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  1. A line of evidence suggests that a contributing factor to sporadic Alzheimer’s disease, that may potentially influence amyloidogeneis upstream of amyloid accumulations, is abnormally elevated activity in default mode network (DMN) neurons during cognitive resting state conditions (Raichle et al., 2001; Buckner et al., 2005, 2008; Cirrito et al, 2005; and Bero et al., 2011). Like Paul Aisen and Reisa Sperling, I agree in the prudence of expanding the first primary prevention trial for Alzheimer’s disease, not just by increasing the sample size, but also by weighing the evidence of abnormal DMN activity along with the amyloid hypothesis, and the suggestions in the 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease (Fargo et al., 2014 https://www.ncbi.nlm.nih.gov/pubmed/25341459), which include commencing trials utilizing combination therapy and the repurposing of medications. DIAN leaders should consider creating small cohorts within this trial, and evaluating the combination of BACE inhibitors with low-dose repurposed medications in the cohorts to target DMN activity, to also measure whether amyloidogenesis and progression of disease can be altered by influencing the DMN. There are currently existing medication candidates available (Bakker A. et al. 2015, Musaeus CS et al. 2017, Gerhard T. et al. 2015, Mertens J. et al. 2015, Stern S. et al. 2017), which could target abnormal network activity, which have a known safety profile, which are inexpensive, which could be monitored, which could be ethically and safely administered at low doses for extended periods of time to DIAN participants; and which are reasonable candidates to test alongside, and in combination with, BACE inhibitors in long-term prevention trials. References: Alzheimer's Association National Plan Milestone Workgroup et al. 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease. Alzheimers Dement. 2014 Oct;10(5 Suppl):S430-52. PubMed: 25341459. Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015 Feb 21;7:688-98. PubMed: 25844322. 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. PubMed: 21532579. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed: 16120771. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008 Mar;1124:1-38. PubMed: 18400922. 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: 16364896. Gerhard T, Devanand DP, Huang C, Crystal S, Olfson M. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015 Jul;207(1):46-51. 2015 Jan 22. PubMed: 25614530. Mertens J et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015 Nov 5;527(7576):95-9. Erratum in: Nature. 2016 Feb 11;530(7589):242. PubMed: 26524527. Musaeus CS, Shafi MM, Santarnecchi E, Herman ST, Press DZ. Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1065-1076. PubMed: 28527204. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):676-82. PubMed: 11209064. Stern S et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. Mol Psychiatry. 2017 Feb 28. PubMed: 28242870.

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  1. Planning the First Primary Prevention Trial for Alzheimer’s Disease