Alzheimer's Disease (AD)

Primer

Alzheimer's Disease (AD) is the most common type of dementia in the world, characterized by gradual progressive memory loss and behavioural changes. Different subtypes of Alzheimer's can have memory, visual, language, or frontal lobe deficit involvement. AD is associated with accumulation of amyloid and tau depositions in the brain.

History
Epidemiology
  • AD is the most common cause of dementia worldwide, and dementia rates start at 5-10% at age 70. By age 85, between 25% and 50% of people will exhibit signs of Alzheimer's disease. The percentage of all dementias due to Alzheimer's disease is at least 50% (with some estimates suggesting 60-90%).
Prognosis
  • The onset of symptoms is usually in the eighth and ninth decades of life. Patients with early onset symptoms in their 50s/60s usually have a genetic cause. The mean survival time is 10 years. During the later stages of illness, patients can become mute or bed bound. Death most commonly results from aspiration in those who survive through throughout the course of illness.
Comorbidity
  • The most common comorbidities in AD include hypertension, osteoarthritis, depression, diabetes, and cerebrovascular disease.[1]
  • There can often be a mixed dementia in Alzheimer's, in particular with Lewy body pathology.[2]
Risk Factors
  • Risk factors for AD include increasing age, sex (female), genetics (APOE4), and a history of head injury.
    • Other less established, but possible risk factors include low educational status or cognitive reserve, sedentary lifestyle, diet, vascular risk factors, sleep deprivation,[3] and hormone replacement therapy.
  • Individuals with APP, PSEN1, PSEN2 have an increased risk of early onset (ages 30 to 60) AD.
    • Down syndrome is also a risk factor for early onset Alzheimer's
      • About 30% will have AD by their 50s, and this reaches 50% by their 60s.[4]
  • Individuals with APOE4 (on chromosome 19) are at increased risk for late onset AD.
    • The ε4 allele is present in about 20 to 25% of the population, if an individual is a:
      • ε4,ε4 homozygote, there is a 50% chance of AD during their 60s
      • ε4 heterozygote, there is a 50% chance of AD during their 70s
      • However, due to low sensitivity and specificity, screening for APOE4 is not recommended!
  • Increasing links are being found between the pathophysiology of Alzheimer's and hyperglycemia.[5] Hypertension in lafe-life is also a risk factor for development of Alzhemier's pathology.[6]

DSM-5 Diagnostic Criteria

Criterion A

The criteria are met for major or mild neurocognitive disorder.

Criterion B

There is insidious onset and gradual progression of impairment in 1 or more cognitive domains (for major neurocognitive disorder, at least 2 domains must be impaired).

Criterion C

Criteria are met for either probable or possible Alzheimer’s disease as follows:

For Major Neurocognitive Disorder

Probable Alzheimer’s Disease is diagnosed if either of the following is present; otherwise, Possible Alzheimer’s Disease should be diagnosed.

  1. Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.
  2. All 3 of the following are present:
    • a. Clear evidence of decline in memory and learning AND at least 1 other cognitive domain (based on detailed history or serial neuropsychological testing).
    • b. Steadily progressive, gradual decline in cognition, without extended plateaus.
    • c. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline).
For Mild Neurocognitive Disorder

Probable Alzheimer’s disease is diagnosed if there is evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history.

Possible Alzheimer’s disease is diagnosed if there is no evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history, and all 3 of the following are present:

  1. Clear evidence of decline in memory and learning
  2. Steadily progressive, gradual decline in cognition, without extended plateaus
  3. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological or systemic disease or condition likely contributing to cognitive decline).

Mnemonic

The mnemonic SAMPLE can be used to remember the 6 key domains of cognitive function:
  • S - Social cognition
  • A - Attention (Complex Attention)
  • M - Memory and Learning
  • P - Perceptual-Motor
  • L - Language
  • E - Executive function
Criterion D

The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.

Signs and Symptoms

  • The “head-turning sign” can be a useful sign in the interview of patients suspected of having AD.[7][8]

NIA-AA Criteria

In 2011, the National Institute on Aging (NIA) at National Institutes of Health (NIH) and the Alzheimer's Association (AA) published the latest guidelines (NIA-AA) for the diagnosis of Alzheimer's disease.[9] These criteria are much more comprehensive than DSM-5 criteria, and the diagnostic framework continues to be revised as of 2018.[10]

Probable

Diagnostic Criteria

McKhann, Guy M., et al. Recommendations from the NIA-AA workgroup. Alzheimer's and dementia 7.3 (2011)263-269.
Criteria for all-cause dementia
1. Interfere with the ability to function at work or at usual activities; and
2. Represent a decline from previous levels of functioning and performing; and
3. Are not explained by delirium or major psychiatric disorder;
4. Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from the patient and a knowledgeable informant and (2) an objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing. Neuropsychological testing should be performed when the routine history and bedside mental status examination cannot provide a confident diagnosis.
5. The cognitive or behavioural impairment involves a minimum of two of the following domains:

• Impaired ability to acquire and remember new information (repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route).

• Impaired reasoning and handling of complex tasks, poor judgment (poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities).

• Impaired visuospatial abilities (inability to recognize faces or common objects or to find objects in direct view despite good acuity, inability to operate simple implements, or orient clothing to the body).

• Impaired language functions (speaking, reading, writing problems - difficulty thinking of common words while speaking, hesitations; speech, spelling, and writing errors).

• Changes in personality, behaviour, or comportment (uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviours, socially unacceptable behaviours).

Probable Alzheimer's

Core clinical criteria
Meets criteria for dementia described earlier in the text, and in addition, has the following characteristics (A to D):
A. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;
B. Clear-cut history of worsening of cognition by report or observation; and
C. The initial and most prominent cognitive deficits are evident on history and examination in 1 of the following categories.

a. Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least 1 other cognitive domain, as defined earlier in the text.

b. Nonamnestic presentations:
• Language presentation: word-finding deficits, but deficits in other cognitive domains should be present.
• Visuospatial presentation: spatial cognition deficits, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present.
• Executive dysfunction: deficits of impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.
D. The diagnosis of probable AD dementia SHOULD NOT be applied when there is evidence of:

a. Substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or
b. Core features of dementia with Lewy bodies other than dementia itself; or
c. Prominent features of behavioural variant frontotemporal dementia; or
d. Prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or
e. Evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.

Probable AD dementia with increased level of certainty

This certainty specifier can be used if one of the criteria below are met
Criteria
Probable AD dementia with documented decline In persons who meet the core clinical criteria for probable AD dementia, documented cognitive decline increases the certainty that the condition represents an active, evolving pathologic process, but it does not specifically increase the certainty that the process is that of AD pathophysiology. Probable AD dementia with documented decline is defined as follows: evidence of progressive cognitive decline on subsequent evaluations based on information from informants and cognitive testing in the context of either formal neuropsychological evaluation or standardized mental status examinations.
Probable AD dementia in a carrier of a causative AD genetic mutation In persons who meet the core clinical criteria for probable AD dementia, evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2), increases the certainty that the condition is caused by AD pathology. The workgroup noted that carriage of the ε4 allele of the apolipoprotein E gene was not sufficiently specific to be considered in this category.

Possible

Possible AD dementia: Core clinical criteria

Criteria
Atypical course Atypical course meets the core clinical criteria in terms of the nature of the cognitive deficits for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates insufficient historical detail or objective cognitive documentation of progressive decline,
Etiologically mixed presentation Etiologically mixed presentation meets all core clinical criteria for AD dementia but has evidence of:
a. concomitant cerebrovascular disease, defined by a history of stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or
b. features of Dementia with Lewy bodies other than the dementia itself; or
c. evidence for another neurological disease or a non-neurological medical comorbidity or medication use that could have a substantial effect on cognition

Subtypes

AD can present under different subtypes, primarily:

Frontal Variant (fvAD)

  • Individuals with frontal variant Alzheimer's disease (fvAD) may have executive dysfunction, language impairment, and/or behavioural changes early in the disease, this can make it challenging to differentiate from the behavioural variant of frontotemporal dementia (bvFTD).[11]
  • Symptomatically, the presentation of fvAD can be very similar to bvFTD.
    • In general, fvAD patients present with greater executive impairment and milder behavioral symptoms compared to bvFTD.
    • Greater accuracy in diagnosis and patient management may be achieved with neuropsychological tests, biomarkers, and neuroimaging.
  • Some studies have suggested that fvAD accounts for approximately 2–3% of AD cases, but is likely to be an underestimate.[12]

Pathophysiology

The amyloid cascade hypothesis and the tau hypothesis are the two predominant theories behind the pathogenesis of AD. Both amyloid plaques and neurofibrillary tangles are found in post-mortem pathology. The loss of cholinergic neurons in the limbic system is also thought to be a core part of AD pathology.

Amyloid

Amyloid precursor protein (APP) is metabolized by alpha-, beta- and gamma- secretase, which generates a small peptide, A-beta (Aβ). Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains. Aβ42 is more prone to aggregation, and is the main component of the amyloid plaques found AD. As Aβ42 deposits accumulate, this is thought to lead to the formation of senile plaques (SPs) and neurofibrillary tangles (NFTs), leading to neuronal cell death, and ultimately dementia.

Tau

Tau build up (also known as aggregation of hyperphosphorylated tau protein) is another hypothesized mechanism for AD. It is hypothesized to be due to increased activity of tau kinases, which causes the tau protein to misfold and clump, forming neurofibrillary tangles (NFTs). The tau filaments in AD are called paired helical filaments.

Differential Diagnosis

The differential diagnosis for Alzheimer's disease is broad, as it overlaps with other neurodegenerative disorders. In older adults, it is particularly important to rule out primary psychiatric disorders (depression in particular) which can mimic dementia.

Investigations

The diagnosis of Alzheimer's Disease remains a clinical diagnosis, though neuroimaging and biomarkers are beginning to play a larger role in diagnosis.

CSF

  • Cerebrospinal fluid (CSF)
    • Decreased levels of CSF Abeta-42 are seen
    • Increased total tau is also seen, but is not specific to AD, and is a just a biomarker of neuronal injury
    • Phosphorylated tau is also increased.[13]

Neuroimaging

  • Positron Emission Tomography (PET) amyloid imaging
    • Can visualize amyloid plaques[14]
  • Fluorodeoxyglucose (FDG) PET scans may provide non-specific evidence for AD, including:
    • Hypometabolism in the bilateral temporoparietal regions[15]
    • Hypometabolism in posterior cingulate cortex (PCC)
    • There is also increased amyloid tracer retention
  • MRI
    • Atrophy with a characteristic pattern involving the medial temporal lobes (MTL), hippocampus, paralimbic and/or temporoparietal cortex[16]

Treatment

Current treatments do not alter the course of the disease. Medications only serve to reduce the rate of decline, and symptomatic improvement.

Caregivers

It is extremely important for education about the illness to be provided to both the patient and their families. Caregiver support is also extremely important as the disease progresses. Better caregiver support and interventions helps delay institutionalization.[17]

Behavioural Symptoms

Dementia

  • For mild-to-moderate AD, acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) as a class are modestly efficacious, and a trial of these medications is recommended for most patients diagnosed with AD.
    • The estimated number needed to treat (NNT) for cognitive improvement is 10.[18]
    • The estimated NNT for global improvement is 12.[19]
    • The number needed to harm (NNH) is 13.
    • Most studies for acetylcholinesterase inhibitors are short in duration (< 1 year)
    • Note that mild cognitive impairment due to AD should not be treated with acetylcholinesterase inhibitors.
  • For moderate-to-severe stages of AD, in addition to acetylcholinesterase inhibitors,Memantine monotherapy is another treatment option for patients
    • Note that memantine in mild AD is not recommended.
  • There is insufficient evidence to recommend for or against the combination treatment with an acetylcholinesterase inhibitor and memantine.[20]

Pharmacotherapy for AD

Medication Type Starting Dose Maintenance Side effects
Rivastigmine Acetylcholinesterase inhibitor 1.5 mg PO BID 6 mg PO BID (maximum) Nausea, vomiting, diarrhea, weight loss, anorexia.
Donepezil Acetylcholinesterase inhibitor 5mg PO 10 mg PO (maximum) Nausea, vomiting, diarrhea, weight loss, anorexia. Vivid dreams.
Galantamine Acetylcholinesterase inhibitor 4 mg PO BID x 4 weeks 12 mg PO BID (maximum) Similar to rivastigmine
Memantine NMDA antagonist 5 mg PO qAM 10 mg PO BID (maximum) Headaches, somnolence, dizziness, agitation/confusion

Depression

  • For depressive symptoms, if a patient had an inadequate response to the nonpharmacological interventions or has a major affective disorder, severe dysthymia or severe emotional lability, a trial of an antidepressant could be considered.[21]
  • However, the response rates are low and possibly lower than non-pharmacological interventions.[22]

Deprescribing

  • Consider deprescribing medications that may worsen cognition, including anticholinergic medications.
    • Deprescribing can be safe and effective.[23]
  • If deprescribing does not go well and there are increased behavioural symptoms, restart the medication at the lowest dose and not back to the original dose, as patients may develop prominent GI symptoms including nausea and vomiting!

Resources

For Patients
For Providers
Articles
Research

References

1) Wang, J. H., Wu, Y. J., Tee, B. L., & Lo, R. Y. (2018). Medical comorbidity in Alzheimer’s disease: a nested case-control study. Journal of Alzheimer's Disease, 63(2), 773-781.
2) Walker, L., McAleese, K. E., Thomas, A. J., Johnson, M., Martin-Ruiz, C., Parker, C., ... & Attems, J. (2015). Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta neuropathologica, 129(5), 729-748.
3) Shokri-Kojori, E., Wang, G. J., Wiers, C. E., Demiral, S. B., Guo, M., Kim, S. W., ... & Volkow, N. D. (2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences, 115(17), 4483-4488.
4) Hartley, D., Blumenthal, T., Carrillo, M., DiPaolo, G., Esralew, L., Gardiner, K., ... & Wisniewski, T. (2015). Down syndrome and Alzheimer's disease: Common pathways, common goals. Alzheimer's & Dementia, 11(6), 700-709.
5) Zheng, F., Yan, L., Yang, Z., Zhong, B., & Xie, W. (2018). HbA 1c, diabetes and cognitive decline: the English Longitudinal Study of Ageing. Diabetologia, 1-10.
6) Arvanitakis, Z., Capuano, A. W., Lamar, M., Shah, R. C., Barnes, L. L., Bennett, D. A., & Schneider, J. A. (2018). Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology, 91(6), e517-e525.
7) Fukui, T. (2011). The “Head turning sign” can be a clinical marker of Alzheimer's disease?. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 7(4), S244-S245.
8) Larner, A. J. (2012). Head turning sign: pragmatic utility in clinical diagnosis of cognitive impairment. J Neurol Neurosurg Psychiatry, jnnp-2011.
9) McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack Jr, C. R., Kawas, C. H., ... & Mohs, R. C. (2011). 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. Alzheimer's & dementia, 7(3), 263-269.
10) Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., ... & Liu, E. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & Dementia, 14(4), 535-562.
11) Woodward, M., Jacova, C., Black, S. E., Kertesz, A., Mackenzie, I. R., Feldman, H., & ACCORD investigator group. (2010). Differentiating the frontal variant of Alzheimer's disease. International journal of geriatric psychiatry, 25(7), 732-738.
12) Sawyer, R. P., Rodriguez-Porcel, F., Hagen, M., Shatz, R., & Espay, A. J. (2017). Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road. Journal of clinical movement disorders, 4(1), 1-9.
13) Sjögren, M., Davidsson, P., Tullberg, M., Minthon, L., Wallin, A., Wikkelso, C., ... & Blennow, K. (2001). Both total and phosphorylated tau are increased in Alzheimer's disease. Journal of Neurology, Neurosurgery & Psychiatry, 70(5), 624-630.
14) Shivamurthy, V. K., Tahari, A. K., Marcus, C., & Subramaniam, R. M. (2015). Brain FDG PET and the diagnosis of dementia. American Journal of Roentgenology, 204(1), W76-W85.
15) Marcus, C., Mena, E., & Subramaniam, R. M. (2014). Brain PET in the diagnosis of Alzheimer’s disease. Clinical nuclear medicine, 39(10), e413.
16) Whitwell, J. L., Jack Jr, C. R., Przybelski, S. A., Parisi, J. E., Senjem, M. L., Boeve, B. F., ... & Josephs, K. A. (2011). Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiology of aging, 32(9), 1531-1541.
17) Mittelman, M. S., Ferris, S. H., Steinberg, G., Shulman, E., Mackell, J. A., Ambinder, A., & Cohen, J. (1993). An intervention that delays institutionalization of Alzheimer's disease patients: treatment of spouse-caregivers. The Gerontologist, 33(6), 730-740.
18) Lanctôt, K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Cmaj, 169(6), 557-564.
19) Lanctôt, K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Cmaj, 169(6), 557-564.
20) Herrmann, N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer's research & therapy, 5(1), S5.
21) Herrmann, N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer's research & therapy, 5(1), S5.
22) Watt, J. A., Goodarzi, Z., Veroniki, A. A., Nincic, V., Khan, P. A., Ghassemi, M., ... & Straus, S. E. (2021). Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. bmj, 372.
23) Herrmann, N., O'Regan, J., Ruthirakuhan, M., Kiss, A., Eryavec, G., Williams, E., & Lanctot, K. L. (2016). A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease. Journal of the American Medical Directors Association, 17(2), 142-147.