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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Alzheimer's disease (AD) is unique among dementias for following a predictable path of progression, terrible for its inevitability but offering some opportunity to plan for and even delay worsening symptoms.

A variety of classification schemes for these stages have been used. With an eye on clinical decision-making, the 2011 National Institute on Aging and Alzheimer's Association (NIA-AA) guidelines defined three phases:

• Preclinical, with early pathologic changes in the brains of cognitively normal individuals

• Mild cognitive impairment (MCI)

• Dementia

Continuum

However, accumulating evidence has continued to paint the disease as a continuum rather than three distinct clinically defined entities, as the NIA-AA officially recognized in 2018 with an that shifted toward a biologically based definition. In 2024, an NIA-AA workgroup took the controversial next step: While largely a for research purposes without advocating testing asymptomatic individuals, the new criterion outlines three broad categories of biomarkers:

• Core biomarkers: Core 1 markers are specific to Alzheimer's changes and become abnormal early in the disease course. These include amyloid PET, approved cerebrospinal fluid (CSF) biomarkers, and certain plasma biomarkers like phosphorylated tau 217 (p-tau217) that map into either the amyloid-beta (Aβ) or Alzheimer's tauopathy pathway.

• Core 2 biomarkers include certain soluble biofluid tau fragments and tau PET. These later-changing biomarkers reflect aggregated tau deposits and can provide prognostic information and increase confidence that Alzheimer's is contributing to symptoms.

• Nonspecific process biomarkers: These biomarkers are important to Alzheimer's but not specific to the disease. They point to injury, dysfunction, or degeneration of neuropil and inflammation. These can include neurofilament light chain and glial fibrillary acidic protein, as well as anatomic MRI or FDG PET scans.

• Biomarkers of non-Alzheimer's co-pathology: These markers reflect commonly co-existing conditions, like vascular brain injury and alpha-synuclein.

Time Course of Alzheimer's Disease

Damage from the disease begins to accrue years or decades before any symptoms begin.

A given individual presenting at age 70 might be expected to spend a decade with preclinical Alzheimer's disease, according to a using clinical definitions plus amyloid accumulation. Then on average, people spend 4 years with MCI before progression to clinical dementia, after which life expectancy is 6 years.

A of the impact of a treatment that slows cognitive decline by 30% -- roughly the impact of lecanemab (Leqembi) or donanemab (Kisunla) -- using data from the Amsterdam Dementia Cohort among amyloid-positive participants and repeat longitudinal Mini-Mental State Examination (MMSE) measurements suggested that a hypothetical patient with MCI with CSF Aβ1-42 of 925 pg/mL would move from an MMSE of 28 to 20 after 8.6 years compared with 6.0 years not on treatment. A hypothetical patient with mild dementia with CSF Aβ1-42 of 625 pg/mL was predicted to go from an MMSE score of 20 to 15 in 2.3 versus 3.3 years with and without such a treatment, respectively.

from MCI to dementia at 3 years were 61% with prodromal AD (any cognitive impairment, abnormal amyloid-β1-42 and tau or abnormal amyloid PET scan) versus 22% without prodromal AD by the 2018 definitions. On the basis of 2024 NIA-AA research framework criteria, MCI patients classified as having "high likelihood AD" had a 3-year progression rate of 59%, while those in lower-risk groups had 3-year progression rates of 5-24%.

Advancing Symptomatic Disease

People with early symptomatic AD may notice they are forgetting familiar words, misplacing objects, and starting to struggle with organizing, planning, socializing, and performing work tasks. Family and close friends may begin to notice these symptoms.

As the disease progresses to dementia, damage in areas of the brain that control language, reasoning, conscious thought, and sensory processing lead to more severe symptoms. This phase is characterized by increasingly poor memory and judgment, deepening confusion, getting lost, and mixing up who people are. Individuals in this stage generally need assistance with daily activities.

Significant neuropsychiatric symptoms are common, such as paranoia, restless or agitated behaviors, disrupted sleep-wake cycles ("sundowning"), and socially inappropriate behaviors. Visual and auditory hallucinations may occur as well.

As severe AD advances, the body becomes rigid, and ability to swallow and control bladder and bowel function are lost.

MCI has several clinical definitions. The define MCI as individuals performing 1.5 standard deviations below normal on memory tasks but who are still able to perform activities of daily living.

The also includes and distinguishes individuals with cognitive impairment in domains beyond memory impairment, classified as amnestic MCI (with subjective and objective memory impairment) and non-amnestic MCI (impairment in a cognitive domain other than memory) and as single- or multiple-domain.

"However, clinical definitions of MCI that do not include neuropathologic changes in the brain as a criterion for diagnosis lack specificity for AD as the underlying cause of impaired cognition," noted a .

The 2024 NIA-AA present seven stage categories, with stages 0 and 1 being asymptomatic, with a deterministic gene or biomarker evidence only, respectively.

Stage 2 is a transitional stage to mild cognitive impairment (stage 3) and is defined by objective or subjective cognitive decline, subtle neurobehavioral difficulties, or a combination thereof.

Stage 4 is dementia with progressive cognitive and mild functional impairment on instrumental activities of daily living (ADL) but independence in basic ADL.

Stage 5 adds moderate functional impairment, with progressive cognitive impairment and need for assistance in basic ADL.

In stage 6, patients become completely dependent for basic ADL.

Once late moderate to severe cognitive impairment sets in, it mainly becomes a disease managed by multidisciplinary teams that may include geriatricians and geriatric psychiatrists. These specialists can help provide decision support regarding long-term care and managing neuropsychiatric symptoms.

Read previous installments in this series:

Part 1: Defining Alzheimer's Disease

Part 2: The Complex Pathogenesis and Genetics of Alzheimer's Disease

Part 3: Making the Alzheimer's Disease Diagnosis

Part 4: Case Study: The Unexpected Benefits of Physiotherapy in a Patient With Alzheimer's Disease

Up next: Monoclonal Antibodies for Early Alzheimer's Disease