Hero

Videos

Slideshows

Articles

Podcasts

Poll

Medical approaches to treating dementia and Alzheimer disease have been mostly unsuccessful. In this Mental Health Minute, Peter J. Whitehouse, MD, PhD, recommends that clinicians go beyond biomedical approaches. Instead, he advocates a suite of public health approaches, based on the research in his latest book, 

American Dementia: Brain Health in an Unhealthy Society

is professor of Neurology and Psychiatry at Case Western Reserve University, and professor of Medicine at the University of Toronto. Along with Daniel R. George, PhD, MSc, of 

How could you incorporate public health into your practice? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

Decades of efforts to find effective medical treatments for dementia and Alzheimers disease have largely failed. Would a public health approach be more effective? 

New Directions for Alzheimer and Dementia Treatment

When it comes to Alzheimer disease (AD) and dementia, treatment gets more attention than prevention. Maybe it is time for that to change, because by combining preventative measures, it is possible to improve up to 40% of the overall risk factors for diseases like AD.

In this Mental Health Minute, James Galvin, MD, MPH, suggests simple but evidence-supported behavioral plans that psychiatrists can recommend to their patients.

is a professor of neurology at the University of Miami Miller School of Medicine and founding director of the Comprehensive Center for Brain Health.

How do you help your patients maintain their brain health? 

What advice can clinicians give patients to lower their overall risk for neurodegenerative diseases? 

How to Reduce the Risk of Late-Life Dementia—Starting in Childhood

A new study conducted by Ben-Gurion University (BGU) of the Negev scientists found that amyloid plaques comprising the beta-amyloid protein can effectively catalyze neurotransmitter degradation.

Amyloid plaques are a key indicator of Alzheimer disease and other neurodegenerative diseases, but it is still not certain if and how such plaques contribute to disease progression. Lead researchers Raz Jelinek, PhD, and doctoral student Elad Arad, in collaboration with Hanna Rapaport, PhD, and Avigail Baruch Leshem, offered an explanation: by breaking up vital neurotransmitters like dopamine and adrenaline, plaques “poison” the brain.

“This study demonstrates, for the first time for a naturally occurring amyloid, that fibrils comprising the 42-residue amyloid-β peptide (Aβ42) exhibit significant catalytic properties,” the researchers wrote.

“Our findings open intriguing new avenues of research into the molecular factors in neurodegenerative diseases that could bring us closer to therapeutic treatments,” Jelinek, Vice President and Dean of Research & Development at BGU, said to the press.

During the study, researchers observed catalytic activity directly caused by beta-amyloid fibrils, not by nonfibril, smaller protein like monomers or oligomers. As neurotransmitter degradation has been observed in brains of Alzheimer disease patients, this fibril-catalysis phenomenon discovered by Jelinek and colleagues may be physiologically significant.

Findings from the study were just published in 

1. Arad E, Leshem AB, Rapaport H, Jelinek R. β-Amyloid fibrils catalyze neurotransmitter degradation. 

https://www.sciencedirect.com/science/article/pii/S2667109321001366?via%3Dihub

2. TPS. Israeli scientists find possible key to understanding Alzheimer’s disease. World Israel News. August 3, 2021. 

https://worldisraelnews.com/israeli-scientists-find-possible-key-to-understanding-alzheimers-disease/

A new study finds amyloid plaques accelerate the breakup of neurotransmitters, worsening neurodegenerative diseases like Alzheimer disease. 

Do Amyloid Plaques Cause Alzheimer Disease? 

Eisai and Biogen’s lecanemab was granted breakthrough therapy designation by the US Food and Drug Administration (FDA) following the 18-month open-label extension (OLE) of the phase 2b proof-of-concept study in patients with early Alzheimer disease (AD). The announcement was shared by the companies at the Alzheimer’s Association International Conference (AAIC) held in Denver, Colorado, virtually held on July 26-30, 2021.

“The findings from the lecanemab Phase 2b OLE study are encouraging as they supply further insights into outcomes with anti-amyloid therapies and we look forward to learning more in the phase 3 studies, Clarity AD and AHEAD 3-45, currently underway,” said Lynn Kramer, MD, Chief Clinical Officer of the Neurology Business Group at Eisai. “The unprecedented confluence of medical knowledge, data analytics, and technological advances make it an incredibly exciting time for Alzheimer research.”

Lecanemab is an investigational monoclonal antibody that preferentially binds to soluble amyloid-beta (Aβ) aggregates. The treatment reduced brain Aβ and slowed clinical decline in the 18-month phase 2b proof of concept study examining early AD.

Post core study, researchers implemented an off-treatment gap period of 9 to 59 months, with an average of 24 months. Following this off-treatment gap, researchers evaluated 10mg/kg IC biweekly lecanemab dosing, assessing the clinical effect via the adjusted mean change of the AD Composite Score (ADCOMS), which was the primary clinical endpoint of the core study. The ADCOMS scale ranges from a score of 0.00 to 1.97, with higher score indicating greater impairment.

Participants who received 10 mg/kg IV performed better than those who received placebo on ADCOMS. Additionally, while off-treatment, participants declined at the same rate on key clinical measures in all core treatment groups. The increase in adjusted mean change between the 3 month core study follow up and OLE baseline for lecanemab biweekly, lecanemab monthly, and placebo dosing respectively were 0.11 (0.07 to 0.18 ), 0.10 (0.12 to 0.22) and 0.09 (0.19 to 0.28) for ADCOMS. This suggests lecanemab has a potential disease-modifying effect.

Low values of plasma Aβ42/40 are recognized as an indicator of elevated amyloid in the brain, and were assessed in a subset of participants in the study. The plasma Aβ42/40 ratio increased during the core phase and OLE in participants treated with lecanemab and decreased during the gap period, suggesting a potential relationship between the plasma Aβ42/40 ratio and treatment.

“The findings from the Open-Label Extension further strengthen our belief in the potential of addressing amyloid beta pathology in Alzheimer disease. We look forward to our ongoing collaboration with Eisai to study lecanemab and continuing to pioneer to address the high unmet need for Alzheimer disease patients,” said Alfred Sandrock, Jr, MD, PhD, Head of Research and Development at Biogen.

These findings, as they are based on limited data, are being further evaluated in the ongoing phase 3 Clarity study for early AD. In March 2021, 1795 participants with early AD were enrolled, and the study is expected to be completed by the end of September 2022. The phase 3 clinical study, AHEAD 3-45, is currently evaluating lecanemab in individuals with preclinical AD.

1. Late-breaking AAIC presentation explores potential clinical effects of lecanemab (BAN2401). PR Newswire. News release. July 29, 2021. 

https://www.prnewswire.com/news-releases/late-breaking-aaic-presentation-explores-potential-clinical-effects-of-lecanemab-ban2401-301344730.html

2. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. 

More potential good news for treating Alzheimer disease, as an 18-month open-label extension for lecanemab allows for its breakthrough status. 

Moving Forward: Alzheimer Treatment Granted Breakthrough Therapy Designation 

Alzheimer disease (AD) remains one of the most dreaded diagnoses a patient can get. The US Food and Drug Administration (FDA) raised hopes when it approved aducanumab, which promised to be the first disease-modifying drug for AD. But the approval immediately proved controversial. Three FDA board members 

 its patient label, and in mid-July, major hospitals announced that they would not administer the 

, Helen Lavretsky, MD, MS clarifies the issues in the aducanumab debate and offers guidance for clinicians whose patients may ask about it. Going beyond pharmacology, she points out that other treatment options, including mind-body interventions and diet changes, have been shown to slow AD’s progression.

Advice for talking to patients and caregivers about aducanumab and other novel pharmacological options

Mind-body and lifestyle interventions for AD

AD prevention programs, including nutrition, exercise, and stress reduction

Taking care of caregivers, including psychiatrists and other medical professionals

is a professor in-residence in the Department of Psychiatry at the University of California, Los Angeles. Her work on geriatric depression and integrative mental health using mind-body interventions has received national attention, and she has won numerous grants supporting that work. A distinguished fellow of the American Psychiatric Association and a fellow of the American College of Neuropsychopharmacology, she is also on the board of 

Although the new drug aducanumab has grabbed all the headlines, the future of Alzheimer treatment may be just as much about public health campaigns as it is about psychopharmacology. In this episode of Psych Pearls, we find out why.   

What Will the Future of Alzheimer Disease Treatment Look Like? 

The English word apathy originates from the Greek word apathes, which means “without pathos or feeling,”

 but scholars have shared various definitions. For example, Robert S. Martin, MD, defined apathy as a syndrome of primary motivational loss that is not attributable to emotional distress, intellectual impairment, or 

 According to Drs Richard Levy and Bruno Dubois apathy is the quantitative reduction of self-generated voluntary and purposeful behaviors, which are observable and can be quantified.

 In addition, the underlying mechanism(s) responsible for apathy may be seen as dysfunctions occurring at the level of elaboration, execution, and control of goal-directed behaviors. According to an international consensus criterion, apathy is defined as a disorder of motivation in which the symptoms are present for at least 4 weeks.

 In addition, 2 of the following 3 should be present: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions. Furthermore, these symptoms cause clinically significant impairments in personal, social, occupational, or other important areas of functioning, with such symptoms not exclusively explained by or due to other causes (ie, physical disabilities [such as blindness or loss of hearing], motor disabilities, diminished level of consciousness, or direct physiological effects of a substance [such as a drug of abuse or a medication]).

 of individuals who have no cognitive deficits.

 It is also seen among individuals with major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. Apathy is more prevalent among individuals with neurodegenerative disorders than in those free of such disorders.

Apathy has been noted throughout the spectrum of neurocognitive disorders (

 The prevalence rates for apathy among individuals with mild cognitive impairment ranges from 

 Apathy is also the most frequently reported behavioral symptom among individuals with dementia. The results of one study showed that individuals with frontotemporal dementia (FTD) and vascular dementia (VaD) report more severe apathy than individuals with Alzheimer disease (AD).

Apathy usually appears early in dementia and tends to persist throughout; it is associated with longer illness duration and it worsens with the 

 Risk factors for developing apathy include older age and greater severity of cognitive impairment. Akyol et al found that apathy was correlated with the degree of cognitive impairment among individuals with AD and VaD, but not with FTD; but apathy did not correlate with age or gender in individuals with AD, FTD, and VaD. Additionally, the degree of apathy correlated with the level of functional impairment and dementia severity across all 3 types of dementia.

Individuals with dementia who present with apathy often have more rapid cognitive decline and are more impaired in their activities of daily living.

 In addition, apathy increases the risk for earlier institutionalization among individuals with dementia.

 Distress is also significantly higher among caregivers of individuals with dementia who have apathy, when compared with individuals with dementia without it.

Emerging evidence indicates that apathy in individuals with dementia occurs due to a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics.

 Among individuals with AD, apathy is associated with an increased neurofibrillary tangle burden in the parahippocampal, frontal, and parietal regions, in addition to the anterior cingulate gyrus. Emerging evidence indicates that the severity of apathy is also associated with amyloid plaque burden, especially in bilateral frontal cortices and the right anterior cingulate gyrus along with 

One study that evaluated the cerebrospinal fluid (CSF) biomarkers among individuals with AD showed that apathy was significantly correlated with tau and p-tau, but not with amyloid β١–٤٢.

 Another study examined regions of cortical thinning and CSF biomarkers (amyloid-β ١-٤٢, total tau, and phosphorylated tau) among 3 groups—clinically normal elderly individuals, individuals with mild cognitive impairment, and individuals with mild AD dementia with apathy—and found that reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time.

 The investigators of this study did not find any association between CSF biomarkers and the severity of apathy in cross-sectional or longitudinal analyses.

Another study found that individuals with AD and apathy had a loss of white matter integrity in the genu of the corpus callosum when compared with individuals with AD without apathy.

 In addition, the loss of white matter integrity in the genu, body, and splenium of the corpus callosum was negatively correlated with the severity of apathy among individuals with AD. Neuroradiological studies indicate that the dysfunction of the anterior cingulate cortex is the strongest anatomical correlate of apathy in AD, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders.

Neuroimaging studies indicate that the apathy among individuals with behavioral variant of FTD is associated with prominent atrophy in: the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, right caudate (including the ventral striatum), right temporoparietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region.

A recent meta-analysis that analyzed data from 41 studies indicated that apathy is associated with hypometabolism and a decrease in gray matter volume in the left inferior frontal gyrus.

 The investigators also found altered brain perfusion and decreased gray matter volume in the anterior cingulate cortex among individuals with AD, and decreased gray matter volume in the inferior frontal gyrus and parietal cortex among individuals with FTD. These findings indicate that apathy occurs due to a cortical dysfunction of areas involved with executive cognitive processing (action planning) and emotional regulation (autoactivation and reward processing).

Individuals with AD and apathy have been found to have reduced dopaminergic activity in the putamen, reduced acetylcholine in the lateral frontal cortex, and lower levels of plasma gamma-aminobutyric acid.

 In evaluating the association between apolipoprotein E ɛ4 allele and apathy in probable AD, investigators found that the presence of this allele was indeed significantly associated with apathy in these individuals.

Among individuals with dementia, the assessment of apathy is often complicated. It is particularly difficult to distinguish between reduced motivation to do things due to apathy and the loss of ability or motivation secondary to cognitive dysfunction. Additionally, there may be overlap between symptoms of apathy and depression (

 Often, as well, psychotropic medications (ie, antipsychotics, antidepressants) are used to treat neuropsychiatric symptoms (NPS) of dementia, and the adverse effects of these medications include fatigue, lethargy, listlessness, and decreased initiative to respond to external stimuli. These AEs can mimic symptoms of apathy among individuals with dementia.

The scales that have been developed for the assessment of apathy include the Apathy Evaluation Scale (AES), the Structured Clinical Interview for Apathy, the Apathy Scale, the Apathy Inventory, the Dementia Apathy Interview and Rating (DAIR), and the Lille Apathy Rating Scale (LARS).

 Among these scales, only the DAIR was designed for use among individuals with dementia. The Apathy Scale for Dementia Patients in Nursing Homes was designed to measure apathy among individuals with dementia who live in institutional settings.

 The Neuropsychiatric Inventory (NPI) is considered the gold standard for the assessment of NPS among individuals with dementia. However, the use of a single domain from the NPS prevents a comprehensive assessment of all dimensions of apathy among individuals with dementia. A recent systematic review found that the DAIR, the AES–clinical version (AES-C) in AD, and the LARS in Parkinson disease (PD) had psychometrically favorable qualities and the highest quality among the scales used to assess apathy among individuals with neurodegenerative disorders.

Available evidence indicates that both nonpharmacological and pharmacological treatment modalities can benefit individuals with dementia who present with apathy (

A systematic review by Brodaty et al found that therapeutic activities—including stimulation, creative activities, cooking, Montessori methods, music, exercise, multisensory stimulation, and pet therapy—as well as placement in special care units may improve apathy among individuals with dementia.

 Another recent systematic review by Cai et al, evaluating the effectiveness of nonpharmacological interventions among individuals with dementia and apathy, also found that multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are useful in improving symptoms of apathy.

 Cai et al found limited evidence as well for the efficacy of art, exercise, reminiscence, and occupational therapies; dementia special care units; comprehensive interventions; nursing staff education; and behavioral management techniques (ie, therapeutic conversations, progressive muscle relaxation). They found that the effects of psychomotor therapy and validation therapy were still unclear; evidence also indicates that receptive music therapy is better than interactive music therapy. Pet therapy that includes the introduction of domestic pets and companion robots tends to reduce loneliness and improve well-being. Tailoring the overall lifestyle of individuals with dementia to increase recreational activities, physical exercise, cognitive stimulation, and social activities also reduces apathy.

Various pharmacological agents have been trialed for the treatment of apathy,

 including acetylcholinesterase inhibitors (ChEIs), memantine, stimulants, calcium antagonists, and antipsychotics.

 In their systematic review and meta-analysis, Sepehry et al found a total of 15 randomized controlled trials that assessed the efficacy of pharmacotherapy.

 For cognitive enhancers (donepezil and galantamine), there was no was significant effect of treatment on apathy (Hedges’ g = –0.055; 

 = .687). The average donepezil dosage was 10 mg/day, while galantamine dosage ranged between 16 mg/day and 32 mg/day. All but 1 study used the NPI-apathy subscale as an outcome measure, and these trials included individuals with mild-to-severe AD.

For memantine, the investigators found a small and nonsignificant benefit for apathy (Hedges g = .092; P = .423). The average dose of memantine was 20 mg/day, and the trials included individuals with moderate-to-severe AD and used the NPI-apathy subscale. The effect of psychostimulants on apathy was small and nonsignificant when compared with placebo (Hedges’ g = –.063; 

 = .903). All stimulant trials included individuals with mild-to-moderate AD, used multiple scales including the NPI-apathy and Frontal Systems Behavior Scale (FrSBe) apathy subscale, and included mixed drugs with noncomparable dosages. The investigators did not find enough individual studies to do a meta-analysis for antipsychotics and drug classes with antidepressant properties, but the data from the individual atypical antipsychotic studies did not support their use for apathy in AD. The investigators indicated that the analysis for cognitive enhancers and memantine were appropriately powered, whereas the psychostimulant studies were underpowered due to limited patient enrollment in each arm of the trials.

In another quantitative meta-analysis, Ruthirakuhan et al included data from 21 studies.

 The investigators found that methylphenidate may improve apathy when compared with placebo; this held true when apathy was assessed using the AES (mean difference [MD] = – 4.99) but not when using the NPI-apathy subscale (MD = –.08).

The investigators further found that methylphenidate may also improve cognition (MD = –.08) and instrumental activities of daily living (MD = 2.30), when compared with placebo. There was no difference between methylphenidate and placebo in the risk of developing an adverse event (risk ratio = 1.28). The investigators indicated that there was insufficient evidence from a small study of modafinil to determine its effect on apathy assessed with the FrSBe-apathy subscale (MD = 0.27). They reported that in all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. The investigators considered the evidence on apathy from these studies to be indirect and associated with publication bias. They reported that there was low or very low quality of evidence on ChEIs, ChEI discontinuation, antipsychotics, antipsychotic discontinuation, antidepressants (2 studies), and valproate for the treatment of apathy in dementia.

A recent systematic review by Theleritis et al evaluated data from 90 unique studies and relevant reviews but noted that in many studies, apathy was not considered the primary outcome measure.

 They concluded that after considering the amount of evidence, ChEIs may be the best available pharmacological treatment choice for the treatment of apathy, while data from 3 studies indicated that gingko biloba may also be effective. The investigators found weaker evidence for memantine’s efficacy. Stimulants like methylphenidate alone or in combination with ChEIs were found to be beneficial in treating apathy. Atypical antipsychotics, however, appear to have limited benefit for this purpose, and their long-term use is not recommended due to their adverse effect profile. Data from one study indicated that the combination of citalopram and memantine reduced apathy among individuals with AD when compared with placebo.

Apathy can be described as the quantitative reduction of self-generated voluntary and purposeful behaviors that are observable and quantifiable. Apathy commonly presents in individuals with many different illnesses, including major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. However, apathy is more prevalent among individuals with neurodegenerative disorders, including dementias. Among individuals with dementia, apathy is considered to be the most frequently reported behavioral symptom. Apathy worsens morbidity and mortality in AD and is associated with greater caregiver distress.

The exact neurobiological mechanisms associated with apathy in dementia are unclear, but emerging evidence indicates a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics. The assessment of apathy is often complicated, and it is difficult to distinguish between reduced initiative to do things due to the loss of cognitive ability vs the loss of motivation due to apathy. In addition, there may be an overlap between symptoms of apathy and depression. Among the many scales that have been developed to assess apathy, the DAIR, the AES-C in AD, and the LARS in PD have the highest quality. Emerging evidence indicates efficacy for both nonpharmacological and pharmacological treatments for improving apathy. Multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are beneficial nonpharmacological treatments; and among pharmacotherapy options, ChEIs may be the best available treatment choice, followed by gingko biloba, memantine, and stimulants like methylphenidate either alone or in combination with ChEIs.

Future directions in the evaluation of apathy in dementia should include the study of animal models as well as genetic studies that improve the knowledge of the neurobiological mechanisms underlying this condition. In addition, well-designed clinical trials of nonpharmacologic and pharmacological interventions that exclusively target apathy in dementia are needed. These trials should assess not only the symptomatic improvement of apathy but also evaluate its effect on the individual’s functioning and on caregiver burden. These studies should use advances in both neuroimaging techniques and biomarkers to provide surrogate metrics for treatment response.

is chairman of the Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

1. Cipriani G, Lucetti C, Danti S, Nuti A. Apathy and dementia. nosology, assessment and management. 

2. Marin RS. Apathy: a neuropsychiatric syndrome. 

3. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. 

4. Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. 

5. Harrison F, Aerts L, Brodaty H. Apathy in dementia: systematic review of recent evidence on pharmacological treatments. 

6. Theleritis C, Politis A, Siarkos K, Lyketsos CG. A review of neuroimaging findings of apathy in Alzheimer’s disease. 

7. Lanctôt KL, Agüera-Ortiz L, Brodaty H, et al. Apathy associated with neurocognitive disorders: recent progress and future directions. 

8. Sherman C, Liu CS, Herrmann N, Lanctôt KL. Prevalence, neurobiology, and treatments for apathy in prodromal dementia. 

9. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. 

10. van Dyck CH, Arnsten AFT, Padala PR, et al. Neurobiologic rationale for treatment of apathy in Alzheimer’s disease with methylphenidate. 

11. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. 

12. Akyol MA, Küçükgüçlü Ö, Yener G. Investigation of factors affecting apathy in three major types of dementia. 

13. Sepehry AA, Sarai M, Hsiung G-YR. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. 

14. Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. 

15. Marshall GA, Donovan NJ, Lorius N, et al. Apathy is associated with increased amyloid burden in mild cognitive impairment. 

16. Skogseth R, Mulugeta E, Jones E, et al. Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer’s disease. 

17. Donovan NJ, Wadsworth LP, Lorius N, et al; Alzheimer Disease Neuroimaging Initiative. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. 

18. Hahn C, Lim H-K, Won WY, et al. Apathy and white matter integrity in Alzheimer’s disease: a whole brain analysis with tract-based spatial statistics. 

19. Starkstein SE, Brockman S. The neuroimaging basis of apathy: empirical findings and conceptual challenges. 

20. Massimo L, Powers C, Moore P, et al. Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. 

21. Eslinger PJ, Moore P, Antani S, et al. Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. 

22. Raimo S, Santangelo G, D’Iorio A, et al. Neural correlates of apathy in patients with neurodegenerative disorders: an activation likelihood estimation (ALE) meta-analysis. 

23. Agüera-Ortiz L, Gil-Ruiz N, Cruz-Orduña I, et al. A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH. 

24. Radakovic R, Harley C, Abrahams S, Starr JM. A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions. 

25. Brodaty H, Burns K. Nonpharmacological management of apathy in dementia: a systematic review. 

26. Cai Y, Li L, Xu C, Wang Z. The effectiveness of non-pharmacological interventions on apathy in patients with dementia: a systematic review of systematic reviews. 

27. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer’s disease. 

28. Theleritis CG, Siarkos KT, Politis AM. Unmet needs in pharmacological treatment of apathy in Alzheimer’s disease: a systematic review. 

29. Zhou T, Wang J, Xin C, et al. Effect of memantine combined with citalopram on cognition of BPSD and moderate Alzheimer’s disease: a clinical trial. 

Apathy occurs throughout the spectrum of neurocognitive disorders, but it is easy to mistake for other conditions, like depression. How can clinicians identify apathy, and treat it?

Addressing Apathy in Dementia

Weeks of criticism for the approval of Biogen’s aducanumab for the treatment of anyone with Alzheimer disease (AD) has led to the US Food and Drug Administration (FDA) deciding to 

 to only patients with milder forms of AD.

The FDA stated that there is “no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”

Aducanumab—Biogen’s anti-amyloid, disease-modifying agent—is the 

first new treatment approved for Alzheimer disease since 2003

 It was approximately a month ago, June 2021, when the drug received 

After “ongoing conversations with prescribing physicians, FDA and patient advocates,” Biogen requested the update. Research head 

Alfred Sandrock Jr, MD, PhD, told the press this

: “[W]e submitted this label update with the goal to further clarify the patient population that was studied across the 3 [aducanumab] clinical trials that supported approval. We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option.”

Following the original FDA approval, criticism and questions arose concerning the 

 Medicare, which covers most AD patients in the US, might not be able to cover the cost of aducanumab. However, Biogen maintains that aducanumab’s launch would only target the 1 to 2 million mild disease patients, rather than the entire AD market.

Furthermore, this new label could help narrow reimbursement decisions and get aducanumab to the appropriate patients faster, according to Jefferies analysts.

“It helps get people going on the right direction to refined and appropriately focused reimbursement, which helps get everyone comfortable that 

,” Jefferies analyst Michael Yee said to the press.

Biogen reported satisfaction with this update.

1. Higgins-Dunn N. Biogen, FDA walk back controversial Aduhelm label after weeks of fierce criticism. Fierce Pharma. July 8, 2021. Accessed July 8, 2021. 

https://www.fiercepharma.com/pharma/facing-pushback-biogen-and-fda-agree-to-narrow-aduhelm-s-broad-label?mkt_tok=Mjk0LU1RRi0wNTYAAAF-JWkHTIeL0uFqfSeMOe7ihwmdeyy8jOopH3QueVDjp1-zlnj6tmhh5ijO--P6DNp1Uwf1fnemcemk5285MEDwewcfLhm9kqk9JrshzwCUCjKlKo0pHL4&mrkid=112621670

2. US Food and Drug Administration. FDA grants accelerated approval for Alzheimer’s drug. June 7, 2021. Accessed July 8, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

3. Kuntz L. First new treatment approved for Alzheimer disease in nearly 2 decades. June 7, 2021. Accessed July 8, 2021. 

https://www.psychiatrictimes.com/view/first-new-treatment-approved-for-alzheimer-disease-in-nearly-2-decades

4. Biogen. FDA approves updated ADUHELM™ prescribing information to emphasize population studied in clinical trials. News release. July 8, 2021. Accessed July 8, 2021. 

https://investors.biogen.com/news-releases/news-release-details/fda-approves-updated-aduhelmtm-prescribing-information-emphasize

5. Higgins-Dunn N. A $57B drug? Medicare faces a massive bill for Biogen's Aduhelm—even if it limits coverage. Fierce Pharma. June 24, 2021. Accessed July 8, 2021. 

https://www.fiercepharma.com/pharma/11-500-copays-and-diagnostic-hoops-biogen-s-alzheimer-s-56k-drug-aduhelm-set-to-balloon

6. Reuters staff. U.S. FDA narrows use of Biogen Alzheimer's drug; shares rise. News release. July 8, 2021. Accessed July 8, 2021. 

https://www.reuters.com/article/us-biogen-alzheimers-fda/us-fda-narrows-use-of-biogen-alzheimers-drug-shares-rise-idUSKCN2EE18V

Following criticism for its wide-labeled June approval, the FDA has decided to narrow the patient recommendation for aducanumab.  

Narrower Label for Alzheimer Disease Treatment, Aducanumab 

Videogames that help cure Alzheimer disease (AD)? Crowds of interactive gamers mapping the brain? In their quest for new discoveries in brain research, innovative investigators are developing games that harness the power of crowdsourcing.

Cornell University’s Schaffer-Nishimura lab is one such group. They study the intersection of clogged, or 

, capillaries and the progress of AD. They use animal models to evaluate the efficacy of potential treatments by analyzing the stalls (capturing images of capillaries in the brains of mice quickly), but analyzing this data takes time.

Enter the gamers. With the assistance of the Human Computation Institute, the Schaffer-Nishimura lab created Stall Catchers. Gamers aged 6 to 88, or catchers, navigate a set of training images provided by the lab, determine whether the capillary is flowing or stalled, and then compare their response to those of the researchers. There are approximately 30,000 volunteers helping to analyze the lab’s images.

Stall Catchers demonstrates the power of crowdsourcing. Crowdsourcing unleashes a lab’s research potential by tapping into a scientific-minded community of volunteers. Aside from increasing the volume of analysis, volunteers check the quality of each other’s work.

Other labs are also using crowdsourcing to accelerate their research. For example, a video game called 

, created by Princeton University’s Seung Lab, calls upon volunteers to map neurons in the brain, in the hopes of eventually mapping the entire brain.

, a game created by McGill’s center for Bioinformatics, asks volunteers to match colors corresponding to base pairs of genetic sequences,

 which helps identify specific genes involved in diseases like breast cancer. Like Stall Catchers, these games are user-friendly, fast-paced tools to engage citizen scientists. The crowdsourcing approach accelerates research, expands the volume of analysis, and includes a larger crowd in scientific discovery.

is from Evanston, IL. She is 16 years old and has contributed several reflective pieces for

1. Human Computation Institute. Stall Catchers. 2019. Accessed June 23, 2021. 

2. EyeWire. A game to crowdsource brain mapping. Accessed June 23, 2021. 

https://www.citizenscience.gov/eyewire-brain-mapping/#

3. Kawrykow A, Roumanis G, Kam A, et al. Phylo: a citizen science approach for improving multiple sequence alignment.

How can volunteering to play video games help brain research?

Crowdsourcing Brain Research: The Power of Volunteers

The US Food and Drug Administration (FDA) has granted 

 for donanemab, Eli Lilly and Company's investigational antibody therapy for Alzheimer disease (AD).

, a monoclonal antibody, was designed to target a particular form of post-translationally modified Aß, N-terminal pyroglutamate, and completely clear amyloid plaques.

The Breakthrough Therapy designation, created to expedite the development of drugs meant to treat serious conditions when preliminary evidence suggests the drug may demonstrate substantial improvements over already available therapies that have full FDA approval, is based on clinical evidence from Eli Lilly and Company’s phase 2 trial, TRAILBLAZER-ALZ for donanemab.

TRAILBLAZER-ALZ studied the efficacy and safety of donanemab in patients with early, symptomatic AD. The safety, tolerability, and efficacy of donanemab are also being evaluated in the ongoing randomized, placebo-controlled, double-blind, multi-center phase 3 study TRAILBLAZER-ALZ 2.

“At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo,” wrote the study’s authors.

Lilly intends to submit a biologics license application for donanemab under the accelerated approval pathway later in 2021.

1. Eli Lilly and Company. Lilly's donanemab receives U.S. FDA's Breakthrough Therapy designation for treatment of Alzheimer's disease. News release. June 24, 2021. Accessed June 25, 2021. 

https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-receives-us-fdas-breakthrough-therapy

2. Kuntz L. New data for Alzheimer agent presented at international conference. 

. March 23, 2021. Accessed June 25, 2021. 

https://www.psychiatrictimes.com/view/new-data-for-alzheimer-agent-presented-at-international-conference

Donanemab for the treatment of Alzheimer disease has received Breakthrough Therapy designation from the FDA. 

Another New Alzheimer Drug on the Horizon

The big news in Alzheimer disease (AD) is the Federal Drug Administration’s 

. It is the first-ever disease-modifying AD treatment, which works by targeting amyloid beta plaques in the brain.

But its approval has also generated controversy. Three members of the Federal Drug Administration’s advisory committee have resigned, arguing that evidence for the drug’s efficacy was not strong enough to merit 

George Perry, PhD, is among the skeptics. In this Mental Health Minute, he raises questions about the drug’s mechanism. He has long been skeptical of what he calls 

The FDA approval of aducanumab has given hope to millions of patients with Alzheimer disease—but will it live up to the hype?  

Alzheimer Disease