT, Fayazz M, Tedde A, Bracco L, Herholz K, Pupi A. Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):370-6. PubMed.
2. Rimajova M, Lenzo NP, Wu JS, Bates KA, Campbell A, Dhaliwal SS, McCarthy M, Rodrigues M, Paton A, Rowe C, Foster JK, Martins RN. Fluoro-2-deoxy-D-glucose (FDG)-PET in APOEepsilon4 carriers in the Australian population. J Alzheimers Dis. 2008 Mar;13(2):137-46. PubMed.
3. Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752-8. PubMed.
4. Reiman EM, Uecker A, Caselli RJ, Lewis S, Bandy D, de Leon MJ, De Santi S, Convit A, Osborne D, Weaver A, Thibodeau SN. Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease. Ann Neurol. 1998 Aug;44(2):288-91. PubMed.
5. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9. PubMed.
6. Becker JA, Hedden T, Carmasin J, Maye J, Rentz DM, Putcha D, Fischl B, Greve DN, Marshall GA, Salloway S, Marks D, Buckner RL, Sperling RA, Johnson KA. Amyloid-β associated cortical thinning in clinically normal elderly. Ann Neurol. 2011 Jun;69(6):1032-42. PubMed.

External Citations

1. ApoE4
2. Alzheimer’s Disease Neuroimaging Initiative (ADNI

Further Reading

Papers

1. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, Dekosky ST, Caselli RJ. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6820-5. PubMed.
2. Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752-8. PubMed.
3. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9. PubMed.

News

1. API Echoes DIAN: Biomarker Changes Precede Symptoms by 20 Years 8 Nov 2012
2. More ApoE4 Means More Amyloid in Brains of Middle-Aged 2 Apr 2009