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recommendations (Montine et al., 2014; ADRD 2013), as well as with updating, refining, adding to andprioritizing draft recommendations for formal consideration by the NINDS and NAPA Councils,respectively. Each committee met several times via teleconference between October 2015 and March2016. NIH staff provided the committees with responses to a joint NINDS/NIA Request for Information(NOT-NS-15-045) that solicited public input on updating the ADRD research priorities, as well as with aportfolio analysis of grants relevant to ADRD that received NIH funding in FY 2014 and/or 2015 togetherwith publicly available information on major ADRD projects funded by industry and NGOs. Crosscommittee coordination occurred through a monthly teleconference of the Summit OrganizingCommittee consisting of: session committee scientific chairs (as listed in Table 1); the Summit ScientificChair (Dr. David Holtzman); NIH and other federal officials (Table 2), including NINDS/NIH Summit leadDr. Roderick Corriveau; and the Steering Committee (Dr. Tony Phelps from NIA; Dr. Ron Petersen, Chairof the NAPA Council; Dr. Tom Montine, past ADRD Scientific Chair; and NINDS Council members Dr.Karen Chen and Dr. Bruce Obviagele).As in 2013, and at the request of the NAPA Council, the highest priorities have been designated #1 bythe session committees (see full recommendations below). Each session committee had the option ofproposing up to eight recommendations, designating up to two #1, #2, #3, and #4 recommendations indifferent focus areas. As in 2013, each committee estimated the number of years needed to complete orfully implement each recommendation; however, the 2016 recommendations also include more specifictimeframes that represent the session committee’s suggested calendar year for beginningimplementation of recommendations based on readiness of the scientific community.As a result of this preparatory work, the ADRD Summit 2016 agenda and draft recommendations wereposted online before the Summit, distributed to meeting registrants as hard copies, and presented atthe Summit to gather input from all stakeholders present in person or via webcast.Summit. The ADRD Summit 2016 was advertised broadly to the scientific community, governmentagencies, and NGOs, resulting in 490 registrants. Of these, 325 individuals joined in person and therewere more than 300 additional views online. As with the 2013 ADRD Conference, the primary goal of theSummit was to solicit input and feedback from a wide range of ADRD stakeholders on the draftrecommendations, timelines, and timeframes that had been prepared in advance. Following a generaloverview, each session’s chairs presented a summary of scientific progress that had occurred since 2013and then proposed updated and refined research recommendations for public input. The NGO session,which was new in 2016, thus presented two new draft recommendations. Each of the six topic sessionsincluded ample time for discussion and exchange with attendees. Those viewing remotely also had theopportunity to offer online input. The public portion of the Summit concluded March 30 with a review ofall suggested additions and revisions and further opportunity for input from all participants. Directlyafter the summit proceedings, NINDS led a closed executive session during which session chairs, NIH andother federal officials, Steering Committee members, and the Scientific Chair reviewed the proposedrevisions, edited the draft recommendations as agreed upon by the Executive Committee, and assignedduties to complete the work.Post-Summit Follow-Up. Post-summit efforts included a Steering Committee teleconference and severalmeetings among the session committees to further refine ADRD research recommendations content,prioritization, and proposed timelines and timeframes. These activities resulted in the ADRD Summit2016 Draft Prioritized Recommendations that we submit for approval in this Report. Upon acceptanceby the National Advisory Neurological Disorders and Stroke Council and the NAPA Council, the research4

recommendations become ADRD milestones that will be included as part of the National Plan andinform the development of future AD/ADRD bypass budgets.Organizing Participants and Sponsorship. Full membership of the ADRD Summit 2016 sessioncommittees appears in Tables 1 and 2. NIA participation complemented NINDS’ efforts through theefforts of Dr. Richard Hodes, Dr. Tony Phelps, and Dr. Nina Silverberg. Additional Summit sponsorsincluded the NIH Office of Disease Prevention, the Foundation for the National Institutes of Health, theAlzheimer’s Association, Accelerate Cure/Treatments for Alzheimer’s Disease (ACT-AD), the AmericanHeart Association/American Stroke Association, the Association for Frontotemporal Degeneration(AFTD), Axovant Sciences, the BrightFocus Foundation, and the LEAD Coalition (Leaders Engaged onAlzheimer’s Disease Coalition).Session Highlights. The six topic area sessions each included a brief introduction followed bypresentations of the draft recommendations, their rationale, and finally public input during openmicrophone discussions. Summit highlights, including reference to challenges, progress, and prioritiesgoing forward, are described below. Note that the format of the 37 draft 2016 prioritized researchrecommendations (page 10) is not uniform across all six topic areas: this was a deliberate decisionintending to enable flexibility of optimal prioritization within each topic area. Timelines, however, areuniform across topic areas (1-3 yr, 3-7 yr, 7-10 yr, or 10 yr) and reflect time to completion or to achievefully operational status for the recommendation after work is initiated. As previously stated, in 2016, theorganizing committee chose to indicate the suggested start years for implementation for allrecommendations.As was the case with the 2013 ADRD Conference proceedings, all recommendations in this reportrepresent very important research goals. Each topic committee was required to assign rank prioritiesstarting at #1. However, for a research recommendation to be included in this report, it must be amongthe top priorities in its respective field. In addition, timelines and timeframes (starting years) do not inany way reflect prioritization, but rather serve to guide planning and implementation logistics. Finally,ordering of sessions in no way reflects prioritization – all sessions (MED, HD, NGO, LBD, FTLD, VCID) areof equally high priority.Session 1. Multiple Etiology Dementias (MED) – Diagnosing Dementia in the 21st Century(Chairs: David Bennet, MD, David Knopman, MD)The MED session committee re-emphasized the main 2013 MED priority of improving recognition anddiagnosis of cognitive decline, aiming for a balance of aspirational versus operational goals. It isincreasingly clear that symptomatic cognitive impairment and dementia can result from a wide range ofconditions. In individuals over 65 who develop mild cognitive impairment and dementia, thepathological changes that underlie observed symptoms and signs are often due to more than onedisease process. For example, AD pathology (plaques and tangles) is usually accompanied by additionalpathological processes that may also contribute to cognitive decline and dementia. Contributing furtherto diagnostic complexity is a lack of clarity regarding the degree of underlying brain pathologies presentin a given individual during life. This provokes uncertainty about how much each disease processcontributes to observed cognitive impairment and dementia. The revised 2016 MED recommendationsadvocate for a more detailed and streamlined plan of action that carefully addresses the most imminentchallenges associated with recognizing and diagnosing cognitive decline. The first goal, andRecommendation #1, is to be able to reliably detect cognitive impairment when an individual or arelative voices a concern to health care providers. Finally, both the MED and the NGO sessions5

recognized and discussed challenges associated with the variable use of cognitive impairment anddementia terminology by scientists, physicians, patients, and the public at large. As such, the twocommittees developed complementary recommendations on nomenclature, and the Summit agendaincluded a Special Joint Session on nomenclature (see below).Session 2. Non-Governmental Organizations (NGOs) (Chairs: Susan Dickinson, Howard Fillit, MD)A change from the 2013 ADRD Conference was the addition of a dedicated session for NGOs thatrepresented various AD/ADRD communities, including nonprofit disease associations, patient advocacyorganizations, and private foundations. The NGO committee highlighted how NGOs strive to catalyzeADRD research by fostering unique partnerships across diseases, national borders, and stakeholders,and by providing swift and flexible research funding that complements funding from NIH, other federalagencies, and industry. For its Recommendation #1, this committee emphasized that NGOs seek toestablish a more effective dialogue with NIH about activities and progress toward achieving ADRDresearch goals – especially in the years between the NIH-hosted ADRD summits. Like the MEDcommittee, the NGO committee recognized and addressed, in its Recommendation #2, challengesassociated with nomenclature used for cognitive impairment and dementia. Both of these committeesoffered draft recommendations on dementia nomenclature, and these were presented and discussedduring a Special Joint Session on nomenclature.Special Joint Session: Nomenclature Discussion – Led by the NGO (Angela Taylor) and the MEDCommittees (David Knopman, MD)Stakeholders refer to cognitive decline and dementia in diverse ways. There was broad agreement inpre-discussions and at the 2016 Summit itself that the variable use of terminology is a barrier toreducing disease burden. The lack of a standardized lexicon impairs much needed communication withpatients, caregivers, and decision makers at all levels. Consequences are many and include missedtherapeutic opportunities for reversible conditions or treatable symptoms that go unrecognized;confused communication and policy such as when one term is used (e.g., AD) but a broader applicabilityis intended (e.g., all forms of dementia); and frustration when families receive different diagnoses fromdifferent clinicians. A connected challenge is that while clinical diagnosis with a named dementiasyndrome is accurate for some patients, for others it provides an incomplete and/or inaccurate clinicalpicture; moreover, there is a tendency to confound syndromic diagnosis with disease cause andetiology, which frequently remains unknown for all but rare genetic cases of dementia. Because of thehigh potential for impact, including in health disparities and stigma, the NGO and MED sessioncommittees both recommended beginning a national dialogue to establish standards for cognitiveimpairment and dementia nomenclature. There is consensus that although the most effective languageand terms for different stakeholders may not be identical, the language framework must bestandardized and interoperable.Session 3. AD/ADRD Health Disparities (HD) (Chair: Jennifer Manly, PhD)Despite the higher reported prevalence of cognitive impairment in African Americans and Hispanicscompared to age-matched whites, for example in the 2006 Health and Retirement study and the 2016Kaiser Permanente Northern California study, knowledge of relevant epidemiology and mechanisticpathways for ADRD in disparities populations remains more rudimentary than it is for whites. Onereason is because individuals in health disparities populations are less likely to receive a diagnosis, and ifthey do it is typically at a later stage in disease progression. Despite challenges, some research progress6

has been made since the 2013 ADRD Conference, particularly by: leveraging existing studies of diversecohorts to include neuropsychological assessment and adding AD and ADRD biomarkers; using existinglocal expertise and resources to evaluate AD/ADRD in diverse communities; developing or adaptingassessment tools for use in disparities populations; and investigating potential disparities mechanisms.NIH also launched two targeted funding initiatives that address AD/ADRD health disparities: HealthDisparities and Alzheimer’s disease, and Emerging Directions for Addressing Health Disparities inAlzheimer’s disease. To help clarify goals, flow and purpose of the ADRD Health Disparitiesrecommendations, the Health Disparities committee split the two focus areas defined in 2013 into fourfocus areas with seven fully revised recommendations prioritized from #1 to #7. The two original focusareas remain, i.e., Recruitment (now referred to as Community Partnerships, Recruitment, andRetention) as well as Treatment and Prevention Strategies. New focus areas include Monitoring Changesin ADRD Disparities, and Assessment. This reorganization of focus areas reflects new emphasis andprioritization, in particular on research mechanisms of disparities and life-course pathways of disease,tracking cognitive and other relevant changes over time, and the value of equal communitypartnerships.Session 4. Lewy Body Dementias (LBD) (Chairs: Dennis Dickson, MD, Karen Marder, MD)LBD includes Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). These disordersare characterized by aggregation of alpha-synuclein in specific brain regions with dopaminergicdegeneration, along with or in the absence of a variety of other changes. As with other ADRD, LBDresearch and clinical care will benefit significantly from nomenclature standards. There have beenseveral advances over the last three years in defining genetics, brain network changes, biomarkers, andcell biology of LBD, including the potential role of prion-like spreading of synuclein pathology. In 2016,NINDS issued the RFA entitled Biomarkers for the Lewy Body Dementias. The LBD committee retainedRecommendation #1 from 2013, affirming the need to establish longitudinal cohorts; to better definegenetics and network changes; to develop more specific biomarkers for synucleinopathy; and to morethoroughly understand pathogenic mechanisms underlying these disorders that should enable futuretreatments. Initiating clinical trials remains the top priority, and 2016 recommendation refinementsinclude drawing specific attention to both non-motor and motor symptoms of LBD.Session 5. Frontotemporal Lobar Degeneration (FTD) (Chairs: Michael Hutton, PhD, William Seeley,MD)The average age for diagnosis of FTD is about 57, making it a condition with significantly younger onsetand midlife impact compared to AD, which has an average age of diagnosis of about 70. Prevalence ofFTD is rare but uncertain, in significant part due to a lack of diagnostic clarity addressed earlier in thisdocument. Despite the challenges of relatively few specimens being available in brain banks and theexistence of many FTD molecular subtypes and clinical phenotypes, there has been considerableprogress since 2013. Three NIH research teams have been funded to engage in longitudinal studies offamilial and sporadic FTD to understand disease progression both pre- and post-symptom onset; toidentify new biomarkers for diagnosis, progression, and prognosis; and to establish a clinical researchconsortium to support FTD therapy development. Moreover, scientists have discovered that variation inthe C9ORF72 gene can lead to FTD-motor neuron disease (MND). The disease mutations are “repeatexpansions,” in which specific DNA sequences are repeated hundreds or thousands of times. Recentfindings suggest several possible mechanisms leading to disease from these C9ORF72 expansions, andthat the underlying mechanisms could be potential targets for therapies to treat some forms of FTDMND. In 2016, NINDS issued an RFA entitled Centers without Walls for the Identification and Validation7

of Molecular Mechanisms Contributing to Tau Pathogenesis and Associated Neurodegeneration inFrontotemporal Degeneration. The FTD session committee made no major changes to the 2013 basicscience recommendations, with refinement highlights including increased emphasis on understandingtau pathology and tau strain spreading; determining whether TDP-43 and FUS are toxic spreadingdisease proteins; and understanding the normal RNA biology roles of TDP-43 and FUS. FTD clinicalscience recommendations also remain largely unchanged, with recognition of the need for increasedrecruitment outreach, in particular to minority groups, and increased bioinformatics infrastructure tosupport large-scale data collection, analytics, and sharing in genetic and ‘omics studies.Session 6. Vascular Contributions to Cognitive Impairment and Dementia (VCID) (Chairs: S. ThomasCarmichael, MD, PhD, Steven Greenberg, MD, PhD)The 2013 ADRD Conference stimulated significant new interest and activity in VCID (Corriveau et al.,2016). For example, NIH established the M2OVE AD Consortium via a collaborative NIA/NINDS fundingannouncement titled Interdisciplinary Research to Understand the Vascular Contributions to Alzheimer'sDisease. The Alzheimer’s Association hosted a focused think tank on vascular contributions to AD/ADRDwith NIH input, and issued relevant RFAs including on the role of vascular metabolic factors in AD/ADRDpathogenesis. In 2014, for the first time, and with support from NINDS leadership, NIH officiallyrecognized VCID as a field by tracking spending on VCID research in the NIH RePORTER database,aligning the acronym with vascular cognitive impairment/dementia. The science of VCID integrates andcreates a focus for synergy among diverse interdisciplinary aspects of biology that have been separatedhistorically. Thus, VCID research interrogates the roles of multiple cell types that support the function ofneural tissue. In 2016, NINDS issued RFAs designed to establish the Small Vessel VCID BiomarkersConsortium and its Coordinating Center, and to address the Mechanistic Basis of Diffuse White MatterDisease in VCID. Additional scientific progress in VCID features new animal models that portray differenttypes of ischemia in white matter pathology as well as co-morbidity with relevant human conditions.The VCID committee noted significant progress in characterization of the neurovascular unit (NVU),which has led to an updated definition that incorporates new concepts such as segmental differences instructure/function, new cell types, and the contributions of lymphatic flow. Downward temporal trendsin the prevalence of dementia (e.g., Framingham data, data from European studies) continue to raisethe intriguing question of the overall role and impact of traditional cerebro- and cardiovascular riskfactors in dementia. These research questions are being addressed. The VCID committee maintained theoverall structure and main content of the 2013 recommendations, but highlighted several new areassuch as translational imaging methods, aging as a variable, genetics, resilience to VCID, and the role oftau in VCID.Cross-Cutting Areas. Cross-cutting areas diversify research foci presented in the six researchrecommendation areas. These include resources infrastructure (biospecimens, bioinformatics, clinicaltrials); training and workforce needs (research and clinical); type of research (basic, translational,clinical); and nomenclature, as described above. The MED session topics are emblematic of suchoverlap, and as such this session as of 2016 includes a completely new recommendation on training.Notable areas of cross-cutting scientific interest include protein aggregation/degradation/neurodegeneration; the innate immune system; axonal/synaptic injury/repair, circadian and sleepfunction/dysfunction; the NVU/blood brain barrier (BBB); genetics/genomics; and metabolism/diabetes.8

The recommendations in this Report represent national priorities that will inform future NIH AD/ADRDbypass budgets and, as congressionally appropriated funds become available, corresponding funding ofADRD research activities. As Scientific Chair of the ADRD Summit 2016, I respectfully submit this reportto the NINDS Council on behalf of all committee co-chairs and members.Sincerely,David M. Holtzman, MDAndrew B. and Gretchen P. Jones Professor of NeurologyChairman, Department of NeurologyNeurologist-in-Chief, Barnes-Jewish Hospital9

ADRD Summit 2016Draft Prioritized RecommendationsSession 1:Multiple Etiology Dementias (MED) Focus Area 1: Improved Diagnostic Skills in the CommunityRecommendation #1. Detect cognitive impairment when a patient or relative voices a concernto health care providers (3-7 y; 2017). Develop new educational efforts for, and practical trials on, improved diagnosis when there is amemory or cognitive complaint that lead to face-valid useful outcomes for patients and family.Develop educational efforts for improved diagnosis when there is a memory or cognitivecomplaint that is specifically designed for use in underserved populations.Improve basic diagnostic skills for use by primary-care providers regarding later-life cognitivedisorders, emphasizing timely diagnosis of overt cognitive impairment (but not specificallyfocusing on differential etiological diagnosis).Dev

The first ADRD Summit, the ADRD Conference 2013, established initial, detailed ADRD-specific research priorities in the National Plan, including those related to health disparities (HD). As follow-up to the ADRD Conference 2013, NINDS held the second ADRD Summit, the subject of this report to Council, on March 29-30, 2016.