Finding the Path in Alzheimer’s Disease: Early Diagnosis to Ongoing Collaborative Care

Facult Sharon Cohen, MD, FRCP Medical Director, Toronto Memory Program Assistant Professor, University of Toronto Consultant Neurologist, North York General Toronto, Ontario, Canada Dr Sharon Cohen is a behavioral neurologist known for her excellence in patient care, teaching, and clinical research. She completed her neurology residency and behavioural neurology fellowship at the University of Toronto. She is the medical director and site principal investigator (PI) of the Toronto Memory Program, a community-based medical facility she established in 1996 for the purpose of enhancing diagnosis, medical care, and therapeutic options for individuals with, or at risk for, AD and related disorders. Her memory clinic and research site are among the most active in Canada.

Dr Cohen has more than 28 years of experience in clinical research and has been a site PI for more than 100 pharmacological trials. In addition to her focus on AD, she has also participated in pharmacological trials for acute stroke, frontotemporal dementia, Parkinson’s disease dementia, Lewy body disease, Huntington’s disease, and vascular dementia. Her research site has been credited as a “go-to” center for AD trials and has been awarded for superior performance and quality in clinical research.

Dr Cohen represents Canada on international advisory boards and steering committees and is a consultant to a wide range of stakeholders in dementia, including government organizations and patient advocacy groups. She is a frequent lecturer and contributes to media events, including those on medical ethics. She is known for her advocacy for individuals with neurodegenerative diseases.

Despite holding academic and hospital appointments, Dr Cohen chooses to practice in the community, in keeping with her belief that dementia care and clinical research are best offered in the real-world setting.

R. Scott Turner, MD, Ph Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Medical Center Washington, DC Dr Turner is Vice Chair for Clinical Research, Professor of Neurology, and Director of the Memory Disorders Program at Georgetown University, Washington, DC. Before his recruitment to Georgetown in 2008, he was Chief of the Neurology Service at the VA Ann Arbor Healthcare System and Associate Professor and Associate Chair in the Department of Neurology, University of Michigan. He was awarded PhD and MD degrees from Emory University in Atlanta, and completed his internship, residency, and fellowship at the University of Pennsylvania in Philadelphia. He is board certi ed in psychiatry and neurology.

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Dr Turner has received numerous prestigious awards, including a fellowship from the Howard Hughes Medical Institute and a Paul Beeson Scholarship. He lectures widely, serves as a

reviewer for granting agencies and biomedical journals, and has published more than 100 peer-reviewed papers, editorials, and book chapters. He most recently published a single-site phase 2 clinical trial of a repositioned drug, nilotinib, for patients with mild to moderate dementia due to AD (Turner RS, et al. Ann Neurol. 2020;88[1]:183-194).

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The mission of the Georgetown University Memory Disorders Program is to prevent and treat AD and related dementias by conducting innovative research, educating and training healthcare professionals and the public on research advances, and offering state-of-the-art clinical care. To advance the eld, Dr Turner and his colleagues seek older volunteers who are cognitively normal or at risk for AD, or have MCI or early dementia due to AD.

Preambl Target Audienc The educational design of this activity addresses the needs of primary care providers (PCPs) and other clinicians who manage patients with Alzheimer’s disease (AD).

Statement of Need/Program Overvie AD is a common neurodegenerative condition that results in a range of profoundly disabling cognitive, affective, and behavioral symptoms. It affects approximately 5.8 million Americans.1 Barring signi cant clinical efforts and medical breakthroughs that prevent or slow disease development, current estimates suggest that by 2050, AD will af ict 14 million patients in the United States.1 PCPs are on the front lines of early diagnosis of AD, yet many say they feel unprepared and their community lacks adequate specialists in this area.1 Signs and symptoms of mild cognitive impairment (MCI) and even early AD are often con ated with normal aging, leading to late or missed diagnosis.1,2 This is compounded by the lack of a sense of urgency for early, accurate diagnosis because there are no disease-modifying therapies to treat MCI or AD.1,3,4 This eHealth Source activity reviews the pathophysiology of AD, early signs and symptoms, diagnostic rst steps, referral patterns, more-complex diagnostic procedures, and existing nonpharmacologic and pharmacologic management strategies. Drs Cohen and Turner provide expert insight into how PCPs can tailor their practice to better care for these patients.

References 1. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. https://www.alz.org/media/ Documents/alzheimers-facts-and-figures_1.pdf. Accessed November 5, 2020.

2. Judge D, et al. Int J Alzheimers Dis. 2019;2019:3637954.

3. Hampel H, et al. Brain. 2018;141(7):1917-1933.

4. Cummings JL, et al. Ann Clin Transl Neurol. 2015;2(3):307-323.

Educational Objective After completing this activity, the participant should be better able to: • Describe clinically relevant aspects of AD pathophysiology, including amyloid β and tau • Evaluate patients at risk for MCI and AD using cognitive scales, imaging, clinical examination, and patient/caregiver interviews • Identify cases of MCI and AD early during the disease course using current diagnostic criteria and available referral pathways • Collaboratively care for patients with AD using available therapeutic modalities, education on the disease and new treatment options, and open communication with patients and caregivers

Program Agend • Chapter 1: Pathophysiology of AD • Chapter 2: Signs and symptoms of MCI and AD • Chapter 3: Diagnosing early-stage AD

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• Chapter 4: Current and emerging management of AD

Physician Accreditation Statemen This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designatio Global designates this enduring activity for a maximum of 1.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurse Practitioner Continuing Education This activity has been planned and implemented in accordance with the Accreditation Standards of the American Association of Nurse Practitioners (AANP) through the joint providership of Global and Integritas Communications. Global is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 110121.

This activity is approved for 1.75 contact hour(s) (which includes 0.4 hour(s) of pharmacology).

Term of Offerin This activity was released on November 20, 2020, and is valid for 1 year. Requests for credit must be made no later than November 20, 2021.

Global Contact Informatio For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Integritas Communications Contact Informatio For all other questions about this program, please contact Integritas Communications at info@exchangecme.com.

Instructions to Receive Credi In order to receive credit for this activity, the participant must complete the preactivity questionnaire, score 75% or better on the posttest, and complete the program evaluation at www.exchangecme.com/alzheimersehealth.

Fee Information & Refund/Cancellation Polic There is no fee for this educational activity.

Disclosure of Conflicts of Interes

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Global requires instructors, planners, managers and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent con ict of interest they may have as related to the content of this activity. All

identi ed con icts of interest are thoroughly vetted by Global for fair balance, scienti c objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following nancial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Sharon Cohen, MD, FRCPC

Nothing to disclose

R. Scott Turner, MD, PhD

Nothing to disclose

The planners and managers reported the following nancial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Kristin Delisi, NP

Nothing to disclose

Lindsay Borvansk

Nothing to disclose

Andrea Funk

Nothing to disclose

Liddy Knight

Nothing to disclose

Ashley Cann

Nothing to disclose

Gena Dolson, MS

Nothing to disclose

Stacey JP Ullman, MHS

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Disclosure of Unlabeled Us This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global and Integritas Communications do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the of cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaime

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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Introduction

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lzheimer’s disease (AD) affects nearly 6 million Americans and is projected to affect 14 million by the year 2050. It is the fth leading cause of death for Americans 65 years and older and incurs a signi cant economic impact and burden: $305 billion annually for AD and other dementias, which is estimated to rise to $1.1 trillion by 2050.1 Without early and accurate identi cation of mild cognitive impairment (MCI) and AD, patients and caregivers will face an insidious progression of disease and nancial burden, as well as signi cantly decreased quality of life.

Introduction Sharon Cohen, MD, FRCPC R. Scott Turner, MD, PhD

Diagnosis is complex and symptoms are often con ated with signs of normal aging. Without a careful history of longitudinal changes and risk factors for AD; validated memory assessments; imaging or other functional assessments, as needed; and, potentially, even genetic testing, the diagnosis of AD can be missed. As biomarkers for and imaging of key pathophysiologic and structural components become more readily available, diagnosis will become easier.2,3 Primary care providers are on the front lines of identifying and managing the growing population of people with MCI or AD, thus, they need to be prepared to differentially diagnose AD or, at minimum, identify patients for whom further assessment is appropriate.1 There have been many failures in AD clinical trials over the last several decades, but there have been some recent successes,4 providing hope that there may soon be more-effective therapies for this ever-increasing population. Currently available pharmacotherapy treats only treats the symptoms of AD, but there are nonpharmacologic and lifestyle changes that can impact memory decline. Exercise has been linked to a slower decline in memory, as has achieving control of vascular risk factors.5 Implementing these changes, as well as symptomatic treatments early in the disease course, can aid patients and caregivers. Careful monitoring of patients over time for memory and other neuropsychiatric symptoms, such as agitation or depression, is necessary to help maintain quality of life for as long as possible, particularly given the current lack of disease-modifying therapies.6 Despite the absence of positive safety and ef cacy results in past clinical trial programs, there are now a number of promising therapeutic agents in later-stage development, including one agent currently under review for approval by the US Food and Drug Administration (as of November 2020).7,8 Primary care providers must stay abreast of clinical trial results, as new therapies may soon be available for this underserved patient population.

Reference 1. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. https://www.alz.org/media/ Documents/alzheimers-facts-and-figures_1.pdf. Accessed October 28, 2020.

2. Blennow K, Dubois B, Fagan AM, Lewczuk P, de Leon MJ, Hampel H. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement.

2015;11(1):58-69.

3. Brier MR, Gordon B, Friedrichsen K, et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med. 2016;8(338):338ra366.

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4. Piton M, Hirtz C, Desmetz C, et al. Alzheimer’s disease: advances in drug development. J Alzheimers Dis. 2018;65(1):3-13.

5. Joe E, Ringman JM. Cognitive symptoms of Alzheimer’s disease: clinical management and prevention. BMJ. 2019;367:l6217.

6. Cummings JL, Isaacson RS, Schmitt FA, Velting DM. A practical algorithm for managing Alzheimer’s disease: what, when, and why? Ann Clin Transl Neurol. 2015;2(3):307-323.

7. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: 12th Clinical Trials on Alzheimer’s Disease; December 4-7, 2019; San Diego, CA. 8. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther. 2020;12(1):95.

Chapter 1: Pathophysiology of Alzheimer’s Diseas Neurodegeneratio

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eurodegeneration associated with Alzheimer’s disease (AD) involves plaques made from amyloid β (Aβ) peptides, found extracellularly, and neuro brillary tangles (NFTs), found intracellularly. Amyloid plaques are found in the striatum and association neocortex, whereas NFTs are primarily seen in the amygdala, hippocampal formation, parahippocampal gyrus, and temporal association cortex.1-3 Early neuronal death is seen primarily in the hippocampus, nucleus basalis, and entorhinal cortex and is associated with mitochondrial dysfunction.2 As AD progresses, neurodegeneration spreads throughout the brain (Figure 1.1).1

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There is evidence that neurodegeneration is accompanied by neuroin ammation in AD; patients showed an increased level of proin ammatory cytokines in both serum and brain tissue compared with a control group.4,5 These proin ammatory cytokines can upregulate processes that play a role in Aβ formation.6 Aβ deposition is hastened by activated microglia found around amyloid plaques, which release proin ammatory factors.6,7 When activated, they are no longer capable of clearing Aβ plaques.8 In turn, Aβ peptides and brils can activate glial cells, creating a self-perpetuating cycle.9 Proin ammatory cytokines can activate astrocytes, which normally have a role in synaptogenesis and neurogenesis. Once activated in AD, however, they accumulate Aβ plaques.10

Role of A The amyloid cascade hypothesis, rst proposed in 1992, postulates that Aβ deposition is the primary cause of AD, resulting in dementia, neurodegeneration, vascular damage, and NFTs.11 Though the normal role of Aβ is not well understood, some have postulated that it may be involved in protection from oxidative stress, as well as in synaptic plasticity and regulation of cholesterol transport.12-14 Aβ is derived from the amyloid precursor protein (APP) and is metabolized through successive cleavage by 2 enzymes.2,3,15-17 Typically, it is cleaved via αsecretase, which does not lead to toxic Aβ fragments (nonamyloidogenic pathway). Cleavage by α-secretase results in a soluble extracellular fragment, called soluble APPα.18 In AD, however, APP is cleaved by β-secretase, setting an amyloidogenic pathway in motion.2 Following cleavage by β-secretase, the entire Aβ domain is then cleaved by γ-secretase, comprising presenilin (both presenilin 1 [PS1] and 2 [PS2]), nicastrin, anterior pharynxdefective 1, and presenilin enhancer 2, which results in peptides of different lengths (Aβ40 and Aβ42),18 with γ-secretase determining the ratio of Aβ40 to Aβ42.2 Aβ40 is more abundant and primarily deposited in blood vessel walls, whereas Aβ42 is less soluble, more amyloidogenic, and is primarily deposited in extracellular brain parenchyma.3,18,19 Aβ begins as a monomer that then aggregates into oligomers, proto brils, and brils and, nally, forms amyloid plaques, a hallmark of AD pathology (Figure 1.2).18 Oligomers and proto brils are neurotoxic and have recently been postulated to be important therapeutic targets.20 For example, lecanemab targets proto brils, and aducanumab and gantenerumab also target oligomers, although they have a greater af nity for insoluble amyloid species.18

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There is a genetic component to AD, whether it is familial or sporadic. One indication of a genetic link is the elevated rate of AD in patients with Down syndrome (trisomy 21). Because APP is located on chromosome 21, people with Down syndrome have higher levels of Aβ

throughout their lifetime.21 Autosomal dominant AD, which accounts for less than 1% of AD cases, is caused by mutations in APP, PS1, and PS2, which result in increased Aβ42 levels.22,23 Sporadic AD, conversely, accounts for the majority of AD cases and is associated with several genetic risk factors. Of these, ApoE4 is the most common and is present in approximately 25% of the general population.24 Carriers show a 3- to 15-fold increased risk of developing AD, depending on whether they have 1 or 2 copies of ApoE4.25 Studies have shown that approximately two-thirds of patients with AD are ApoE4 carriers.26 This is notable because ApoE4, which normally functions to regulate cholesterol metabolism, decreases clearance of Aβ in patients with AD.23 Aβ clearance pathways have become potential therapeutic targets because Aβ accumulation directly causes neuronal damage and death and is associated with dystrophic neurites and changes in microglia and astrocytes. The changes are wide ranging and encompass atrophy, in ammation, oxidative injury, reduced central nervous system metabolism, synaptic de cits, and reduced hippocampal volume.2,21,27-29

Role of Ta Tau is a phosphorylated microtubule-associated protein that, under normal circumstances, binds to and stabilizes microtubules in neurons to support transportation of organelles, glycoproteins, and neutrotransmitters.15,30 In AD, however, tau is hyperphosphorylated and can no longer bind to microtubules.30 In fact, tau may actively promote microtubule disassembly, which leads to neuronal degeneration.30 Hyperphosphorylated tau will form paired helical laments, which then aggregate into NFTs (Figure 1.2).18,30 Hyperphosphorylated tau is necessary, but not suf cient, to cause AD and correlates better with cognitive decline than Aβ plaque deposition does.2 Therapeutic approaches developed to treat AD have included stabilization of tau conformations and microtubules, clearance of tau aggregates, prevention of aggregation, immunization against phosphorylated tau, and passive immunization.16 Mutations in APP, PS1, and PS2 generally cause early-onset Aβ deposition, which is then followed by accumulation of NFTs.31,32 Aβ alters kinase and phosphatase activity to promote accumulation of NFTs, but NFTs do not promote accumulation of Aβ.21 As a result of Aβ accumulation, tau enables downstream alterations that result in neuronal damage and death.33

Questioning the Amyloid Hypothesi Over the last 25 years, the amyloid hypothesis has been at the forefront of AD research and therapeutic targets. It has occasionally been called into question. A large body of evidence used to question the amyloid hypothesis comprises the repeated failures of clinical trials into Aβ-targeted therapies.15,21,34 Furthermore, there is a disconnect between Aβ plaque burden and cognitive decline. As previously stated, cognitive decline correlates better with NFT burden than with Aβ plaque burden, and evidence of Aβ deposits have been observed during postmortem examinations in patients who did not demonstrate noticeable dementia.2,35 There has been no evidence, or even a hypothesis stipulated, that AD is fundamentally due to loss of presenilin function within γ-secretase, which would provide signi cant support for the amyloid hypothesis.21

In Defense of the Amyloid Hypothesis

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There is, however, evidence to refute many questions about the amyloid hypothesis. First, there have been multiple problems with clinical trials assessing Aβ-targeted therapies, including inadequate preclinical data; poor brain penetration; low (or no) biomarker change as measured by amyloid, tau, and neuronal injury markers; and low therapeutic indices.36 Clinical

trials have also had a wide spectrum of AD inclusion criteria, ranging from very mild AD to severe AD. Clinical trial requirements for amyloid positron emission tomography (PET) imaging were modi ed recently, meaning trials performed before the updated requirement did not, in fact, have entire patient populations with demonstrated amyloid burden. There have been recent successes with Aβ-targeted therapies in better-de ned populations with earlier-stage disease, determined using more-comprehensive imaging and biomarker data.20,37-40 Second, the disconnect between Aβ and cognitive decline may be explained by the timing of Aβ deposits, as they appear earlier in the disease course, and lead to downstream changes that may take effect later in the disease course and cause more neuronal dysfunction.31-33 Furthermore, patients who are determined to have Aβ plaques postmortem may not have been thoroughly tested before death. Amyloid deposits are diffuse and may not have a suf ciently high level of neuritic and glial abnormalities to be detected in another manner.41 Finally, a problem with identifying loss of presenilin function as the cause of AD is that heterozygous mutations are not clinically apparent until patients develop symptoms.

Heterozygous presenilin mutations may cause partial loss of function, but that is insuf cient to fully explain AD, as nearly all patients with AD have wild-type presenilins.21 Though there has been disagreement in the eld over the continued relevance of the amyloid hypothesis, there is enough recent evidence to continue using the amyloid hypothesis as a basis for development of therapeutics.

Clinical Implication AD is characterized by a long prodromal period, with alterations in Aβ and tau evident prior to symptom onset.21,42,43 We now have multiple ways to measure changes in Aβ and tau: isolated cerebrospinal uid (CSF) collection, continuous CSF collection, and PET imaging.21,42 All methods of biomarker measurement reveal abnormalities years before symptom onset. If AD is identi ed at an early stage through use of biomarkers, clinical history, and cognitive testing, clinicians can begin early intervention and monitor changes in symptoms over time.21,44

Video 1: Amyloid Hypothesis Sharon Cohen, MD, FRCPC R. Scott Turner, MD, PhD

Key Take-Home Message • Aβ plaques and NFTs are the pathologic hallmarks of AD • In AD, APP is cleaved by β- and γ-secretase, forming either Aβ40 or Aβ42, which will aggregate into extracellular Aβ plaques • Tau is hyperphosphorylated, destabilizing microtubules and causing neuronal damage; hyperphosphorylated tau aggregates into intracellular NFTs • Neuroin ammation contributes to the pathologic cascade in AD

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• There are genetic components of both familial and sporadic AD: deterministic mutations in APP, PS1, and PS2 cause autosomal dominant (or familial) AD, and the presence of ApoE4 is associated with increased risk for sporadic AD

• Though called into question for nearly 30 years, substantial evidence exists to support the amyloid hypothesis, which postulates that amyloid deposition is an important early pathologic event in AD

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Jeong S. Molecular and cellular basis of neurodegeneration in Alzheimer’s disease. Mol Cells.

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Fillit H, Ding WH, Buee L, et al. Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett. 1991;129(2):318-320.

Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B. Detection of interleukin-6 and alpha 2macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Lab Invest. 1992;66(2):223-230.

Sastre M, Dewachter I, Landreth GE, et al. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003;23(30):9796-9804.

Guo J-T, Yu J, Grass D, de Beer FC, Kindy MS. Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. J Neurosci. 2002;22(14):5900-5909.

Rogers J, Lue LF, Walker DG, et al. Elucidating molecular mechanisms of Alzheimer’s disease in microglial cultures. Ernst Schering Res Found Workshop. 2002(39):25-44.

Barger SW, Harmon AD. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature. 1997;388(6645):878-881.

Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang H-Y. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197-209.

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Baruch-Suchodolsky R, Fischer B. Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry. 2009;48(20):4354-4370.

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14. Puzzo D, Privitera L, Palmeri A. Hormetic effect of amyloid-β peptide in synaptic plasticity and memory. Neurobiol Aging. 2012;33(7):1484.e15-1484.e24.

15. Harrison JR, Owen MJ. Alzheimer’s disease: the amyloid hypothesis on trial. Br J Psychiatry.

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16. Graham WV, Bonito-Oliva A, Sakmar TP. Update on Alzheimer’s disease therapy and prevention strategies. Annu Rev Med. 2017;68:413-430.

17. Laudon H, Winblad B, Näslund J. The Alzheimer’s disease-associated gamma-secretase complex: functional domains in the presenilin 1 protein. Physiol Behav. 2007;92(1-2):115-120.

18. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88.

19. Zhang W, Huang W, Jing F. Contribution of blood platelets to vascular pathology in Alzheimer’s disease. J Blood Med. 2013;4:141-147.

20. Swanson CJ, Zhang Y, Dhadda S, et al. Treatment of early AD subjects with BAN2401, an anti-Aβ protofibril monoclonal antibody, significantly clears amyloid plaque and reduces clinical decline.

Presented at: Alzheimer’s Association International Conference; July 22-26, 2018; Chicago, IL. 21. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608.

22. Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2(8):864-870.

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23. Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(10):a006296.

24. Myers RH, Schaefer EJ, Wilson PW, et al. Apolipoprotein E epsilon4 association with dementia in a population-based study: the Framingham study. Neurology. 1996;46(3):673-677.

25. Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM. APOE and Alzheimer’s disease: evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol. 2019;56(4):2450-2465.

26. Mattsson N, Groot C, Jansen WJ, et al. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement.

2018;14(7):913-924.

27. Braak H, Braak E. Alzheimer’s disease affects limbic nuclei of the thalamus. Acta Neuropathol.

1991;81(3):261-268.

28. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;286(17):2120-2127.

29. Buckner RL, Sepulcre J, Talukdar T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer’s disease. J Neurosci.

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30. Cowan CM, Bossing T, Page A, Shepherd D, Mudher A. Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol.

2010;120(5):593-604.

31. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996;3(1):16-32.

32. Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996;2(10):1146-1150.

33. Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79(6):1094-1108.

34. Drachman DA. The amyloid hypothesis, time to move on: amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement. 2014;10(3):372-380.

35. Esparza TJ, Zhao H, Cirrito JR, et al. Amyloid-β oligomerization in Alzheimer dementia versus highpathology controls. Ann Neurol. 2013;73(1):104-119.

36. Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol. 2014;76(2):185-205.

37. Swanson C, Zhang Y, Dhadda S, et al. Persistence of BAN2401-mediated amyloid reductions posttreatment: a preliminary comparison of amyloid status between the core phase of BAN2401G000-201 and baseline of the open-label extension phase in subjects with early Alzheimer’s disease. J Prevent Alzheimer Dis. 2019;6(suppl 1):S36.

38. Klein G, Delmar P, Kerchner G, et al. Thirty-six-month amyloid PET results show continued reduction in amyloid burden with gantenerumab. J Prevent Alzheimer Dis. 2019;6(suppl 1):S14.

39. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: 12th Clinical Trials on Alzheimer’s Disease; December 4-7, 2019; San Diego, CA. 40. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther. 2020;12(1):95.

41. Hong S, Ostaszewski BL, Yang T, et al. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron. 2014;82(2):308-319.

42. Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol.

2013;12(2):207-216.

43. Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65(11):1509-1517.

44. Anderson ND. State of the science on mild cognitive impairment (MCI). CNS Spectr.

2019;24(1):78-87.

Chapter 2: Signs and Symptoms of Mild Cognitive Impairment and Alzheimer’s Diseas The Prevalence of Cognitive Impairment: From MCI to A

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revised de nition of Alzheimer’s disease (AD) by Dubois and colleagues and the National Institute on Aging–Alzheimer’s Association workgroup was published to improve diagnostic accuracy, de ne earlier stages, and incorporate biomarker data (when available) into clinical criteria.1-3 AD is now viewed as a continuum, and 3 distinct stages are de ned: preclinical (no cognitive impairment), mild cognitive impairment (MCI) or prodromal AD, and dementia due to AD that is mild, moderate, or severe (Figure 2.1).4,5

The preclinical stage of AD, de ned as normal cognition but with pathophysiologic and biomarker changes, begins approximately 20 years prior to symptom onset.4,6 The next stage, MCI or prodromal AD, develops after several years in a large percentage of patients with preclinical AD; it is de ned as the beginning of cognitive decline beyond that of normal aging and with further pathophysiologic and biomarker changes.7 Approximately 29% to 38% of individuals with MCI progress to dementia due to AD within 5 years.8,9 At age 65 years, the annual rate of transition from normal cognition, MCI due to AD, and mild/moderate/severe AD to a more severe state is 8%, 22%, 25%, 36%, and 16%, respectively.10

Recognizing Risk Factors for A

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Advanced age and a family history of AD in a rst-degree relative are the most important risk factors for developing AD, with age as the greater risk factor.11,12 ApoE4 carriers account for a

substantial fraction of the genetic risk found in patients who have a rst-degree relative with AD.13 Familial, or early-onset, AD is caused by autosomal dominant genetic mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2). These mutations cause increased amyloid β (Aβ) 42 production from APPs in the brain, and symptoms appear at an early age (as early as the third, fourth, or fth decade of life).1 Although familial AD is relatively rare compared with sporadic AD, it is because of these mutations resulting in increased Aβ that affected families have been instrumental in the development of the amyloid hypothesis of AD. Although molecular mechansims are unclear, there are numerous modi able risk factors for AD. For example, controlling risk factors for cardiovascular disease (CVD), such as smoking, diabetes, obesity, hypertension, and high cholesterol—particularly during midlife—mitigate the risk of developing AD.12 Smoking increases oxidative stress and in ammation and hyperinsulinemia disrupts Aβ clearance in the brain, leading to an accumulation of Aβ plaques, thus increasing the risk for AD.14,15 Chronic hypertension decreases vascular integrity of the blood-brain barrier, resulting in increased risk for apoptosis, cell damage, and Aβ accumulation.16 Additional modi able risk factors are physical and mental inactivity (which may contribute to obesity), poor diet (which may contribute to high cholesterol), and low educational attainment.6,12 Traumatic brain injury increases risk for AD, as does vitamin D de ciency and sleep-disordered breathing.12,17 A signi cant mitigating factor for progression from MCI to AD is a change in lifestyle: controlling CVD risk factors and increasing exercise, which also help manage CVD risk factors, may prevent or delay onset and slow progression. It is critical that clinicians educate their patients about lifestyle bene ts and screen for cognitive decline.

The rst step in recognizing risk factors for AD is to regularly interview and screen older individuals. Medicare covers an annual wellness visit that includes cognitive evaluation.12 If evidence of impairment in episodic memory is discovered during the cognitive evaluation, the patient will require close monitoring, as the impairment may progress.1 Progression from MCI to AD is increased in individuals with any of the following risk factors: ApoE4 carrier, elevated cerebrospinal uid phosphorylated tau, depression, diabetes, hypertension, older age, female sex, lower Mini-Mental State Exam (MMSE) score, and increased volume of white matter hyperintensity on magnetic resonance imaging (MRI).18

Call to Actio • Evaluate older individuals for risk factors of AD, such as smoking, diabetes, hypertension, hypercholesterolemia, and obesity, as well as family history of the disease • Perform a cognitive evaluation for all older patients annually during the annual wellness visit

Importance of Differentiating Among Causes of Dementi Dementia, similar to shortness of breath, is not a diagnosis. Instead, the clinician should diagnose MCI or dementia as due to a speci c disease, similar to shortness of breath due to pneumonia or due to heart failure. Although the most common etiology of dementia a century ago was tertiary neurosyphilis, the most common current cause of dementia is AD.12

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The path to dementia due to AD, as well as to other dementias, begins with MCI, de ned by a decline in cognitive domains (memory, executive function, attention, language, and visuospatial skills) greater than one would expect due to normal aging, but preserved functional independence.1 Patients with MCI typically do not have signi cant impairments in social or occupational functioning.1 Thus, MCI is often con ated with normal aging by patients,

families, and medical practitioners. It is increasingly important that clinicians distinguish cognitive decline of normal aging from the more signi cant decline of MCI and dementia (Table 2.1).12 The clinician should pay particular attention to any new sign or symptom or pattern of progressive decline over months to years.

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If normal age-related decline is ruled out, clinicians should investigate further and attempt to identify the cause of MCI or dementia. Clinicians should differentiate between the multiple causes of dementia to provide the most accurate prognosis and initiate appropriate treatments. The amnestic presentation, with impaired episodic memory, is the most common presentation of MCI and AD. However, atypical, or nonamnestic, AD exists and is marked by language changes (logopenic aphasia, characterized by de cits in word nding), visuospatial agnosias (posterior cortical atrophy, characterized by de cits in visuospatial processing), or, rarely, frontal or executive dysfunction (frontal variant of AD, which mimics frontotemporal dementia).1,2,19-21 As nonamnestic disease progresses, de cits in other cognitive domains appear (Table 2.2).2

Parkinson’s disease, Huntington’s disease, and HIV infection are also all associated with cognitive impairment and dementia due to distinct pathologies.22 The differential diagnosis of dementia must be considered before diagnosing AD.

Taking the Next Steps in Diagnosi If a patient has signs and symptoms of MCI or mild AD, a clinician should perform basic chemistry, complete blood count, vitamin B12, and thyroid function tests to identify readily treatable causes of cognitive impairment or dementia.25 Clinicians should also rule out HIV, syphilis, Lyme disease, and depression or anxiety as potential causes.17,25 A medication review is essential: anticholinergics, opiates, benzodiazepines, digoxin, antihistamines, tricyclic antidepressants, muscle relaxants, and antiepileptics may cause or contribute to cognitive impairment.26 It is important to wean patients from any medications causing cognitive decline to determine whether symptoms are caused by MCI or AD or are a side effect of central nervous system (CNS)–active medications.27 Primary care providers can refer patients to a specialty clinic if they lack experience assessing MCI or AD or if the patient wants a second opinion or to learn about research opportunities.27

Call to Actio • Identify and attempt to wean patients from medications that may cause or worsen cognitive impairment, particularly anticholinergics • Screen for depression or anxiety and sleep disorders, including obstructive sleep apnea

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• Perform routine laboratory testing, including thyroid function tests and vitamin B12, for underlying conditions that may result in cognitive impairment

• Test for possible CNS infections, including HIV, syphilis, and Lyme disease • Consider referral to a specialty clinic for further evaluation, a second opinion, and/or possible research participation

Evidence for Prevention of Cognitive Decline When a patient presents with MCI or AD, there are measures, largely focused on modi able risk factors, that may be effective in preventing or slowing cognitive decline.6 Exercise and dietary changes may be effective in preserving cognitive function in older patients at risk for AD. The FINGER study enrolled participants in a multidomain intervention comprising diet, exercise, cognitive training, and vascular monitoring. These lifestyle modi cations resulted in improvement in a neuropsychological test battery score.28 Another study demonstrated that better adherence to a Mediterranean diet and physical activity regimen were associated with a reduced risk for AD in older patients without dementia.29 A study of older adults without cognitive impairment showed a lower rate of conversion to AD when they exercised at least 3 times per week.30 Prevention studies in patients at high risk for AD are in progress, including patients with autosomal dominant genetic mutations, preclinical AD, or a positive brain amyloid positron emission tomography (PET) scan.6 Individuals in these trials are given a monoclonal antibody targeting Aβ (solanezumab or gantenerumab) or Aβ proto brils (lecanemab) or placebo, and progression is measured with cognitive tests and AD biomarkers.6,31,32 Clinicians may refer Video 2: Screening for MCI and AD interested and eligible patients and, Sharon Cohen, MD, FRCPC potentially, their family members to learn R. Scott Turner, MD, PhD more about clinical trial participation.27

Call to Actio • Educate patients about modifiable risk factors for MCI, dementia, and AD • Discuss lifestyle changes that may aid in maintaining normal cognition or slowing cognitive decline in patients with or at risk for AD • Refer interested and eligible patients and, potentially, their family members to a specialty clinic to learn more about opportunities for research participation

Key Take-Home Message • MCI and dementia should be distinguished from normal age-related cognitive changes • Regularly educate patients about modi able risk factors, particularly diet and exercise, to help slow cognitive decline due to aging • Screen for MCI, dementia, and AD as the rst diagnostic step • Perform a full review of medications and supplements for drugs that may impair cognition

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• Screen for cognitive and functional decline, behavioral changes, and common AD comorbidities, such as depression or anxiety, sleep problems, or weight loss

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Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement.

2011;7(3):270-279.

McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement.

2011;7(3):263-269.

Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9(11):1118-1127.

Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):257-262.

Progression of Alzheimer’s. Medical Care Corporation website. https://www.mccare.com/ education/alzprogression.html. Accessed November 1, 2020.

Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9(1):71.

Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol.

2013;12(2):207-216.

Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia—metaanalysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 2009;119(4):252-265.

Ward A, Tardiff S, Dye C, Arrighi HM. Rate of conversion from prodromal Alzheimer’s disease to Alzheimer’s dementia: a systematic review of the literature. Dement Geriatr Cogn Dis Extra.

2013;3(1):320-332.

Davis M, O’Connell T, Johnson S, et al. Estimating Alzheimer’s disease progression rates from normal cognition through mild cognitive impairment and stages of dementia. Curr Alzheimer Res. 2018;15(8):777-788.

Anderson ND. State of the science on mild cognitive impairment (MCI). CNS Spectr.

2019;24(1):78-87.

Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. https://www.alz.org/media/ Documents/alzheimers-facts-and-figures_1.pdf. Accessed November 1, 2020.

Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-923.

Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162-4167.

Durazzo TC, Mattsson N, Weiner MW; Alzheimer’s Disease Neuroimaging Initiative. Smoking and increased Alzheimer’s disease risk: a review of potential mechanisms. Alzheimers Dement.

2014;10(3 suppl):S122-S145.

Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates Alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke. 2004;35(11 suppl 1):2628-2631.

Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA. 2014;312(23):2551-2561.

Li J-Q, Tan L, Wang H-F, et al. Risk factors for predicting progression from mild cognitive impairment to Alzheimer’s disease: a systematic review and meta-analysis of cohort studies. J Neurol Neurosurg Psychiatry. 2016;87(5):476-484.

Maia da Silva MN, Millington RS, Bridge H, James-Galton M, Plant GT. Visual dysfunction in posterior cortical atrophy. Front Neurol. 2017;8:389.

Josephs KA, Whitwell JL, Duffy JR, et al. Progressive aphasia secondary to Alzheimer disease vs FTLD pathology. Neurology. 2008;70(1):25-34.

Ossenkoppele R, Pijnenburg YA, Perry DC, et al. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain. 2015;138(Pt 9):2732-2749.

Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.

Villa C, Ferini-Strambi L, Combi R. The synergistic relationship between Alzheimer’s disease and sleep disorders: an update. J Alzheimers Dis. 2015;46(3):571-580.

Besser LM, Gill DP, Monsell SE, et al. Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease. Alzheimer Dis Assoc Disord. 2014;28(1):36-43.

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25. McCarten JR. Clinical evaluation of early cognitive symptoms. Clinics Geriatr Med. 2013;29(4):791-807.

26. Steinman MA, Hanlon JT. Managing medications in clinically complex elders: “There’s got to be a happy medium.” JAMA. 2010;304(14):1592-1601.

27. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(3):126-135.

28. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-2263.

29. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer disease.

JAMA. 2009;302(6):627-637.

30. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81.

31. Bateman RJ, Benzinger TL, Berry S, et al; DIAN-TU Pharma Consortium for the Dominantly Inherited Alzheimer Network. The DIAN-TU Next Generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8-19.

32. Eisai Inc. AHEAD 3-45 study: a study to evaluate efficacy and safety of treatment with BAN2401 in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid. ClinicalTrials.gov website. https:// clinicaltrials.gov/ct2/show/NCT04468659. Accessed November 1, 2020.

Chapter 3: Diagnosing EarlyStage Alzheimer’s Diseas Importance of Recognizing Early Signs and Symptoms of A

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arly diagnosis of dementia due to Alzheimer’s disease (AD) greatly bene ts patients and their families. No further workups or medical appointments to establish diagnosis are needed; instead, patients can take advantage of available counseling and education and begin US Food and Drug Administration (FDA)–approved medications to slow cognitive and functional decline, employ lifestyle modi cations to potentially further slow decline, and plan for the future—both logistically and nancially. Patients and their families typically experience reduced anxiety and uncertainty about signs and symptoms of AD with early diagnosis, which is often con rmatory of their unspoken suspicions.1 Symptoms that necessitate further investigation for mild cognitive impairment (MCI) or AD include mild memory impairment with a longitudinal decline (can include memory loss, executive function, attention, language, or visuospatial skills), dif culty performing complex activities of daily living, and apathy or depression/anxiety.2-5 AD may be amnestic, which is the most common presentation, or nonamnestic, which is characterized by visuospatial agnosias (posterior cortical atrophy), aphasia (logopenic aphasia), or, the rarest form, disruption in frontal/executive functions (similar to frontotemporal dementia [FTD]).4 Nonamnestic symptoms are also eventually accompanied by cognitive decline in other domains.4 Patients with MCI, while exhibiting symptoms of memory and cognitive loss beyond that of normal aging, are de ned by having preserved functional independence.5

Making the Clinical Diagnosi If patients present with signs and symptoms suggestive of MCI or AD, further evaluation and workup should include family history; years of education; occupation; and history of traumatic brain injury (TBI), alcohol or substance use disorder, stroke or transient ischemic attacks, seizures, falls, sleep changes, weight change, and depression or anxiety.3,6 Also integral to diagnosing MCI and AD are the physical examination and laboratory testing, as well as a thorough medication review to identify drugs that could be causing or contributing to cognitive decline.7-10 A referral to a specialty clinic may be required if the clinician feels inadequately experienced to diagnose MCI or AD, wants to obtain a second opinion, or the patient and their family members want to learn about research opportunities.

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Patients may not be completely reliable when describing their symptoms because of unawareness (anosognosia) or a desire to minimize symptoms. A caregiver, family member, or other informant typically provides more reliable data about cognitive and functional decline, particularly longitudinal information, and their input should always be sought when evaluating MCI, dementia, or AD.3 In addition to interview questions, short validated screening tools, such as the Ascertain Dementia 8-item Informant Questionnaire (AD8), General Practitioner assessment of Cognition (GPCOG) for informants, and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), may be used with knowledgeable family members, caregivers, or other informants.11 There are also validated tools available, such as the MiniCog or GPCOG for patients, to screen and assess possible cognitive decline in patients who report memory concerns, patients in whom family members have reported decline, or annually

at a patient’s wellness visit (Table 3.1).11 A physician is not essential for their administration; a trained clinician may perform these tests, for the so-called fth vital sign, in preparation for the physician visit. The following screening tools are available online and in the Clinical Resource Center.

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Another effective tool includes a word list learning test—with multiple trials—to plot a learning curve.5 American Academy of Neurology guidelines recommend using validated screening tools (listed above) and the Alzheimer’s Association provides an algorithm for assessing both patients and caregivers to determine which patients should have a more in-depth evaluation (Figure 3.1).8,11 For example, when patients present with signs and symptoms of cognitive decline, clinicians should conduct a brief structured assessment of the patient and the caregiver, family member, or informant, if possible. If the results of those assessments trigger concerns, a full dementia evaluation of the patient is warranted.11 Neuropsychologic testing is available when needed to further evaluate cognition, employing a standardized battery of tests with performance compared with population normative data.19

Not all tests are appropriate for patients with MCI and many have shortcomings for patients with AD. For example, a low score on the Mini-Mental State Exam (MMSE) is not diagnostic of AD, and there is a wide variation in sensitivity and speci city for predicting conversion from MCI to AD.20 Likewise, the Mini-Cog has a wide range of speci city and sensitivity, depending on the speci c population tested.21 It is, however, recommended by the Alzheimer’s Association that a short screening test such as the Mini-Cog be routinely employed, where appropriate, in the primary care provider’s clinic.3

Call to Actio • Take a thorough personal and family history at least annually • If there is suspicion of cognitive decline: - Conduct blood tests and a medication review - Consult with a family member or caregiver for further information, including administrative of short assessments to gauge longitudinal changes - Perform short cognitive tests to assess the patient’s status - Refer the patient to a specialty clinic, as needed

Role of Imaging and Biomarkers in A

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Although typically restricted to research rather than clinical practice, positron emission tomography (PET) neuroimaging and plasma or cerebrospinal uid (CSF) biomarkers, when combined with cognitive assessment, aid in diagnosing MCI and AD. Investigators have

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Although FDG-PET neuroimaging may sometimes be obtained for clinical diagnosis (particularly to distinguish early AD from FTD), amyloid PET and tau PET are currently available only in the research setting (or via self-pay). There are 3 FDA-approved PET tracers to measure Aβ/amyloid and 1 FDA-approved ligand to measure tau/NFTs. Florbetapir, orbetaben, and utemetamol have high speci city and sensitivity for detecting Aβ pathology in the brain.23-25 The uptake of ortaucipir, a tau PET tracer, is elevated in patients with mild AD and correlates with CSF p-tau levels (Figure 3.3).26

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recently proposed the A/T/N system, which groups biomarkers into 3 categories, namely, amyloid-based (A), tau or neuro brillary tangle (NFT) pathology (T), and neurodegenerative or neuronal injury markers (N).19,22 To be positive for amyloid, a patient must exhibit either high ligand retention on amyloid PET scan or low CSF amyloid β (Aβ) 42. The presence of tau pathology is evaluated by a positive tau PET Video 3: Instruments in Practice scan or by elevated CSF phosphorylated tau (p-tau). Neuronal injury or Sharon Cohen, MD, FRCPC neurodegeneration is marked by high CSF R. Scott Turner, MD, PhD total tau (t-tau), uorodeoxyglucose (FDG)PET hypometabolism, and atrophy on structural magnetic resonance imaging (MRI) in brain regions characteristic of AD (Figure 3.2).22

Performing a lumbar puncture on every patient with cognitive decline is impractical and associated with potential adverse events, thus limiting its clinical utility as a diagnostic tool.

CSF Aβ is inversely correlated with amyloid burden on PET scans, though it is important to note that CSF Aβ is decreased in conditions other than AD (including HIV-associated dementia).22,27 T-tau re ects neuronal degeneration and may also be temporarily increased, without a change in p-tau, in patients with TBI, stroke, and Creutzfeldt-Jakob disease (CJD).

P-tau is a more reliable and speci c biomarker of AD.22,27 As our knowledge of plasma and CSF biomarkers advances, they may gain traction in routine clinical practice, particularly to identify individuals who may bene t from emerging, potentially disease-modifying, therapies.

The ApoE gene accounts for much of the genetic risk seen in rst-degree relatives of patients with sporadic (nonfamilial) AD; ApoE4 carriers have increased risk for AD and lower age of onset.28 Direct-to-consumer genetic testing is commercially available and individuals can learn their ApoE genotype and, thus, their risk for AD and many other genetic disorders without input from a clinician; however, consumer understanding of the implications is limited.29 First, individuals may not understand what the test result—either positive or negative—means.

Second, patients may become anxious or upset about their results or experience other negative consequences. Third, results can inform individual lifestyle modi cation to potentially reduce the risk for AD, though the patient must understand that a reduced risk is not certain.29 Patients should also temper their desire to learn their ApoE genotype with the potential risk to their continued or future insurability (health, disability, life, and long-term care); discrimination based on genotype is illegal only with respect to health insurance. Thus, it is critical that desired policies are instated before genetic testing is performed.29

Video 4: Imaging in AD

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Sharon Cohen, MD, FRCPC R. Scott Turner, MD, PhD

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The workup for cognitive decline and dementia includes a neuroimaging study, a noncontrast brain MRI or, less commonly, noncontrast computed tomography (CT).

Functional MRI (fMRI) remains a research tool and measures brain activity via blood oxygenation levels; this provides information about functional abnormalities that may contribute to memory impairment. fMRI can aid in detecting MCI and distinguishing dementia with Lewy bodies from AD.30-32 CT is less sensitive than MRI, but CT has a lower cost and shorter acquisition time than MRI.33 Furthermore, CT is requested on patients with claustrophobia or with

implanted metal devices (eg, pacemakers) for whom MRI is precluded.33 A CT or MRI of the brain may reveal strokes; hemorrhages, including subdural hematoma; normal-pressure hydrocephalus; cancer; or other structural lesions. MRI may also be diagnostic of CJD. It is important to note that older individuals, including those with normal cognition, typically have some degree of cerebral atrophy and white matter changes, which are still considered normal aging and nonspeci c ndings in these patients.34 Patients with dementia will have more extensive and more speci c neuroanatomical changes.

Electroencephalogram (EEG) can indirectly measure brain function and may help to differentiate healthy individuals from those with MCI, AD, or other dementias.19,35 EEG recordings can be obtained with the patient awake, at rest, asleep, and may also be task oriented, although the latter may induce anxiety that impairs the patient’s ability to perform a task.35,36 Finally, EEG can be useful when CJD or a seizure disorder is suspected.

Approximately 10% to 30% of individuals with AD may have associated epilepsy.37

Key Take-Home Message • There are several validated short screening tools to assess cognition that may be applied in a primary care setting—some focused on the patient’s performance and others surveying an informant • A diagnosis of MCI or AD requires a medical history (from the patient and informant), physical examination, cognitive testing, laboratory testing, neuroimaging (MRI or CT), and, increasingly, biomarkers of AD pathologies • Neuropsychologic testing, FDG-PET scan, and CSF biomarkers are clinically available, but may not be covered by third-party payers • Direct-to-consumer genetic testing offers easy-to-access genetic testing to assess risk for AD (ApoE genotyping) and many other genetic diseases • Amyloid and tau PET scans and plasma and CSF biomarkers of AD are employed in research to con rm a diagnosis, predict cognitive decline, and determine target engagement and ef cacy of new treatments

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Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.

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McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement.

2011;7(3):263-269.

Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement.

2011;7(3):270-279.

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10. Steinman MA, Hanlon JT. Managing medications in clinically complex elders: “There’s got to be a happy medium.” JAMA. 2010;304(14):1592-1601.

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Dementia Care Central website. https://www.dementiacarecentral.com/mini-mental-state-exam/.

Updated October 7, 2020. Accessed November 1, 2020.

13. Montreal Cognitive Assessment Test (MoCA) for dementia & Alzheimer’s. Dementia Care Central website. https://www.dementiacarecentral.com/montreal-cognitive-assessment-test/. Updated May 29, 2020. Accessed November 1, 2020.

14. Standardized Mini-Cog© Instrument. Mini-Cog website. https://mini-cog.com/mini-cog-instrument/ standardized-mini-cog-instrument/. Accessed November 1, 2020.

15. Memory Impairment Screen (MIS). Alzheimer’s Association website. https://www.alz.org/media/ Documents/memory-impairment-screening-mis.pdf. Accessed November 1, 2020.

16. General Practitioner Assessment of Cognition. Dementia Collaborative Research Centres website. http://gpcog.com.au/. Accessed November 1, 2020.

17. AD8 dementia screening interview. Alzheimer’s Association website. https://www.alz.org/media/ Documents/ad8-dementia-screening.pdf. Accessed November 1, 2020.

18. Informant questionnaire on cognitive decline in the elderly. Australian National University Research School of Population Health website. https://rsph.anu.edu.au/research/tools-resources/informantquestionnaire-cognitive-decline-elderly. Accessed November 1, 2020.

19. Turner RS, Stubbs T, Davies DA, Albensi BC. Potential new approaches for diagnosis of Alzheimer’s disease and related dementias. Front Neurol. 2020;11:496.

20. Arevalo-Rodriguez I, Smailagic N, Roqué I Figuls M, et al. Mini-Mental State Examination (MMSE) for the detection of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2015;2015(3):CD010783.

21. Chan CC, Fage BA, Burton JK, et al. Mini-Cog for the diagnosis of Alzheimer’s disease dementia and other dementias within a secondary care setting. Cochrane Database Syst Rev. 2019;9(9):CD011414.

22. Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87(5):539-547.

23. Clark CM, Schneider JA, Bedell BJ, et al; AV45-A07 Study Group. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011;305(3):275-283.

24. Hatashita S, Yamasaki H, Suzuki Y, Tanaka K, Wakebe D, Hayakawa H. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer’s disease.

Eur J Nucl Med Mol Imaging. 2014;41(2):290-300.

25. Sabri O, Sabbagh MN, Seibyl J, et al; Florbetaben Phase 3 Study Group. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimers Dement.

2015;11(8):964-974.

26. Brier MR, Gordon B, Friedrichsen K, et al. Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med. 2016;8(338):338ra366.

27. Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614-629.

28. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-923.

29. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66(2):421-423.

30. Galvin JE, Price JL, Yan Z, Morris JC, Sheline YI. Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. Neurology. 2011;76(21):1797-1803.

31. Hojjati SH, Ebrahimzadeh A, Khazaee A, Babajani-Feremi A; Alzheimer’s Disease Neuroimaging Initiative. Predicting conversion from MCI to AD by integrating rs-fMRI and structural MRI. Comput Biol Med. 2018;102:30-39.

32. Machulda MM, Ward HA, Borowski B, et al. Comparison of memory fMRI response among normal, MCI, and Alzheimer’s patients. Neurology. 2003;61(4):500-506.

33. Pasi M, Poggesi A, Pantoni L. The use of CT in dementia. Int Psychogeriatr. 2011;23(suppl 2):S6S12.

34. Jack CR Jr, Lowe VJ, Weigand SD, et al; Alzheimer’s Disease Neuroimaging Initiative. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009;132(Pt 5):1355-1365.

35. Vecchio F, Babiloni C, Lizio R, et al. Resting state cortical EEG rhythms in Alzheimer’s disease: toward EEG markers for clinical applications: a review. Suppl Clin Neurophysiol. 2013;62:223-236.

36. Kim J-S, Lee S-H, Park G, et al. Clinical implications of quantitative electroencephalography and current source density in patients with Alzheimer’s disease. Brain Topogr. 2012;25(4):461-474.

37. Acharya JN, Acharya VJ. Epilepsy in the elderly: special considerations and challenges. Ann Indian Acad Neurol. 2014;17(suppl 1):S18-S26.

Chapter 4: Current and Emerging Management of Alzheimer’s Diseas Nonpharmacologic Management Strategies in A

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ollowing diagnosis of either mild cognitive impairment (MCI) or Alzheimer’s disease (AD), patients, caregivers, and clinicians should discuss strategies, whether nonpharmacologic or pharmacologic, that may slow patients’ cognitive decline. As with all disease states, nonpharmacologic therapy can play a role alongside pharmacotherapy.

Physical exercise and control of cardiovascular disease risk factors may be bene cial in patients with MCI but have shown little evidence of bene t once patients have been diagnosed with AD.1-3 Exercise is theorized to result in reduced amyloid and tau accumulation, though that has not been consistently supported in biomarker trials of patients with mild AD, or even MCI; these data may be limited by lack of consistent biomarker use and differing trial methodologies and patient populations.4,5 Collaborative care among the patient, caregiver, and medical team is an essential part of managing AD. Successful management of AD includes the identi cation and management of any comorbidities, education of the patient and caregiver, social interaction opportunities for the patient, and implementation of nonpharmacologic and pharmacologic treatment strategies.6 These care models can improve care coordination and reduce Video 5: Discussing Expectations and burden on patients, caregivers, and Planning With Patients and Care clinicians. Shared decision making among Partners patients, caregivers, and clinicians is critical, Sharon Cohen, MD, FRCPC especially as a patient’s cognitive decline R. Scott Turner, MD, PhD worsens due to progressing AD. Eventually, this collaborative care process will need to include nancial and legal considerations and end-of-life care.7 There are organizations, whether advocacy, support, or education, that can aid patients with AD and their caregivers.

For direct links to these organization websites, please visit the Clinical Resource Center.

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Caregiving for patients with AD entails not only assisting with basic activities of daily living, such as dressing and bathing, and instrumental activities of daily living, such as paying bills and grocery shopping, but also providing emotional support, coordinating with family members and clinicians, ensuring safety at home, and managing comorbidities.6 Caregivers for patients with AD report a higher burden than caregivers for patients with other conditions; many caregivers acknowledge a high or very high level of emotional (59%) and physical (38%) stress, as well as concern about maintaining their own health.6 It is vital that treatment planning assimilate current and, potentially, future caregivers, including regular reviews of their well-being and prompt referral for support when necessary.8

Call to Action: For Patients Diagnosed With A • Discuss possible benefits of exercise and lifestyle modification • Create a management plan that is centered on the patient and caregiver • Provide external resources and information about support groups • Ensure the caregiver is not overburdened • Discuss future life planning with the patient and caregiver

Pharmacologic Management Strategies in A

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Pharmacologic management strategies are lacking in AD; the only therapies currently available are symptomatic treatments, not disease-modifying therapies (as of November 2020).6 The majority of available symptomatic therapies are cholinesterase inhibitors (ChEIs), which work to prolong the action of endogenous acetylcholine.9 Acetylcholine is used by all cholinergic neurons as a neurotransmitter; these neurons help regulate attention, learning, memory, sensory information, and wakefulness. As AD progresses, cholinergic neurons are injured or lost, making preservation of existing acetylcholine critical.10 There are 3 ChEIs currently used in clinical practice: donepezil, US Food and Drug Administration (FDA) approved in 1996; rivastigmine, FDA approved in 2000; and galantamine, FDA approved in 2001. Memantine, an N-methyl-D-aspartate receptor antagonist that regulates glutamine transmission, was FDA approved in 2003 for patients with moderate-to-severe AD (Table 4.1).9

ChEIs are indicated for use in mild, moderate, and severe AD dementia and, though not formally indicated for MCI, are sometimes used off-label in these patients. Though dosing and formulations differ among these pharmacotherapies, their ef cacy is similar: all provide modest bene t on cognition and function.8 Patients should be prescribed a ChEI upon diagnosis and should be assessed 2 to 4 weeks after treatment initiation to screen for adverse events.

Cognition and function should be monitored for 3 to 6 months after treatment initiation. If the patient does not exhibit stable or a slower decline in cognition or reports intolerable adverse events, the dosage should be changed or therapy switched (Figure 4.1).7,8

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Memantine has shown modest bene t on cognition and function, as well as behavior, in patients with moderate-to-severe AD.11 There is no clear effect or indication for use in mild AD, but it is often prescribed in these patients. Memantine is often combined with a ChEI, and it is available as a single pill in combination with donepezil, FDA approved in 2014 for moderate-to-severe AD.9

Behavioral Manifestations in A AD is accompanied by behavioral changes in addition to dementia; approximately one-third of patients with early AD exhibit neuropsychiatric symptoms.12 Depression is common in AD—it is seen in nearly 50% of patients—though there are few clinical trials on antidepressants in patients with AD.13,14 Treatment of depression may improve other neuropsychiatric symptoms often seen in AD, such as agitation or anxiety,12 but it can be dif cult to identify the most appropriate treatment for individual patients with AD exhibiting neuropsychiatric symptoms because the mechanism of depression in AD varies from that in the general population.15,16 What is known, however, is that antidepressants with anticholinergic effects (eg, tricyclic antidepressants) should be avoided in patients with AD because it can further dampen cholinergic neuron functionality, which is already impaired in patients with AD.17 Conversely, some evidence points to selective serotonin reuptake inhibitors as a promising treatment in patients with AD and depression and may have the added bene t of reducing amyloid β (Aβ) burden and reducing proin ammatory cytokines.12,18,19

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Sleep disturbance is another common manifestation of AD and becomes highly disruptive to both the patient and caregiver, especially if the caregiver is the spouse of or lives with the

patient.20 Whereas the general population can use benzodiazepines, these can increase the risk for falls in patients with AD. Suvorexant, a selective dual orexin receptor antagonist, was FDA approved in 2020 as the rst medication for treating sleep disorders in AD.21 Paying attention to basic sleep hygiene can be bene cial as well. A patient’s quality of life is affected not only by memory impairment but also by neuropsychiatric symptoms. Recognizing these other symptoms and initiating nonpharmacologic and pharmacologic treatment will have a positive effect on both the patient’s and caregiver’s quality of life.

Call to Actio • Identify patients with AD as early as possible and refer to a specialist or prescribe a ChEI or other medication upon diagnosis with AD • Monitor cognition and daily function and collaborate with a specialist to adjust medication if necessary • Assess for and treat depression • Monitor for agitation, sleep disturbances, and other behavioral manifestations of AD

Looking Ahead: The Future of AD Management

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The eld of pharmacotherapy for AD has seen some recent successes after years of unsuccessful clinical trials. Aducanumab, an anti-amyloid monoclonal antibody, is currently under Fast Track review by the FDA (as of November 2020). Of 2 large pivotal trials in early AD (de ned as MCI or mild AD with con rmed amyloid pathology)—EMERGE and ENGAGE— EMERGE met its primary, secondary, and substudy clinical and biomarker endpoints and showed signi cant reductions with high-dose aducanumab in Clinical Dementia Rating scale– Sum of Boxes, or CDR-SB, which was the primary endpoint (Figure 4.2), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) 13 items, and Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale adapted for patients with MCI (secondary endpoints; nal data set at week 78), as well as reduction in cerebrospinal uid (CSF) tau and positron emission tomography (PET) amyloid substudies (Figure 4.3).22

Though the overall ENGAGE trial population—with the same inclusion criteria as EMERGE— did not meet its primary or secondary cognitive endpoints, results from a subgroup of patients exposed to high-dose aducanumab in the ENGAGE study support the EMERGE results.22 It is important to note that aducanumab is given intravenously and, if approved, clinics would require the resources to administer aducanumab. This would increase the need for a wellestablished multidisciplinary care team to ensure adherence, comorbidity treatment, and insurance coverage. The FDA Fast Track review is based on the ef cacy of aducanumab in patients with early AD in the EMERGE trial. If approved, aducanumab will be the rst treatment to demonstrate improvement both in cognition and in biomarkers.

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Another emerging therapy that has demonstrated complete amyloid plaque removal on PET imaging is lecanemab, also known as BAN2401, which binds preferentially to proto brils and clears large Aβ oligomers. A large phase 2 clinical trial found a signi cant difference from baseline in both AD Composite Score and ADAS-Cog, which were larger in ApoE4 carriers compared with noncarriers, and a signi cant difference from baseline in CSF phosphorylated tau.23,24 Additionally, a phase 3 trial for lecanemab in patients with early AD is nearing enrollment completion. Another amyloid-targeting therapy, ALZ-801, inhibits formation of amyloid oligomers, without plaque interaction. In a re-analysis of two phase 3 trials in mild-tomoderate AD, it met its primary endpoint, measured as improvement on both ADAS-Cog and CDR-SB, in high-risk ApoE4 homozygous patients with mild AD.25 Many other anti-amyloid approaches have been unsuccessful in mid- or late-stage AD clinical trials, though a few are

progressing through clinical development. Notably, solanezumab, which targets Aβ monomers, is continuing in a phase 3 trial of preclinical AD.26 Studies of gene therapy and treatments targeting innate immunity dysfunction or other aspects of AD pathology are underway.27 Previous tau-targeted therapies have failed clinical trials, but several studies are ongoing.28 Overall, this an exciting time in AD management.

Several promising agents are in late-stage development, and aducanumab has an FDA Fast Track designation as of November 2020. Patients and clinicians alike are optimistic about future treatment options in AD, including the prospect of prevention of disease progression in preclinical AD, as well as combination therapy in later stages of disease.

Key Take-Home Message • Exercise and lifestyle changes may slow cognitive decline in patients with MCI • Collaborative care is critical for managing symptoms in patients with MCI or AD, as well as their comorbidities • Clinicians should be aware of caregiver burden as patient AD progresses • Although there are currently no disease-modifying therapies, clinicians can expedite treatment with ChEIs or memantine (or both) by identifying patients with early or mild AD • After many years of unsuccessful AD clinical trial results, recent successes with amyloidtargeted therapies and other compounds are providing hope for improved symptomatic therapies and the advent of disease-modifying therapies

Reference 1.

Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81.

2. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer disease.

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3. Rovio S, Kåreholt I, Helkala E-L, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005;4(11):705-711.

4. van der Kleij LA, Petersen ET, Siebner HR, et al. The effect of physical exercise on cerebral blood flow in Alzheimer’s disease. Neuroimage Clin. 2018;20:650-654.

5. de Souto Barreto P, Andrieu S, Payoux P, Demougeot L, Rolland Y, Vellas B; Multidomain Alzheimer Preventive Trial/Data Sharing Alzheimer Study Group. Physical activity and amyloid-β brain levels in elderly adults with intact cognition and mild cognitive impairment. J Am Geriatr Soc. 2015;63(8):1634-1639.

6. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. https://www.alz.org/media/ Documents/alzheimers-facts-and-figures.pdf. Accessed October 29, 2020.

7. Segal-Gidan F, Cherry D, Jones R, Williams B, Hewett L, Chodosh J; California Workgroup on Guidelines for Alzheimer’s Disease Management. Alzheimer’s disease management guideline: update 2008. Alzheimers Dement. 2011;7(3):e51-e59.

8. Cummings JL, Isaacson RS, Schmitt FA, Velting DM. A practical algorithm for managing Alzheimer’s disease: what, when, and why? Ann Clin Transl Neurol. 2015;2(3):307-323.

9. Joe E, Ringman JM. Cognitive symptoms of Alzheimer’s disease: clinical management and prevention. BMJ. 2019;367:l6217.

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12. Lozupone M, La Montagna M, D’Urso F, et al. Pharmacotherapy for the treatment of depression in patients with Alzheimer’s disease: a treatment-resistant depressive disorder. Expert Opin Pharmacother. 2018;19(8):823-842.

13. Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of antidepressants for depression in Alzheimer’s disease: systematic review and meta-analysis. J Alzheimers Dis. 2017;58(3):725-733.

14. Panza F, Frisardi V, Capurso C, et al. Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry. 2010;18(2):98-116.

15. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry.

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16. Geerlings MI, Schoevers RA, Beekman AT, et al. Depression and risk of cognitive decline and Alzheimer’s disease. Results of two prospective community-based studies in The Netherlands. Br J Psychiatry. 2000;176:568-575.

17. Modrego PJ. Depression in Alzheimer’s disease. Pathophysiology, diagnosis, and treatment. J Alzheimers Dis. 2010;21(4):1077-1087.

18. Cirrito JR, Disabato BM, Restivo JL, et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A. 2011;108(36):14968-14973.

19. Walker FR. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology. 2013;67:304-317.

20. Okuda S, Tetsuka J, Takahashi K, Toda Y, Kubo T, Tokita S. Association between sleep disturbance in Alzheimer’s disease patients and burden on and health status of their caregivers. J Neurol. 2019;266(6):1490-1500.

21. Hamuro A, Honda M, Wakaura Y. Suvorexant for the treatment of insomnia in patients with Alzheimer’s disease. Aust N Z J Psychiatry. 2018;52(2):207-208.

22. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: 12th Clinical Trials on Alzheimer’s Disease; December 4-7, 2019; San Diego, CA. 23. Swanson CJ, Zhang Y, Dhadda S, et al. Persistence of BAN2401-mediated amyloid reductions post-treatment: a preliminary comparison of amyloid status between the core phase of BAN2401G000-201 and baseline of the open-label extension phase in subjects with early Alzheimer’s disease. J Prevent Alzheimer Dis. 2019;6(suppl 1):S36.

24. Swanson CJ, Zhang Y, Dhadda S, et al. Treatment of early AD subjects with BAN2401, an anti-Aβ protofibril monoclonal antibody, significantly clears amyloid plaque and reduces clinical decline.

Presented at: Alzheimer’s Association International Conference; July 22-26, 2018; Chicago, IL. 25. Abushakra S, Porsteinsson A, Scheltens P, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alzheimers Dis. 2017;4(3):149-156.

26. Eli Lilly and Company. Clinical trial of solanezumab for older individuals who may be at risk for memory loss (A4). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02008357.

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28. Cummings J, Blennow K, Johnson K, et al. Anti-tau trials for Alzheimer’s disease: a report from the EU/US/CTAD Task Force. J Prev Alzheimers Dis. 2019;6(3):157-163.

Summar

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The hallmark pathology of AD, Aβ plaques and NFTs, arise through abnormal cleavage of proteins and hyperphosphorylation of tau, resulting in neuroin ammation and neurodegeneration. This pathology is evident many years before patients develop clinical symptoms. As people age, it is important that clinicians carefully evaluate cognition through family and personal history, laboratory tests, cognitive instruments, and, if warranted, imaging or biomarkers. If a person has symptoms suggestive of MCI or AD, further evaluation is required, with primary and specialty care needing to work together to provide the best path forward for these patients. AD is a challenging disease to manage because of its insidious nature and the current lack of disease-modifying therapies. Though existing pharmacotherapy treats only symptoms, a ChEI should still be started upon diagnosis and memantine added once a patient enters the moderate stage of disease. As AD progresses, the burden on the caregiver will grow, and it is critical to continue shaping the care plan around the caregiver’s, as well as the patient’s, needs. Though there have been many setbacks over the last few decades in developing new AD pharmacotherapies, recent successes and ongoing trials are likely to change the future of treatment and are providing hope to patients with AD and their families.

Clinical Resource Cente Clinical Practice Guideline The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.

Albert MS, DeKosky ST, Dickson D, et al. Alzheimers Dement. 2011;7(3):270-279. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1016/j.jalz.2011.03.008

The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.

McKhann GM, Knopman DS, Chertkow H, et al. Alzheimers Dement. 2011;7(3):263-269. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1016/j.jalz.2011.03.005

Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Petersen RC, Lopez O, Armstrong MJ, et al. Neurology. 2018;90(3):126-135. https://n.neurology.org/content/90/3/126.long

Patient and Caregiver Resource AD8 dementia screening interview

https://www.alz.org/media/Documents/ad8-dementia-screening.pdf

Alzheimer’s Associatio https://www.alz.org/

Alzheimer’s Disease Education and Referral (ADEAR) Cente https://www.nia.nih.gov/health/about-adear-center

Family Caregiver Allianc https://www.caregiver.org/

General Practitioner Assessment of Cognition (GPCOG) http://gpcog.com.au/

Informant Questionnaire on Cognitive Decline in the Elderly (IQ-CODE)

https://rsph.anu.edu.au/research/tools-resources/informant-questionnaire-cognitive-decline-elderly

Mini-Mental State Exam (MMSE) Alzheimer’s / dementia test: administration, accuracy and scorin https://www.dementiacarecentral.com/mini-mental-state-exam/

Memory Impairment Screen (MIS)

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https://www.alz.org/media/Documents/memory-impairment-screening-mis.pdf

Montreal Cognitive Assessment Test (MoCA) for dementia & Alzheimer’s https://www.dementiacarecentral.com/montreal-cognitive-assessment-test/

Standardized Mini-Cog© Instrument

https://mini-cog.com/mini-cog-instrument/standardized-mini-cog-instrument/

Suggested Readings 2020 Alzheimer’s disease facts and gures.

Alzheimer’s Association. https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf

EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease.

Budd Haeberlein S, von Hehn C, Tian Y, et al. Presented at: 12th Clinical Trials on Alzheimer’s Disease; December 4-7, 2019; San Diego, CA. https://www.neurologylive.com/view/new-analyses-suggest-highdose-aducanumab-reduces-clinicaldecline-in-early-alzheimer-disease

Neuroin ammation in Alzheimer’s disease: current evidence and future directions.

Calsolaro V, Edison P. Alzheimers Dement. 2016;12(6):719-732. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1016/j.jalz.2016.02.010

Alzheimer’s disease prevention: from risk factors to early intervention.

Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimers Res Ther. 2017;9(1):71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596480/

A practical algorithm for managing Alzheimer’s disease: what, when, and why?

Cummings JL, Isaacson RS, Schmitt FA, Velting DM. Ann Clin Transl Neurol.

2015;2(3):307-323. https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.166

Revising the de nition of Alzheimer’s disease: a new lexicon.

Dubois B, Feldman HH, Jacova C, et al. Lancet Neurol. 2010;9(11):1118-1127. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(10)70223-4/fulltext

Update on Alzheimer’s disease therapy and prevention strategies.

Graham WV, Bonito-Oliva A, Sakmar TP. Annu Rev Med. 2017;68:413-430. https://www.annualreviews.org/doi/10.1146/annurev-med-042915-103753? url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

Alzheimer’s disease: the amyloid cascade hypothesis.

Hardy JA, Higgins GA. Science. 1992;256(5054):184-185. https://science.sciencemag.org/content/256/5054/184.long

Alzheimer’s disease: the amyloid hypothesis on trial.

Harrison JR, Owen MJ. Br J Psychiatry. 2016;208(1):1-3.

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Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers.

Jack CR Jr, Knopman DS, Jagust WJ, et al. Lancet Neurol. 2013;12(2):207-216. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70291-0/fulltext

A/T/N: an unbiased descriptive classi cation scheme for Alzheimer disease biomarkers Jack CR Jr, Bennett DA, Blennow K, et al. Neurology. 2016;87(5):539-547. https://n.neurology.org/content/87/5/539.long

Molecular and cellular basis of neurodegeneration in Alzheimer’s disease.

Jeong S. Mol Cells. 2017;40(9):613-620. http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2017.0096

Cognitive symptoms of Alzheimer’s disease: clinical management and prevention.

Joe E, Ringman JM. BMJ. 2019;367:l6217. https://www.bmj.com/content/367/bmj.l6217

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A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease.

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In order to receive credit, participants must complete the preactivity, postactivity questionnaire, and program evaluation at ExchangecCME.com/AlzheimerseHealth. Participants must also score at least 75% on the posttest.