We evaluated whether apolipoprotein E ( APOE ) genotype-guided slow titration of monoclonal antibodies reduced amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease. We retrospectively analyzed ARIA incidence in 25 patients on aducanumab and 19 patients on lecanemab on a genotype-informed protocol in a private practice setting. ARIA-E and ARIA-H each occurred in 4% of the aducanumab group and 5% of the lecanemab group. Plaque clearance was achieved in 50% of evaluable aducanumab patients and 26.3% of lecanemab patients. Compared to clinical trial ARIA rates, our results suggest that individualized, genotype-informed titration improves safety although plaque clearance rates were less robust.

Aducanumab is a monoclonal amyloid beta-directed antibody that was contingently approved by the US FDA for treating Alzheimer's disease (AD) in a controversial decision.1 The FDA initially approved the drug without specifying severity level or biomarker confirmation and subsequently limited approval to those with MMSE above 23 and AD biomarker confirmation.1-3 In pivotal clinical trials, amyloid related imaging abnormalities (ARIA) of brain edema, microhemorrhages, and superficial siderosis were seen in 30% of the group receiving 3 mg/kg dose (all ApoEε4 carriers), 21% in the 6 mg/kg group (fewer ApoEε4 carriers) and 41% in the 10 mg/kg group, noted most often in the first 8 months of treatment.4 There are as yet, no available reports on using aducanumab in a clinical setting. We retrospectively reviewed side effect and tolerability data on 20 patients treated with aducanumab in a community-based setting. This report concerns 19 persons with a diagnosis of AD and one with amnestic mild cognitive impairment treated with aducanumab in a community-based practice. There were 13 women and 7 men (Table 1) with an average age of 70 years (range 32–83). The average educational attainment was 16 years (range 13–20 years). Nineteen were Caucasian, one was Asian. Diagnoses were all confirmed with biomarker testing (positive amyloid scans = 11; positive cerebrospinal fluid analysis = 9). The average mini-mental state examination (MMSE) score was 22 (range 9–29). Seventeen were ApoEε4 carriers (two were APOE4/4; one with PSEN1 mutation). Institutional review board approval was obtained from the Feinstein Northwell. Postulating that rapid plaque dissolution may exacerbate the ARIA, a slower titration schedule was adopted in these patients than was used in the pivotal trials. ApoEε4 carriers were titrated up by 1 mg/kg every 4 months and non-carriers every 3 months. At the time of writing, 16 have completed at least 8 infusions and have had at least one MRI and 10 patients have completed at least 12 infusions and have had two MRIs. All but one was ApoEε4 carriers. The current average dose is 3 mg/kg (range 1–6 mg/kg). Among the 20 patients treated, none have developed clinically apparent ARIA, confirmed in the 16 with available post-treatment MRIs. Two patients, both homozygous carriers, complained of transient headaches. One patient developed a subdural from a fall, and her infusion was stopped for a month, then restarted at 1 mg/kg. Another missed an infusion and was restarted at 1 mg/kg. A third patient opted to stop treatment after 7 months after seeking another opinion. Amyloid plaques predate the onset of symptoms by as much as 25 years.5 ARIA is a major clinical concern for physicians and patients considering anti-amyloid therapies for AD, notwithstanding debate about clinical efficacy. Careful screening and a slower titration schedule may be useful in reducing the incidence of ARIA in the clinical use of drugs of this class. There are no conflicts of interest. The author was responsible for the conception of study, data analysis, and writeup of the study. The author would like to acknowledge Casey Linnane for her help with data collection. There are no sponsors or funding for the study. The author received no funding for this work.

Article purpose:The clinical approach to Alzheimer's disease (AD) is challenging, particularly in high-functioning individuals. Accurate diagnosis is crucial, especially given the significant side effects, including brain hemorrhage, of newer monoclonal antibodies approved for treating earlier stages of Alzheimer's. Although early treatment is more effective, early diagnosis is also more difficult. Several clinical mimickers of AD exist either separately, or in conjunction with AD pathology, adding to the diagnostic complexity. To illustrate the clinical decision-making process, this study includes de-identified cases and reviews of the underlying etiology and pathology of Alzheimer's and available therapies to exemplify diagnostic and treatment subtleties.Problem:The clinical presentation of Alzheimer's is complex and varied. Multiple other primary brain pathologies present with clinical phenotypes that can be difficult to distinguish from AD. Furthermore, Alzheimer's rarely exists in isolation, as almost all patients also show evidence of other primary brain pathologies, including Lewy body disease and argyrophilic grain disease. The phenotype and progression of AD can vary based on the brain regions affected by pathology, the coexistence and severity of other brain pathologies, the presence and severity of systemic comorbidities such as cardiac disease, the common co-occurrence with psychiatric diagnoses, and genetic risk factors. Additionally, symptoms and progression are influenced by an individual's brain reserve and cognitive reserve, as well as the timing of the diagnosis, which depends on the demographics of both the patient and the diagnosing physician, as well as the availability of biomarkers.Methods:The optimal clinical and biomarker strategy for accurately diagnosing AD, common neuropathologic co-morbidities and mimickers, and available medication and non-medication-based treatments are discussed. Real-life examples of cognitive loss illustrate the diagnostic and treatment decision-making process as well as illustrative treatment responses.Implications:AD is best considered a syndromic disorder, influenced by a multitude of patient and environmental characteristics. Additionally, AD existing alone is a unicorn, as there are nearly always coexisting other brain pathologies. Accurate diagnosis with biomarkers is essential. Treatment response is affected by the variables involved, and the effective treatment of Alzheimer's disease, as well as its prevention, requires an individualized, precision medicine strategy.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

•TMS is well tolerated in patients with chronic neurologic diseases.•Pain at the stimulation site was the most common side effect, with one of 235 patients with transient focal seizures.•TMS treatment was associated with less decline on verbal fluency and naming measures in AD and aMCI patients over years.•Better retention of naming and verbal fluency are clinically meaningful outcomes for patients and their caregivers.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

BACKGROUND Identifying the cognitive changes associated with the menopausal transition prevents misattribution of symptoms to more ominous causes such as neurodegenerative disease. CASE Two women with cognitive loss and objective evidence of menopause-related cognitive impairment are presented, misattributed to Alzheimer disease in one case and frontotemporal dementia in the other. Neurocognitive testing, neuroimaging, and laboratory findings are reviewed. Both women were diagnosed with menopause-related cognitive impairment and were stable in follow-up over 4 or more years. CONCLUSIONS Recognizing the cognitive changes associated with menopause and distinguishing from cognitive impairment resulting from other etiologies-including neurodegenerative diseases such as Alzheimer disease-has important clinical implications both for treatment and for prognosis.

Background Alzheimer’s disease is a heterogenous disorder with multiple phenotypes and genotypes, although they eventually converge to a final common clinicopathological endpoint. However, Alzheimer’s disease drug trials do not account for the heterogeneity of the disease in trial design, impeding development of effective drugs. Discussion Alzheimer’s disease drug trials commonly have wide inclusion criteria that subsume multiple subtypes of the condition, with varying genotypes, phenotypes, and clinical courses. The outcome variables used in many trials may not be sensitive for the particular disease subtype and trials may not follow patients for the appropriate length of time necessary for the subtype of disease. Methods of stratifying treatment trial design to account for disease heterogeneity using algorithms incorporating demographics, neuroimaging, genetics, and clinical phenotypes, as well as more tailored outcome measures, are proposed to allow for personalized, precision medicine in Alzheimer’s disease therapeutics development. Summary Approaching Alzheimer’s disease as a heterogenous disorder will likely improve yield in the search for effective treatments for the condition.

My leg's given out on me, said Edgar, the metal sculptor, with his fringe of white hair growing like a collar around his bald head.

BACKGROUND:Accumulating evidence suggests repetitive transcranial magnetic stimulation (rTMS) may be beneficial in ameliorating cognitive deficits in Alzheimer's disease (AD).METHODS:AD patients received four high-frequency rTMS sessions over the bilateral dorsolateral prefrontal cortex (DLPFC) over two weeks. Structured cognitive assessments were administered at baseline, at 2 weeks after completion of rTMS, and at 4 weeks post treatment. At these same times, tolerant patients underwent functional magnetic resonance imaging (fMRI) while performing structured motor and cognitive tasks. We also reviewed literature regarding the effects of rTMS on cognitive function in AD.RESULTS:A total of 12 patients were enrolled, eight of whom tolerated the fMRI. Improvement was seen in Boston Diagnostic Aphasia Examination tests of verbal and non-verbal agility 4 weeks post-treatment. The fMRI analysis showed trends for increased activation during cognitive performance tasks immediately after and at 4 weeks post-treatment. Our literature review revealed several double-blind, sham-controlled studies, all showing sustained improvement in cognition of AD patients with rTMS.CONCLUSIONS:There was improvement in aspects of language after four rTMS treatments, sustained a month after treatment cessation. Our results are consistent with other studies and standardization of treatment protocols using functional imaging may be of benefit.

OBJECTIVE:The results of the Women's Health Initiative studies dramatically altered hormone therapy use around the world. In countries outside the United States, self-use in physicians remained unaltered while prescription use declined, implying that physicians may not concur with the findings. We wished to explore prevailing attitudes among American physicians by examining New York City obstetrician-gynaecologists' self-use and prescription use of hormone therapy.STUDY DESIGN:All board-certified obstetrician-gynaecologists in New York City were invited to complete and return a detailed, previously validated questionnaire concerning hormone therapy use.RESULTS:Two hundred and nine questionnaires were returned, for a response rate of 12% (209/1797). Gynaecologists agreed with the findings from the Women's Health Initiative studies regarding indications and contraindications to hormone therapy use. Even so, three-quarters of female gynaecologists and female partners of male gynaecologists (74%; 67/91) use or have previously used hormone therapy. However, only 27.3% (21/77) of male gynaecologists and 12.3% (14/114) of female gynaecologists recommend hormone therapy to all menopausal women regardless of contraindications. Gynaecologists remain divided in their attitude toward hormone therapy; 30% of gynaecologists felt that hormone therapy use generally prolonged women's lives, 36% felt it was not useful in prolonging women's lives, and 33% were unsure.CONCLUSION:Since the publication of the Women's Health Initiative findings, New York City gynaecologists prescribe hormone therapy to fewer patients. However, they continue to self-use hormone therapy at much higher rates, even as they seem to concur with Women's Health Initiative recommendations, contributing to the ongoing controversy surrounding the validity of the Women's Health Initiative findings.

Objective: To assess whether 1) repetitive transcranial magnetic stimulation (rTMS) can ameliorate aphasia in Alzheimer9s disease (AD) patients and 2) whether there are changes in activation patterns in relevant cortical areas using functional brain imaging subsequent to rTMS. Background Among the earliest manifestations of AD are deficits in language that significantly impair patients9 quality of life. Currently approved agents for slowing progression of AD do not target aphasia. Studies have demonstrated beneficial effects of rTMS in improving cognition and language deficits in patients with neurological disorders. rTMS may be a potential therapeutic tool to help improve aphasia in AD patients. Design/Methods: Eleven AD patients with aphasia underwent 4 sessions of rTMS applied to the dorsolateral prefrontal cortex at a frequency of 10-15 Hz over two weeks. They underwent standardized cognitive tests at baseline, immediately after completing the course of rTMS, and 4-weeks after the last rTMS treatment. All patients underwent concomitant functional MRI (fMRI) scans at the time of the tests while performing cognitive paradigms in the scanner. Results: All patients completed the cognitive portions of the study. Three patients could not tolerate imaging and therefore did not complete the imaging portion of the study. There was improvement in verbal and non-verbal agility on testing that was seen 4-weeks post-treatment relative to baseline (p Conclusions: These preliminary results suggest that rTMS may serve as an effective adjunctive treatment for aphasia found in AD patients. Further research using control stimulation is needed. Disclosure: Dr. Devi has nothing to disclose. Dr. Levine has nothing to disclose. Dr. Voss has nothing to disclose. Dr. de Boisblanc has nothing to disclose. Dr. Heier has nothing to disclose. Dr. Halper has nothing to disclose.

BACKGROUND/RATIONALE:Episodic memory loss is a hall-mark of Alzheimer's disease (AD), with recall of recent events becoming progressively difficult. A commonly used tool, the recollection of US presidents, was assessed in evaluating episodic versus semantic memory loss among AD patients compared with spouse controls.METHODS:A total of 36 patients (12 men, 24 women) with possible or probable AD were asked to "give the names of 5 US presidents" and concurrently administered the Mini-Mental State Examination (MMSE). Twenty-three spouses (12 men, 11 women) were controls. The year 1980 demarcated "remote" versus "recent" presidents.RESULTS:Patients were older, had lower MMSE scores (P < .001), and recalled fewer presidents than controls (P < .005), after controlling for age. Among patients, men were more educated than women (P < .05) and recalled more presidents (P < .001). No gender differences were observed in controls.CONCLUSIONS:Patients with AD preferentially recalled remote presidents, supporting retention of semantic memory in this group. There were no gender differences between groups.

Journal of Women's HealthVol. 18, No. 6 Message from AMWAAMWA Position Statement: Genetic TestingGayatri Devi, Michele Glodowski, and Elizabeth ShinGayatri DeviThe New York Memory and Healthy Aging Services, New York, New York.Departments of Neurology and Psychiatry, NYU School of Medicine, New York, New York.Search for more papers by this author, Michele GlodowskiThe New York Memory and Healthy Aging Services, New York, New York.Search for more papers by this author, and Elizabeth ShinThe New York Memory and Healthy Aging Services, New York, New York.Search for more papers by this authorPublished Online:10 Jun 2009https://doi.org/10.1089/jwh.2009.1483AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "AMWA Position Statement: Genetic Testing." , 18(6), pp. 785–786FiguresReferencesRelatedDetails Volume 18Issue 6Jun 2009 InformationCopyright 2009, Mary Ann Liebert, Inc.To cite this article:Gayatri Devi, Michele Glodowski, and Elizabeth Shin.AMWA Position Statement: Genetic Testing.Journal of Women's Health.Jun 2009.785-786.http://doi.org/10.1089/jwh.2009.1483Published in Volume: 18 Issue 6: June 10, 2009Online Ahead of Print:May 20, 2009PDF download