Alzheimer's Disease

Jonathan Weiss, M.D., Matthew E. Peters, M.D., Constantine G. Lyketsos, M.D.

DEFINITION

  • Dementia Due to Alzheimer’s Disease (AD) is a neurodegenerative disease and the most common cause of dementia
    • Dementia is a syndrome characterized by global cognitive decline that significantly affects daily functioning in the absence of delirium.
    • AD is thought to account for 50-70% of dementia cases worldwide[1]
  • Cognitive impairment due to AD is classified under the Major and Mild Neurocognitive Disorder (NCDs) section of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Text Revision (DSM-5 TR).[2]
  • Proposed pathophysiology (Amyloid hypothesis):
    • Amyloid Precursor Protein (APP) is a transmembrane protein that likely helps with neuronal growth and maturation (full function is not yet elucidated)[3]
    • When α-secretase and γ-secretase cleave APP, the protein gets degraded and recycled. However, when β-secretase and γ-secretase cleave APP, the protein does not fully degrade and instead leads to aggregates of amyloid proteins[4]
      • This leads to the build up of amyloid-predominant neuritic plaques in-between neurons, impacting neuronal function[4]
      • Additionally, possibly due to the neuritic plaques, tau-predominant neurofibrillary tangles develop within neurons, causing further damage[4]
      • Subsequent neuronal death and cortical atrophy, initially in the hippocampus and entorhinal areas and later spreading throughout the temporal and frontal cortices. Cerebellum is usually spared[5]

EPIDEMIOLOGY

  • In the general population, dementia is increasingly recognized as a serious public health concern[6]
  • As of 2021, an estimated 57 million are living with dementia worldwide[6], corresponding with 28 to 40 million people with AD[1]
    • The prevalence is projected to double every 20 years, reaching an estimated worldwide caseload of about 115 million by 2050
  • Aggregate payments for health care, long-term care, and hospice for people with AD and other dementias are projected to increase from $200 billion in 2012 to $1.1 trillion in 2050 in the U.S. alone[7]
    • In 2019, global ecomonic burden of dementia was 1.3 trillion US dollars, largely from care provided informally by loved ones[6]
  • Women are more impacted than men, both in severity of disease and in that women provide 70% of care hours for people with dementia[6]
  • Higher prevalence among black and hispanic populations, thought to be related to disparities in health-related access as well as genetics[8]
  • Although rates of conversion vary, transition from MCI to dementia averages 12%-15% per year in community samples[9]
  • Age is the primary risk factor for onset of AD and other forms of dementia
    • Other risk factors include: traumatic brain injury, reduced reserve capacity of the brain, depression, limited educational or occupational attainment, brain vascular disease, hyperlipidemia, hypertension, atherosclerosis, coronary heart disease, atrial fibrillation, smoking, obesity, and diabetes
  • Familial forms of AD exist, with onset typically earlier in life (before age 65)[1]:
    • The inheritance is autosomal dominant and involves mutations in the gene associated with APP on chromosome 21, as well as presenilin 1 and 2 genes (on chromosomes 14 and 1, respectively)
    • People with Down Syndrome (Trisomy 21) have increased risk of AD and earlier onset, likely related to the additional 21st chromosome leading to higher concentrations of APP that can be improperly cleaved and aggregated[10]
  • Many other genes are thought to contribute to the development of AD:
    • The apolipoprotein E (APOE) gene ε4 allele is a known risk factor for AD and also of cognitive decline earlier in life
  • Many other genes have been proposed as risk factors for other forms of dementia, with both familial and polygenic forms of inheritance

DIAGNOSIS

Clinical Presentation

  • AD usually progresses gradually, sometimes with brief plateaus, from mild cognitive impairment to severe dementia and ultimately death[11]
    • Mean duration of survival after dementia onset is 4-5 years at the population level, or 10-12 years in patients who attend memory clinics
    • Onset is usually in the eighth and ninth decades
      • Early-onset forms are seen as early as the fifth or sixth decades of life
    • Rapidly progressive or intermittently progressive forms of AD are less common but do occur
  • Typical course starts with loss of memory fairly early (amnesia), followed by development of agnosia, apraxia, and aphasia
    • These are sometimes remembered as the four As of AD
    • Following with this course, increasing levels of functional impairment often progress to severe difficulties with mobility and incontinence
  • Neuropsychiatric symptoms (NPS) (behavioral disturbances) affect as many as 98% of persons with AD over the course of their illness
    • The presence of NPS are associated with faster progression of dementia, added disability for patients, and can be very frustrating for caregivers
    • NPS are core features of AD thought to be caused by the same neurodegenerative process that causes cognitive decline
    • Examples are: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating disruption
    • NPS in patients with AD by percentage[12]:
  • There is a pre-symptomatic stage that biomarkers are beginning to detect (see tests and procedures below)[8]

Tests and Procedures

  • Traditionally, cliical interview and history from the patient as well as family/friends/caregivers has been paramount in establishing the diagnosis, however brain imaging and biomarkers have become increasingly relevant
  • The evaluation should include physical and neurological exams, as well as some objective measure of cognition, inventory of behaviors, and symptom progression:
    • A brief bedside measure of cognition is adequate in most cases
      • For example, Mini-Mental State Examination (MMSE)[13] or Montreal Cognitive Assessment (MoCA)[14]
      • If impairments are more subtle or diagnosis is unclear, referral for neuropsychological testing may be indicated
    • Nature of symptom onset and progression over time can assist in the diagnosis, with AD most often characterized by gradual onset and slow progression over years[1]
  • Biologically-based diagnostic studies are becoming increasingly specific and useful:
    • Imaging:
      • Computed tomography (CT) and later magnetic resonance imaging (MRI) have been used for years to identify large structural changes that occur in AD, primarily atrophy of gyri (especially at the hippocampus), widening of sulci, and enlargement of ventricles[15]
      • Positron emission tomography (PET)
        • Amyloid PET identifies neuritic plaques even in early stages, but has limited prognostic utility (quantity of plaque identified does not correlate tightly with symptoms severity or time course. This is widely available and is currently covered by Medicare for antibody therapy assessment[8]
        • Tau PET is less available and mostly limited to research at this time, however identification of tau does appear to correlate more with clinically-meaningful symptomatology[8]
    • Cerebrospinal fluid (CSF) studies
      • Used diagnostically via identification of the following biomarkers: Αβ42 (low concentration indicates more plaque has deposited), t-tau, p-tau, and MTBR-tau243[8]
      • Amyloid PET has been slowly replacing CSF analysis as part of the workup in clinic
    • Blood tests
      • Major strides in the past 5-8 years, now some with FDA approval, though not yet in regular practice and ongoing development of the most useful serum biomarkers is underway[8]
      • Phosphorylated tau 217 (Ptau217) is currently, as of summer 2025, the most promising and correlates well with both PET and autopsy findings[8]
    • Determination of when to implement the above biomarkers is an area of active investigation[8]
  • Other studies are typically obtained as part of a cognitive and psychiatric evaluation, largely to rule out other treatable causes of symptoms[1]:
    • Thyroid studies, liver tests, metabolic panel, complete blood count, vitamin B12, and folate levels are recommended.
    • Additional tests, such as a heavy metal screen, syphilis serology, toxicology, EKG, EEG, and chest x-ray are also considered
  • Genetic testing is used in research but rarely in clinical practice.

Differential Diagnosis

TREATMENT

General

  • General principles include treating cognitive and neuropsychiatric symptoms, reducing medication burden (many medications can impair cognition), managing medical co-morbidities, preventing delirium, ensuring safe environments, finding meaningful social engagement for patients, and supporting caregivers.

Pharmacotherapy

  • Monoclonal antibody therapies (mABs)
    • In 2021 the first mAB (Aducanumab [Aduhelm]) was approved by the FDA.[16] Aducanumab has since been discontinued and now Licanamab (Leqembi) and Donanemab (Kisunla) are in use, currently to a limited extent[8]
      • Administered through intravenous infusion every 2-4 weeks for 18 months[8]
      • Both Licanamab and Donanemab robustly remove amyloid plaque but are only mild-to-moderately able to slow the rate of disease progression (thought to be about 25% decrease in the rate of cognitive decline)[8]
        • The modest clinical impact despite impressive plaque clearance may be due damage already taking place once plaque is present, suggesting earlier treatment will improve outcomes. Early treatment is limited, however, by the potential for severe adverse effects as described below[8]
    • Mild adverse effects include infusion reactions, headache, nausea, joint pain, fatigue[17]
    • Severe adverse effects include amyloid-related imaging abnormalities (ARIA), which represents cerebral swelling or bleeding. The impact of these can range from being clinically insignificant to causing confusion and difficulty walking to leading to seizures and severe hemorrhage to causing death[8][17]
    • Because of the risk of ARIA, patients receive 4-5 MRIs over the first year of treatment for monitoring[8]
    • As of 2025, these therapies are not widely utilized and there is ongoing work to balance the risks with benefits and determine optimal timing for initation and monitoring. Currently, patients and families engage in an extensive informed decision-making discussion. The therapy is offered in a limited number of specialized clinics, therefore those who do opt fo the therapy are typically those who have sought out such treatment early in their disease course when they can engage in the complex risk/benefit discussion. The use of these treatments is expected to evolve substantially in the near future, especially as the utility of biomarkers also expands.
  • Cholinesterase inhibitors were introduced in 1993[18] and have been the first-line pharmacotherapy agents for AD, though treatment effects tend to be modest and depend on long-term use[19]
    • These drugs work by inhibiting the breakdown of acetylcholine by blocking acetylcholinesterase in the brain (primarily)[19]
      • Acetylcholine is a neurotransmitter important in memory
    • Examples include: donepezil (Aricept®), galantamine (Razadyne®), and rivastigmine (Exelon®)[19]
      • All are FDA-approved for mild-to-moderate AD
      • Donepezil carries an FDA indication for severe AD
      • Rivastigmine carries an FDA indication for Parkinson disease dementia
      • Minimal data exists to steer clinicians to choose one over another, though can consider rivastigmine patch in patients who are particularly sensitive to gastrointestinal adverse effects[8]
      • Expert opinion suggests the effects lead to 6-12 month delay in symptom progression and that there are some unpredictable and idiosyncratic positive responses in some patients[8]
    • A Cochrane review from 2006[20] showed that there are notable improvements in cognitive function when these medications are used in mild-to-moderate AD
      • There was also improvement in activities of daily living and behavior with their use, though treatment effects were small
    • Most common reported side effects are nausea, vomiting, and diarrhea[19]
      • A less common, but potentially more serious side effect is bradycardia
      • Adverse effects are minimized by slow titration
    • Cholinesterase inhibitors increase the risk of hospitalization for bradycardia, syncope, pacemaker placement, and hip fracture[21][22]
      • Therefore, caution is advised when prescribing cholinesterase inhibitors in patients with preexisting bradycardia, cardiovascular disease, or concurrently taking other medications which may lower heart rate
  • Memantine (Namenda®), a low-affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia
    • Memantine is FDA-approved for moderate-to-severe AD. Treatment effects, again, are modest at best
    • A Cochrane review from 2006[23] showed a small beneficial effect of memantine in moderate-to-severe AD in terms of cognition and behavior, supported by clinical impression of change
      • In mild-to-moderate AD there was a marginal benefit on cognition, no effect on behavior, and little detection of improvement clinically
      • Patients taking memantine were slightly less likely to develop agitation
      • Memantine tends to be well-tolerated
    • Expert opinion suggests the benefits of memantine are often not cliically apparent[8]
  • Cholinesterase inhibitors and memantine are often combined. However, there is limited clinical trial evidence to support this combination
    • A 2012 systematic review suggests a small cognitive, but not functional, benefit from combination therapy[24]
    • A one-year clinical trial reported no significant benefit from the combination of donepezil plus memantine versus donepezil alone in patients with moderate-to-severe AD[25]
  • Because aggression, agitation, depression, and psychosis occur in the majority of people with dementia, the efficacy and safety of neuroleptic medications is important to consider
    • All neuroleptics carry an FDA black box warning for "Increased Mortality in Elderly Patients with Dementia-Related Psychosis."
      • The risk of first-generation antipsychotics is greater than that of second-generation antipsychotics[26]
      • Due to associated risks and comparable efficacy to the antidepressant citalopram (see below), the use of antipsychotics as first-line therapy is not recommended unless there are compelling reasons
  • Antidepressants have also been studied for the treatment of agitation and psychosis in dementia.
    • A Cochrane review from 2011[27] showed that SSRIs lead to a reduction in symptoms of agitation compared to placebo and are well-tolerated. However, this review noted that further study is needed
    • A 2014 study confirmed the efficacy of citalopram 30mg for the treatment of agitation but also revealed the risk of QT prolongation at this dose[28]
      • Citalopram dosed at 20-30mg daily should be considered as a first-line treatment option for agitation in AD
    • Subsequently, a 2019 meta-analysis demonstrated that 8-12 weeks of fluoxetine, but not other antidepressants, led to improvement in MMSE scores compared to placebo[29]
  • Management of other areas of health, including vascular brain disease and its risk factors is part of the care for patients with AD:
    • Exercise:
      • Aerobic exercise is associated with lower risks of dementia and increased hippocampal size, though data is not clear as to the impact of exercise on affecting the progression of AD[8]
    • Cognitive rehabilitation:
      • Education is a protective factor for development of AD and continued cognitive impairment is thought to minimize progressio of the disease, though trials are lacking and no specific set of cognitive exercises is deemed most effective[8]
      • There are a number of companies with "brain training" programs
    • Traetment of comorbid depression is important if present[8]
    • Hearing and balance
      • Supporting patients with hearing aides and vestibular rehabilitation is thought to be valuable in the management of AD[8]
    • For patients with proven, significant brain vascular disease and AD, low-dose aspirin therapy, or if appropriate other forms of anticoagulation, can be considered, however a 2020 RTC demonstrates aspirin does not reduce the risk or dementia and probable AD[30]
    • HMG-CoA reductase inhibitors ("statins") have been observed to decrease the incidence of dementia, however are not known to be effective in the treatment of AD or other dementias[31]
    • Management of blood pressure (in the 130-150 systolic range), blood glucose, or other active comorbidities may delay AD progression[32][33]
    • Use of NSAIDs have a theoretical benefit prior to disease onset but do not affect progression of AD and may be harmful once the disease process has begun[34]
    • Estrogen therapy may be protective for women[35]

Psychotherapy

  • Given limitations with disease-modifying treatments for AD, the most effective treatments are environmental or behavioral
    • The same holds true for the neuropsyhiatric symptoms of AD
  • It is important to provide proper support to the family and other informal caregivers of patients with dementia
    • Areas to address are: educating caregivers, teaching problem-solving skills, accessing resources, long-range planning, emotional support, and respite

WHEN TO REFER

  • If a medical provider is concerned about new-onset cognitive impairment in a patient, or a patient’s family is concerned about a cognitive change from baseline, the provider should consider referral to a geriatric psychiatrist or neurologist
  • Given the complexities and risks involved in the pharmacologic management of neuropsychiatric symptoms in AD, the principles of care require giving serious consideration to the involvement of a specialist with expertise in the pharmacologic treatment of NPS in AD (e.g., a geriatric psychiatrist)

COMMENTS

  • For a caregiver/patient guide to AD, we recommend The 36 Hour Day by Nancy Mace and Peter Rabins[36]
  • For a more thorough review on treatment for practitioners, we recommend Practical Dementia Care by Rabins, Lyketsos, and Steele[37]

PATIENT EDUCATION

Patient Education Author:
Michael Bray, M.D.
  • Alzheimer’s disease is the most common cause of dementia. This is a kind of “neurodegenerative disease” in which progressing death and dysfunction of brain cells leads to changes in our ability to think and take care of the things that we need to do. This disease typically progresses slowly, affecting memory, thinking, and behavior.
    • Early symptoms include impaired ability to form new memories. For this reason, people with Alzheimer’s disease may notice they are forgetting where they put things, may ask the same question multiple times, or may forget other things that happened to them recently.
    • Later, even longer-term memories may become more difficult to recall. It may become more and more difficult for a person to take care of themselves over time and they may need additional supports later in life to do things like feed themselves, bathe themselves, and get dressed.
    • Neuropsychiatric symptoms like changes in personality, depression, apathy, and even hallucinations or delusions are common. These symptoms may improve with medicine or therapy with the help of a psychiatrist, neuropsychiatrist, or behavioral neurologist.
  • Alzheimer’s disease is more common in older people and the risk of developing this increases the older a person gets.
  • While it is normal to have some changes in thinking with age, Alzheimer’s disease is NOT a part of normal aging.
  • There is no cure for Alzheimer’s disease yet but some medicines may help slow its progression, though currently these are not without risk. This is a rapidly developing field and it is hopeful more medicines will become available in the future that can slow disease progression. You should talk to your doctor about which possible treatments may be the right fit for you or your loved one.
  • Caring for an individual with dementia can be difficult, and self-care for caregivers is important for both the patient and the caregiver. We recommend the book, “The 36 Hour Day” for more information and advice on caring for those afflicted.
  • For more information and resources, see the Alzheimer’s Association’s website or this extended information page from Johns Hopkins.

References

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Last updated: October 1, 2025