Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, Christensen J, McDade E, Wang G, Xiong C, Cairns NJ, Hassenstab J, Marcus DS, Fagan AM, Jack CR Jr, Hornbeck RC, Paumier KL, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal JP, Correia S, Förster S, Fox NC, Graff-Radford NR, la Fougère C, Levin J, Masters CL, Rossor MN, Salloway S, Saykin AJ, Schofield PR, Thompson PM, Weiner MM, Holtzman DM, Raichle ME, Morris JC, Bateman RJ, Benzinger TL. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. Lancet Neurol. 2018 Mar;17(3):241-250. Epub 2018 Feb 1 PubMed.

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  1. This is a terrific study modeling the temporal and spatial changes of amyloid, metabolic patterns, and atrophy in a large sample of well-characterized individuals with autosomal-dominant Alzheimer’s disease. This group of individuals is perfectly suited to investigate these questions, as we can stage them along a time axis that indicates the estimated years before the onset of symptoms. This study reveals the complexity of the interaction between amyloid and neurodegenerative accumulations during the long time window before the first symptoms become evident.

    Consistent with CSF data and recent studies (Bateman et al., 2012; Quiroz et al. 2018), this study supports the evidence that amyloid pathology drives neurodegenerative processes in early onset AD, observations that we have also reported in preclinical late-onset AD. For me there are two exciting observations in this study.

    First, the study challenges us to look more closely at regional differences in the temporal time line of biomarkers. Overall, amyloid deposition occurred on average 20 years before the expected onset, followed by a decrease in glucose metabolism (18 years prior to expected onset), and this was then followed by changes in gray-matter volume 13 years before onset of symptoms. Interestingly, the precuneus was the region showing the earliest amyloid deposition, followed by the orbitofrontal cortex. The vulnerability of the precuneus/posterior cingulate cortex to Alzheimer’s disease pathology has been reported earlier in early onset AD (Benzinger et al., 2016). But the hippocampus showed a different temporal order of events, in which atrophy occurred before amyloid deposition. The medial temporal lobe regions are vulnerable to tau pathology, but also have strong connections to the precuneus/posterior cingulate cortex. These connections may be related to the mechanisms underlying the interaction between amyloid and tau pathology in Alzheimer’s disease. Furthermore, the heterogeneity in some of these regional temporal events may suggest that biomarkers should not be stage-specific, but potentially contain also some region-specific information.

    Second, Gordon and colleagues report a curvilinear pattern for the FDG data, showing a slight increase in metabolism before the decline in glucose metabolism. This is intriguing and opens up the question of whether this is a cause or a consequence of amyloid. Is this reflecting amyloid-related hyperexcitibility, or is this increase in glucose metabolism driving amyloid deposition (Cirrito et al., 2005; Bero et al., 2011)? The current data does not yet answer such a causality question, but future animal or intervention studies may be able to throw more light on it.

    References:

    Quiroz YT, Sperling RA, Norton DJ, Baena A, Arboleda-Velasquez JF, Cosio D, Schultz A, Lapoint M, Guzman-Velez E, Miller JB, Kim LA, Chen K, Tariot PN, Lopera F, Reiman EM, Johnson KA. Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):548-556. PubMed.

    Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. PubMed.

    Benzinger TL, Gordon BA, Friedrichsen KA, Su Y, Christensen J, Hornbeck RC, Mishra S, Aldea P, Cash L, Ances B, McConathy J, Koeppe RA, McDade E, Cairns NJ, Morris JC, Bateman R, Buckles V, the Dominantly Inherited Alzheimer Network (DIAN) Study Group. Tau PET Imaging With Av-1451 in Autosomal Dominant Alzheimer's Disease: Update from the Dominantly Inherited Alzheimer Network (DIAN). Alzheimer's & Dementia, July 2016

    Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.

    Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. Epub 2011 May 1 PubMed.

    View all comments by Heidi Jacobs

  2. This study provides convincing evidence that the pattern of functional decline in autosomal-dominant Alzheimer's disease begins with Aβ deposition, progresses to metabolic decline, and ultimately culminates with structural decline before dementia symptoms arise—consistent with previous cross-sectional studies.

    Whereas previous analyses have provided an incomplete timeline of disease progression, this longitudinal study uses a large cohort and documents relatively consistent biomarker ordering across neuroanatomical regions. The considerable heterogeneity observed across regions, which suggests that vulnerability evolves both spatially and temporally as the disease progresses, will be useful in guiding future biomarker research and in designing clinical trials. For example, it is notable that the occipital and temporal regions diverged from the aforementioned pattern of decline in that they did not exhibit significant metabolic decline, though Aβ accumulation and structural atrophy occurred.

    The authors present some of the most reliable evidence to date for early biomarkers of Alzheimer's disease more than 20 years before dementia onset. Further longitudinal examination of genetically vulnerable individuals, including the examination of tau pathology, will be key for establishing accurate temporal and spatial sequencing of biomarkers.

    View all comments by Arthur Toga

  3. Gordon and colleagues provide further evidence of brain changes in non-demented individuals with autosomal-dominant AD, several years before estimated clinical onset. The temporal sequence they reported, from amyloid deposition to hypometabolism to cortical thinning, is quite consistent with what we and others have reported in cross-sectional studies of individuals with AD-causing mutations. I think the most interesting and novel finding of this paper is that amyloid levels in the precuneus could distinguish between carriers and noncarriers more than 20 years before expected onset. This is a very nice paper, and the authors did an amazing job describing the temporal and spatial patterns of biomarker changes in preclinical AD, which has great relevance for clinical practice and clinical trials.

    View all comments by Yakeel T. Quiroz

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  1. Aβ, Then Metabolism, Then Atrophy: In Familial AD, Cascade is Definitive
  2. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show