The Phases of Alzheimer's Disease

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Alzheimer's disease (AD) stands out among other forms of dementia due to its distinct and predictable progression. While this characteristic can be distressing because of its certainty, it also presents a chance for individuals and families to prepare for the future and potentially postpone the advancement of more severe symptoms.

Various classification systems have been employed for these stages. Focusing on clinical decision-making, the 2011 guidelines from the National Institute on Aging and Alzheimer's Association (NIA-AA) outlined three distinct 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 update that shifted toward a biologically based definition. In 2024, an NIA-AA workgroup took the controversial next step: While largely a diagnostic and staging definition 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.

Progression Timeline of Alzheimer's Disease

The effects of the disease start to build up years or even decades prior to the appearance of any symptoms.

A given individual presenting at age 70 might be expected to spend a decade with preclinical Alzheimer's disease, according to a large multi-cohort study 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 projection 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.

Progression rates 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%.

Progressing Manifestations of Illness

Individuals experiencing early symptoms of Alzheimer's disease might find themselves forgetting common words, losing track of items, and facing challenges with organization, planning, social interactions, and completing work responsibilities. These signs may become apparent to family members and close friends as well.

As dementia advances, it causes further deterioration in brain regions responsible for language, reasoning, conscious thought, and sensory processing, resulting in more pronounced symptoms. This stage is marked by significant memory loss and impaired judgment, heightened confusion, disorientation, and difficulty recognizing familiar individuals. People in this phase typically require help with everyday tasks.

Common neuropsychiatric symptoms include notable issues like paranoia, restlessness or agitation, irregular sleep-wake patterns often referred to as "sundowning," and behaviors that may be deemed socially inappropriate. Additionally, individuals may experience visual and auditory hallucinations.

As advanced Alzheimer's disease progresses, the body becomes stiff, resulting in a loss of the ability to swallow and control bladder and bowel functions.

MCI has several clinical definitions. The Peterson criteria 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 Winblad criteria 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 2022 review.

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

Stage 2 serves as a transitional phase leading to mild cognitive impairment (stage 3) and is characterized by either noticeable or perceived cognitive decline, along with subtle neurobehavioral challenges, or a combination of these factors.

Stage 4 of dementia is characterized by a gradual decline in cognitive abilities and some mild difficulties with instrumental activities of daily living (ADL), while the individual still maintains independence in basic ADL tasks.

Stage 5 introduces a level of moderate functional decline, accompanied by increasing cognitive difficulties, necessitating support for essential activities of daily living (ADL).

In stage 6, individuals require full assistance for essential activities of daily living (ADL).

When moderate to severe cognitive impairment progresses, it typically transforms into a condition that requires management by multidisciplinary teams, which often consist of geriatricians and geriatric psychiatrists. These professionals can offer valuable assistance in making decisions about long-term care and addressing neuropsychiatric symptoms.